KRAS G12C inhibitors

Abstract

The present disclosure provides compounds and methods useful for treating and inhibiting cancer, for example, cancers characterized by KRAS G12C. Also provided are pharmaceutical compositions comprising such compounds and processes for preparing such compounds.

Description

[Technical Field]

[0001] The present disclosure provides compounds useful for treating or inhibiting cancer, particularly compounds useful for treating or inhibiting cancer characterized by KRAS G12C mutations. Also provided are pharmaceutical formulations containing such compounds, processes for preparing such compounds, and methods of using such compounds in treating or inhibiting cancer. [Background technology]

[0002] KRAS is a molecular switch. Under normal physiological conditions, the protein is bound to guanosine diphosphate (GDP) in the "off state." In response to signaling through receptor tyrosine kinases (RTKs) such as EGFR, GDP is exchanged for guanosine triphosphate (GTP) in a process facilitated by guanine nucleotide exchange factors (GEFs) such as SOS. The GTP-bound form of KRAS is in the "on state" and interacts with proteins such as RAF and PI3K to promote downstream signaling that leads to cell proliferation and survival. KRAS can return to the off state by slowly hydrolyzing GTP to GDP in a process facilitated by GAPs (GTPase-activating proteins).

[0003] KRAS mutations are found in approximately 30% of all human cancers and are particularly prevalent in the three most lethal cancers: pancreatic (95%), colorectal (45%), and lung (35%). Combined, these cancers affect more than 200,000 patients annually in the United States alone. One particular mutation, a glycine-to-cysteine ​​substitution at position 12 (G12C), occurs in more than 40,000 patients annually. The KRAS G12C mutation inhibits the hydrolysis of GTP to GDP, trapping KRAS in the on state and promoting cancer cell proliferation.

[0004] The G12C cysteine ​​residue offers an opportunity to develop targeted covalent drugs against this mutant KRAS. Early clinical trial results of the KRAS G12C inhibitors AMG 510 and MRTX849 have shown promising results in non-small cell lung cancer (NSCLC), but the data are less convincing in colorectal cancer (CRC). Furthermore, even when patients respond to initial treatment, there are indications that the duration of response is limited and resistance can develop rapidly.

[0005] Most inhibitors of KRAS mutants preferentially bind to the GDP-bound form of the protein. For example, Amgen's KRAS inhibitor AMG510 and Mirati's KRAS inhibitor MRTX849 react with the GDP-bound form of KRAS G12C at least 1,000 times faster than the GTP-bound form of the protein. One form of resistance that has been observed is that cancer cells increase signaling through RTKs, resulting in an increase in the amount of GTP-bound KRAS, which is less affected by current inhibitors. Therefore, creating molecules that can bind to and inhibit both the GDP-bound and GTP-bound forms of KRAS could be of great utility.

[0006] What is needed are compounds useful in the treatment of cancers, such as those characterized by KRAS G12C. Additionally, there is a need for compounds useful in the treatment of cancers characterized by KRAS G12C that bind to and inhibit both the inactive GDP-bound and the active GTP-bound forms of KRAS. Additionally, there is a need for compounds useful in the treatment of cancers characterized by KRAS G12C that exhibit improved inhibition of the GTP-bound form of KRAS G12C.

[0007] Compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1), and Formula (II-2), as well as pharmaceutically acceptable salts and / or isotopic variants thereof (including embodiments disclosed herein), can be used in methods for inhibiting KRAS G12C in cells by contacting a cell in which inhibition of KRAS G12C activity is desired with an amount of a compound effective to inhibit KRAS G12C activity. Inhibition can be partial or total. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. Summary of the Invention

[0008] In a first aspect, there is provided: A compound of formula I or formula II, or a salt thereof; and / or an isotopic substitution thereof: TIFF2024540410000001.tif65128 formula, R x is selected from hydrogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R y is selected from hydrogen, C1-C4 alkyl, and halo; R z is selected from hydrogen, C1-C4 alkyl, and halo; R 1 is a 4-8 membered saturated carbocyclic or heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2 is R 2a , R 2b , R 2c , R 2d , and R 2e selected from the group consisting of: R 3is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C7 cycloalkyl, CN, and C2-C3 alkynyl; R 2a is -NR 5 R 6 and; R 5 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 6 is -C1-C6 alkylene-S(O)2-CH=CHR 7 or R 5 and R 6 together with the nitrogen to which they are attached form a 4- to 7-membered saturated heterocyclic group containing one ring and one nitrogen as the only heteroatom in the ring, said 4- to 7-membered saturated heterocyclic group being -(CH2) n -S(O)2-CH=CHR 7 is replaced by; R 7 is hydrogen, -C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -(CH2) m -NR 8 R 9 selected from the group consisting of: R 8 and R 9 is independently selected from the group consisting of -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen atom in the ring and optionally substituted by halo; n is 0 or 1; m is 1 or 2; R 2b is -NR 10 R 11 and; R 10 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 11 teeth, -(C1-C4 alkylene)-N(R 12 )-CN, and -(CH2) w -R 13 or selected from the group consisting of: R 10 and R 11 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said 4-8 membered saturated heterocyclic group being -(CH2) x -N(R 14 )-CN and a 4- to 6-membered saturated heterocyclic group containing one ring and one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen atom is substituted with cyano; cyano, provided that when cyano is a substituent, R 10 and R 11 and the 4-8 membered saturated heterocyclic group they form together with the nitrogen to which they are attached contains a second nitrogen ring atom, and the cyano is connected to the 4-8 membered saturated heterocyclic group at the second ring nitrogen. and is substituted with one substituent selected from the group consisting of: R 12 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 13is a 4-5 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, said nitrogen being substituted with cyano, and said heterocyclic group being optionally further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo; or R 13 is a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatom(s) in the ring, one of the nitrogens being substituted with cyano, and the heterocyclic group optionally being further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C cyanoalkyl, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bound to a heteroatom; or R 13 is a 7-membered saturated heterocyclic group containing one nitrogen and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur as the only heteroatom(s) in the ring, wherein one of the nitrogen ring atom(s) is / are substituted with cyano, and the heterocyclic group is optionally further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C cyanoalkyl, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; R 14 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; w is 0, 1 or 2; x is 0 or 1; R 2c is -NR 15 R 16 and; R 15is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy, optionally substituted with CN; R 16 teeth, -(C1-C4 alkylene)-N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 , and -(CH2) y -R 21 or selected from the group consisting of: R 15 and R16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said heterocyclic group being -(CH2) q -N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 and, -C(O)C(R 19 )=C(R 20 )R 18 where -C(O)C(R 19 )=C(R 20 )R 18 is a substituent, R 15 and R 16 and the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen ring atom, and the -C(O)C(R 19 )=C(R 20 )R 18 is attached to the heterocyclic group at the second ring nitrogen, 19 )=C(R 20 )R 18 and and is substituted with one substituent selected from the group consisting of: R 17 is selected from the group consisting of hydrogen, —C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 18is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)O-C1-C4 haloalkyl, -C(O)-C1-C4 alkyl, -C(O)-C1-C4 haloalkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(CH2) u -R 34 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, -S(O)2-C1-C4 haloalkyl, and R 35 and R 20 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; or R 18 and R 20 can be taken together with the carbon to which they are attached to form a 4-5 membered carbocyclic or heterocyclic ring containing one heteroatom selected from N, O, and S, which carbocyclic or heterocyclic ring can be optionally substituted with, for example, methyl, halo, hydroxy, methoxy, or carbonyl; R 19 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 21 teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 the 4-5 membered saturated heterocyclic group is substituted by, and the heterocyclic group is either unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, or is further substituted with two halo substituents; A 6-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is —C(O)C(R 19 )=C(R 20 )R 18 the 6-membered saturated heterocyclic group is substituted by, and the heterocyclic group is either unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or is further substituted with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) of the heterocyclic group is / are -C(O)C(R 19 )=C(R 20 )R 18 the 7-membered saturated heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or is further substituted with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom. Selected from; R 22 and R 23 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 34is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, CH2-(C3-C6 heterocyclyl), and C2-C3 alkynyl; R 35 teeth, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. is a 5- to 6-membered heteroaryl group optionally substituted by 0, 1, 2, or 3 substituents independently selected from y is 0, 1 or 2; z is 1 or 2; q is 0 or 1; u is 0, 1 or 2; R 2d teeth, -NR 24 R 25 , -C(O)N(R 27 )-(C1-C4 alkylene)-C(O)CH=CHR 26 , and -O-(C1-C2 alkylene)-C(O)CH=CHR 26 selected from the group consisting of: R 24 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 25 is -(C1-C4 alkylene)-C(O)CH=CHR 26 or R 24 and R 25together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, the heterocyclic group being -(C0-C2 alkylene)-C(O)CH=CHR 26 and the heterocyclic group is optionally further substituted with C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 26 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 27 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2e is -NR 28 R 29 and; R 28 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 29 is -(CH2) t -R 30 and; R 30 teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C≡CR 31 the 4-5 membered saturated heterocyclic group is substituted by, which heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; A six-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is -C(O)C≡CR 31the 6-membered saturated heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C cyanoalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atoms of the heterocyclic group is -C(O)C≡CR 31 the 7-membered saturated heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom. Selected from; R 31 is -(CH2) v -NR 32 R 33 and -(CH2) p -R 36 selected from the group consisting of: R 32 and R 33 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; t is 0, 1 or 2; v is 1 or 2; p is 0, 1 or 2; R 36is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; provided that when the compound is of formula I, R 2c teeth TIFF2024540410000002.tif25128; and with the further proviso that when the compound is of formula II, R 2c Ha-NR 15 R 16 Instead, R 15 and R 16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom in the ring, and the second nitrogen is substituted with -C(O)-CH=CH2.

[0009] In some embodiments, including any of the embodiments in the preceding paragraphs, the compound is selected from the group consisting of the compounds in Table 1, and all salts and isotopic substitutions thereof.

[0010] In another aspect, there is provided a pharmaceutical formulation comprising a compound described herein (including but not limited to, the compounds described in the preceding paragraph) and a pharmaceutically acceptable carrier, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0011] In another aspect, provided is a method of treating or inhibiting cancer, comprising administering a therapeutically effective amount of a compound described herein (including but not limited to the compound described in the preceding paragraph) or pharmaceutical formulation (including but not limited to the pharmaceutical formulation described in the preceding paragraph) to a subject in need thereof, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt. In some embodiments, the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. In some embodiments, the cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate cancer, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine corpus, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, The cancer is selected from the group consisting of plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. In some embodiments, including any of the foregoing embodiments, the method is for treating cancer. In some embodiments, including any of the foregoing embodiments, the method is for inhibiting cancer. In some embodiments, including any of the foregoing embodiments, the cancer is a KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the subject has been diagnosed with a KRAS G12C-mediated cancer. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

[0012] In another aspect, there is provided the use of a compound described herein, including but not limited to, any of the preceding embodiments, as a pharmaceutical. In another aspect, there is provided the use of a compound described herein, including but not limited to, any of the preceding embodiments, for the treatment or inhibition of cancer. In another aspect, there is provided the use of a compound described herein, including but not limited to, any of the preceding embodiments, in the manufacture of a medicament for use in the treatment or inhibition of cancer. In some embodiments, including any of the preceding embodiments, the use is for treating cancer. In some embodiments, including any of the preceding embodiments, the use is for inhibiting cancer.

[0013] In another aspect, provided is a compound as described herein, including but not limited to, any of the preceding embodiments, for use in the manufacture of a medicament for treating or inhibiting cancer. In another aspect, a compound as described herein, including but not limited to, any of the preceding embodiments, for use in the treatment or inhibition of cancer. In another aspect, a compound as described herein, including but not limited to, any of the preceding embodiments, for use in the manufacture of a medicament for the treatment or inhibition of cancer. In some embodiments, including any of the preceding embodiments, the use is for treating cancer. In some embodiments, including any of the preceding embodiments, the use is for inhibiting cancer.

[0014] It is understood that descriptions of compounds, compositions, formulations, and methods of treatment described herein include "comprising," "consisting," and "consisting essentially of" embodiments. In some embodiments, for all compositions described herein and all methods of using the compositions described herein, the composition can include or "consist essentially of" the recited elements or steps. When a composition is described as "consisting essentially of" recited elements, the composition includes the recited elements and may include other elements that do not substantially affect the condition being treated, but does not include other components other than the explicitly recited elements that substantially affect the condition being treated. Alternatively, if the composition includes additional components other than the recited elements that substantially affect the condition being treated, the composition does not include the additional components in a concentration or amount sufficient to substantially affect the condition being treated. When a method is described as "consisting essentially of" recited steps, the method includes the recited steps and may include other steps that do not substantially affect the condition being treated, but does not include other steps other than the explicitly recited steps that substantially affect the condition being treated. As a specific, non-limiting example, when a composition is described as "consisting essentially of" a component, the composition may further include any amount of pharmaceutically acceptable carriers, vehicles, or diluents, and other such elements that do not substantially affect the condition being treated.

[0015] Additional embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description and practice of the disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0016] Provided herein are compounds useful for treating cancer, and methods of using such compounds for treating cancer. In some embodiments, the compounds are useful for treating cancer characterized by KRAS G12C. In some embodiments, the compounds advantageously inhibit both the inactive GDP-bound form and the activated GTP-bound form of KRAS G12C. In some embodiments, the compounds advantageously improve inhibition of the GTP-bound form of KRAS G12C.

[0017] Abbreviations used herein have their conventional meaning within the chemical and biological arts unless otherwise specified.

[0018] It is understood that the description of compound structures, including possible substitutions, is limited to what is chemically possible.

[0019] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as shown. Compounds marked with an (or) in the first column of Table 1 are single enantiomers whose absolute stereochemistry has been arbitrarily assigned (e.g., based on the chiral SFC elution described in the Examples section). Compounds marked with an (and) in the first column of Table 1 are mixtures of enantiomers, with the relative stereochemistry as shown. Compounds with a stereocenter whose configuration is not shown in the depicted structure and that do not have a listing in the first column of Table 1 are mixtures of enantiomers at that center. Compounds marked with no listing or (abs) in the first column of Table 1 are single enantiomers with the absolute stereochemistry as shown. For example, compound 1 is a pure enantiomer with the stereochemistry shown.

[0020] TIFF2024540410000003.tif49128

[0021] In some cases, the first column of Table 1 contains different designations selected from (abs), (or), and (and) to indicate different stereocenters in the molecule.

[0022] For example, compound 43 contains the notation "(or) fused piperidine (abs) pyrrolidine" in the first column of Table 1.

[0023] TIFF2024540410000004.tif38128

[0024] This compound is a single enantiomer, and the stereochemistry of the pyrrolidine group is (S) as shown, because it was prepared from enantiopure starting materials. The stereochemistry of the fused cyclopropyl group is either (R,S) or (S,R), but is arbitrarily assigned rather than a mixture of the two. When a mixture of enantiomers or diastereomers is separated into the corresponding single enantiomers or diastereomers by chromatography, the stereochemistry is often arbitrarily assigned.

[0025] One skilled in the art would be able to separate racemic compounds into their individual enantiomers using art-known methods such as chiral chromatography, chiral recrystallization, etc. Reference to a compound that is a racemic mixture is meant to include the individual enantiomers contained within the mixture.

[0026] References herein to "about" a value or parameter include (and describe) a variation that refers to the value or parameter itself. For example, a statement of "about X" includes a statement of "X." As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in reference to a temperature, dose, amount, or weight percent of a component of a composition or dosage form, refer to a dose, amount, or weight percent that would be recognized by a person skilled in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dose, amount, or weight percent.

[0027] As used herein, the terms "a" and "an" mean one or more, unless the context clearly dictates otherwise.

[0028] The terms "subject," "individual," and "patient" refer to an individual organism, preferably a vertebrate, more preferably a mammal, and most preferably a human. Examples of patients include humans, livestock such as cattle, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, and horses. In some embodiments, the subject has been identified or diagnosed as having a cancer or tumor with a KRAS G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).

[0029] "Treatment" of a disorder with the compounds and methods described herein is defined as administering one or more of the compounds described herein, with or without an additional therapeutic agent, to alleviate or eliminate the disorder or one or more symptoms of the disorder, or to slow the progression of the disorder or one or more symptoms of the disorder, or to reduce the severity of the disorder or one or more symptoms of the disorder.

[0030] "Suppression" of a disorder by the compounds and methods described herein is defined as administering one or more of the compounds described herein, with or without an additional therapeutic agent, to suppress the clinical manifestations of the disorder or to suppress the onset of adverse symptoms of the disorder. The difference between treatment and suppression is that treatment occurs after adverse symptoms of the disorder appear in a subject, whereas suppression occurs before adverse symptoms of the disorder appear in a subject. Suppression can be partial, substantially complete, or complete. In some embodiments, genetic screening can be used to identify patients at risk for the disorder. The compounds and methods disclosed herein can then be administered to asymptomatic patients at risk for developing clinical symptoms of the disorder to suppress the onset of any adverse symptoms.

[0031] The "therapeutic use" of the compounds described herein is defined as the use of one or more of the compounds described herein to treat or suppress a disorder as defined herein.A "therapeutically effective amount" of a compound is an amount of compound that, when administered to a subject, is sufficient to alleviate or eliminate a disorder or one or more symptoms of the disorder, slow the progression of a disorder or one or more symptoms of the disorder, or reduce the severity of a disorder or one or more symptoms of the disorder, or suppress the clinical manifestation of a disorder, or suppress the manifestation of adverse symptoms of a disorder.A therapeutically effective amount can be given in one or more administrations.

[0032] The term "KRAS G12C-mediated cancer" is used interchangeably herein with "cancer characterized by KRAS G12C" to indicate that the cancer comprises cells that contain the KRAS G12C mutation.

[0033] While the compounds described herein can exist and be used as neutral (non-salt) compounds, the present disclosure is intended to encompass all salts of the compounds described herein and methods of using such salts of the compounds. In some embodiments, the salts of the compounds include pharmaceutically acceptable salts.

[0034] A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable to humans and / or animals and that retains at least some of the desired pharmacological activity of the parent compound upon administration. Such salts include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts formed with formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucohepanesulfonic acid, and the like. or (b) acid addition salts formed with organic acids such as acetic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (b) salts formed when the acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0035] As used herein, all stereoisomers of a compound, including diastereomers and enantiomers, are included, where chemically relevant. Also included are mixtures of possible stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly shown in a structure, the structure is intended to encompass all possible stereoisomers of the depicted compound. When stereochemistry is explicitly shown for one or more portions of a molecule but not for another portion or portions of the molecule, the structure is intended to encompass all possible stereoisomers of the portion or portions where stereochemistry is not explicitly shown.

[0036] As used herein, the term "isotopically enriched" refers to a compound whose isotopic composition differs from its "natural" isotopic composition. "Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the isotopic composition or abundance that naturally occurs for a given atom. Atoms with a natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds listed herein are meant to represent any stable isotope of that atom. For example, unless otherwise specified, if a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen at its natural isotopic composition. The description of compounds herein also includes all isotopic substitutes of all compounds herein, and in some embodiments, partially deuterated or perdeuterated analogs. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopic enrichment" refers to the amount of a particular isotope incorporated into a given atom in a molecule instead of the natural isotopic abundance of that atom. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at that position. Since the distribution of naturally occurring deuterium is approximately 0.0156%, the deuterium enrichment at any position of a compound synthesized using non-enriched starting materials will be approximately 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0037] "Alkyl" means a saturated monovalent hydrocarbon radical of the specified number of carbons which may be linear, branched, cyclic, or a combination thereof. For example, C1-C4 alkyl includes, for example, methyl, ethyl, propyl, 2-propyl, butyl, cyclopropyl, cyclobutyl, etc.

[0038] "Alkylene" means a saturated divalent hydrocarbon group of the specified number of carbons, which may be linear, branched, cyclic, or a combination thereof. For example, C1-C4 alkylene includes, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, etc. "C0 alkylene" means a bond. For example, C0-C2 alkylene includes, for example, a bond, methylene, ethylene, etc.

[0039] "Alkynyl" means a linear or branched monovalent hydrocarbon radical having the specified number of carbons and at least one carbon-carbon triple bond. For example, C2-C4 alkynes include, for example, ethynyl, propynyl, 2-propynyl, butynyl, and the like.

[0040] "Alkoxy" means -OR o group (in the formula, R o is alkyl as defined above), or -R o 'OR o ” group (in the formula, R o ' is alkylene and R o " is an alkyl group as defined above), and the specified number of alkyl carbons in the alkoxy group is o ' and R o " is equal to the total number of carbons in the alkyl group. For example, C1-C4 alkoxy refers to, for example, methoxy, ethoxy, propoxy, 2-propoxy, n-, iso-, tert-butoxy, cyclopropoxy, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, and the like. In some embodiments, alkoxy refers to -OR o In some embodiments, alkoxy is a -R group. o 'OR o In some embodiments, when a nitrogen is substituted with an alkoxy group, the alkoxy group is not attached to the nitrogen through an oxygen in the alkoxy group or a carbon immediately adjacent to the oxygen. For example, an alkoxy-substituted nitrogen is an N—OR o But N-CH2-OR o "But neither.

[0041] "Alkoxyalkoxy" means OR r group (in the formula, R r is alkoxy as defined above, with the proviso that R r The point of attachment of -R is not an oxygen atom), or -R r 'OR r ” group (in the formula, R r is alkylene and R r " is an alkoxy group as defined above, provided that R r " is not an oxygen atom), and the defined number of alkyl carbons in an alkoxyalkoxy group is r ' and R r " is equal to the total number of carbons in the alkyl group. For example, C1-C6 alkoxyalkoxy refers to, for example, -OCH2OCH3, -OCH2CH2OCH3, -OCH2CH2OCH3, -CH2OCH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, and the like. In some embodiments, alkoxyalkoxy refers to -OR r In some embodiments, the alkoxyalkoxy is a -R r 'OR r In some embodiments, when a nitrogen is substituted with an alkoxyalkoxy group, the alkoxyalkoxy group is not attached to the nitrogen through an oxygen in the alkoxyalkoxy group or a carbon immediately adjacent to the oxygen. For example, an alkoxyalkoxy substituted nitrogen can be an N—OR r But N-CH2-OR r "But neither.

[0042] "Aminoalkyl" means -NHR n group (in the formula, R n is alkyl as defined above) or -NR n R n ' group (in the formula, R n and R n ' is an alkyl group as defined above) or -R n "NH2 group (in the formula, R n " is an alkylene group as defined above) or -R n "NHR n group (in the formula, Rn " is an alkylene group as defined above, and R n is an alkyl group as defined above) or -R n ”NR n R n ' group (in the formula, R n " is an alkylene group as defined above, and R n and R n where R' is an alkyl group as defined above, and the defined number of alkyl carbons in the aminoalkyl group n , R n ' and R n " (if applicable). For example, C1-C6 aminoalkyl refers to, for example, -NHCH3, -NHCH2CH3, -NHCH2(CH3)2, -N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)2, -CH2NH2, -CH2CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, etc. In some embodiments, aminoalkyl refers to -NHR n In some embodiments, the aminoalkyl is a —NR n R n In some embodiments, the aminoalkyl is an -R n "NH group. In some embodiments, the aminoalkyl is -R n "NHR n In some embodiments, the aminoalkyl is a —R″NR n R n In some embodiments, when an oxygen is substituted with an aminoalkyl group, the aminoalkyl group is not attached to the oxygen through a nitrogen in the aminoalkyl group or a carbon immediately adjacent to the nitrogen. For example, an aminoalkyl-substituted oxygen is an O—NR n But O-CH2-NHR n But not.

[0043] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon radical having the specified number of carbon atoms. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0044] "Cyanoalkyl" refers to an alkyl group as defined above that is substituted with a cyano group (-CN). Cyanoalkyls may also be called alkylnitriles.

[0045] "Halo" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro or chloro.

[0046] "Haloalkyl" means an alkyl group, as defined above, that is substituted with one or more halogen atoms, from 1 to 5 halogen atoms, e.g., fluorine or chlorine, and includes groups substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When the alkyl is substituted with only fluoro, it can be referred to in this application as fluoroalkyl.

[0047] "Haloalkoxy" means -OR a group (in the formula, R a is haloalkyl as defined above), or -R b OR c group (in the formula, R b and R c is an alkyl or haloalkyl group as defined above), and the specified number of alkyl carbons in the haloalkoxy group is b and R c The halo atom(s) is / are equal to the total number of carbon atoms in the b , or R c , or both, except that R b and R cwherein at least one of the following groups contains a halo atom. For example, C1-C4 haloalkoxy refers to, for example, -OCF3, -OCHF2, -CH2OCF3, -CH2CH(F)CH2OCH3, -CH2CH(F)CH2OCHF2, etc. In some embodiments, haloalkoxy refers to, for example, -OR a In some embodiments, the haloalkoxy is a -R b OR c A haloalkoxy group is a group. When all of the halo atoms in the haloalkoxy group are fluoro, it can be referred to as a fluoroalkoxy in this application. In some embodiments, when a nitrogen is substituted with a haloalkoxy group, the haloalkoxy group is not bonded to the nitrogen through an oxygen in the haloalkoxy group or the carbon immediately adjacent to the oxygen. For example, a haloalkoxy-substituted nitrogen can be represented by N-OR a But NC(H) n (X) 2-n -OR c But not.

[0048] "Hydroxyalkyl" means an alkyl group as defined above that is substituted with one or more hydroxyl (-OH) groups, e.g., one to three hydroxyl groups, e.g., -CHOH, -CHCHOH, -C(OH)(CH), -CH(OH)CH, and the like.

[0049] "Heterocyclic group," unless otherwise specified, means a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms, where 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the remainder of the ring is C. Sulfur groups can be present as either -S- or -S(O)2-. Unless otherwise specified, heterocyclic groups include monocyclic and polycyclic ring systems, including fused, bridged, and spiro ring systems. In some embodiments, a heterocyclic group is monocyclic. In some embodiments, a heterocyclic group contains two fused rings. In some embodiments, a heterocyclic group contains two spiro rings. In some embodiments, a heterocyclic group contains a bridged ring system.

[0050] "Carbocyclic group," unless otherwise specified, means a saturated or partially unsaturated cyclic group containing 3 to 12 ring atoms, where the ring atoms are C. Unless otherwise specified, carbocyclic groups include monocyclic and polycyclic ring systems, including fused, bridged, and spiro ring systems. In some embodiments, a carbocyclic group is monocyclic. In some embodiments, a carbocyclic group contains two fused rings. In some embodiments, a carbocyclic group contains two spiro rings. In some embodiments, a carbocyclic group contains a bridged ring system.

[0051] "Heteroaryl," unless otherwise specified, means a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms, where one or more (in some embodiments, 1, 2, or 3) ring atoms are heteroatom(s) independently selected from N, O, or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

[0052] A "spiro" cycloalkyl group indicates that the cycloalkyl group is attached to the remainder of the compound via a spiro bond. A "spiro" cycloalkyl substituent has two bonds attached to the same carbon of the substituted moiety, forming a spiro bond. For example, a cyclohexyl group substituted with a "spiro C3-C4 cycloalkyl" group is: Showing TIFF2024540410000005.tif14128.

[0053] As used herein, "in need of treatment" means that the patient is being treated by a physician or other caregiver after diagnosis of the disease or after the patient is determined to be at risk of developing the disease. In some embodiments, the patient has been diagnosed with a KRAS G12C-mediated cancer. In some embodiments, the patient has been determined to be at risk of developing a KRAS G12C-mediated cancer.

[0054] "Administration," "administering," and the like, when applied to, e.g., a patient, cell, tissue, organ, or biological fluid, refer to the contact of, e.g., a compound of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1), or Formula (II-2), or a pharmaceutically acceptable salt and / or isotopic variant thereof, a pharmaceutical composition comprising same, or a diagnostic agent, with the subject, cell, tissue, organ, or biological fluid. In the context of cells, administration also includes contact of a reagent with a cell (e.g., in vitro or ex vivo), and contact of a reagent with a fluid (where the fluid is in contact with the cell).

[0055] "Optional" or "optionally" means that the subsequently described event or circumstance may occur but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0056] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0057] As used herein, the term "disease" is generally intended to be synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "condition" (e.g., medical condition), all of which reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function, is typically manifested by characteristic signs and symptoms, and reduces the lifespan or quality of life of the human or animal.

[0058] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the diseases or disorders described in this disclosure. Such administration includes the co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single capsule or tablet with a fixed ratio of active ingredients, or in multiple separate capsules or tablets for each active ingredient. Furthermore, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen will bring about the beneficial effect of the drug combination in the treatment of the disease conditions or disorders described herein.

[0059] Cancer treatment methods The compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1) and Formula (II-2), and pharmaceutically acceptable salts and / or isotopic substitutions thereof (including the embodiments thereof disclosed herein), are useful in the treatment of cancer, including, but not limited to, various types of cancer, including, for example, lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer. More specifically, cancers that can be treated by the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1) and Formula (II-2), and pharmaceutically acceptable salts and / or isotopic derivatives thereof (including the embodiments thereof disclosed herein), include, for example, glioblastoma multiforme, low-grade glioma, head and neck squamous cell carcinoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate cancer, ovarian serous cystadenocarcinoma, uterine endometrial carcinoma, cervical adenocarcinoma, and the like. Cancers include, but are not limited to, squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphoblastic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma. In some embodiments, including any of the foregoing embodiments, the cancer is a KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the subject has been diagnosed with a KRAS G12C-mediated cancer. In some embodiments, including any of the foregoing embodiments, the subject has been determined to be at risk for developing a KRAS G12C-mediated cancer.

[0060] In some embodiments, including any of the foregoing embodiments, the subject and / or cancer is resistant or refractory to treatment with a KRAS inhibitor (e.g., a G12C KRAS inhibitor).

[0061] test Compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1) and Formula (II-2), and pharmaceutically acceptable salts and / or isotopic substitutions thereof (including embodiments disclosed herein) can be tested, for example, by the methods described in the Examples below, or by known and generally accepted cellular and / or animal models.

[0062] The ability of compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1) and Formula (II-2), and pharmaceutically acceptable salts and / or isotopic substitutions thereof, to inhibit the activity of the GTP-bound form of KRAS G12C can be tested using methods such as the in vitro assays described below in Examples 308 and 309. In Example 308, the half-maximal inhibition (IC) of binding of KRAS G12C loaded with the GTP analog GMPPNP to cRaf as the Ras binding domain (RBD) was measured for various compounds. 50 Example 309 describes measuring half-maximal inhibition (IC) of binding of KRAS G12C loaded with the GTP analog GMPPNP to PI3Kα as the Ras binding domain (RBD) for various compounds. 50 Example 310 describes testing compounds for their ability to inhibit cell viability in the MCF10A G12C / A59G mutant, which inhibits GTPase activity and prevents hydrolysis of GTP to GDP.

[0063] Pharmaceutical Composition In general, compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1), and Formula (II-2) of the present disclosure, as well as pharmaceutically acceptable salts and / or isotopic derivatives thereof (also referred to herein as "compounds" or "compounds of the present disclosure"), are administered in therapeutically effective amounts by any of the accepted modes of administration for drugs that serve similar utilities. Therapeutically effective amounts of compounds of the present disclosure may range from about 0.01 to about 500 mg per kg of patient body weight per day, and may be administered in single or multiple doses. In some embodiments, suitable dosage levels may be from about 0.1 to about 250 mg / kg per day, or from about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be from about 0.01 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg per day, or from about 0.1 to about 50 mg / kg per day. Within this range, dosages can be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg per day. For oral administration, the compositions can be provided in tablet form containing about 1.0 to about 1000 milligrams of active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient. The actual amount of a compound of the present disclosure, i.e., active ingredient, will depend on numerous factors, including the severity of the condition being treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and other factors.

[0064] Generally, the compounds of the present disclosure are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (for example, transdermal, intranasal, or suppository), or parenteral (for example, intramuscular, intravenous, or subcutaneous) administration.The preferred mode of administration is oral administration, using a convenient daily dosage regimen that can be adjusted according to the degree of pain.The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, liquid, suspension, elixir, aerosol, or any other suitable composition.

[0065] The choice of formulation will depend on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, e.g., enteric-coated or delayed-release tablets, pills, or capsules, are preferred) and the bioavailability of the drug substance.

[0066] Composition generally consists of the compound of the present disclosure and at least one pharmaceutically acceptable excipient combination.Acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic effect of the compound of the present disclosure.Such excipient can be any solid, liquid, semi-solid, or gaseous excipient in the case of aerosol composition that is generally available to those skilled in the art.

[0067] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, nonfat powdered milk, etc. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0068] The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Injectable formulations can be provided in unit dosage form, e.g., in ampoules, or in multi-dose containers, with an additional preservative added. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The formulations can be provided in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0069] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0070] In addition to the formulation described above, compound can also be formulated as depot preparation.Such long-acting preparation can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Therefore, for example, compound can be formulated with suitable polymer or hydrophobic material (for example, as emulsion in acceptable oil) or ion exchange resin, or as poorly soluble derivative, for example as poorly soluble salt.

[0071] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0072] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0073] Certain compounds of the present disclosure can be administered topically, i.e., by non-systemic administration. This includes applying the compound externally to the epidermis or oral cavity so that the compound does not significantly enter the bloodstream, as well as instilling such compounds into the ear, eye, and nose. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0074] Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for administration to the eye, ear, or nose. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% to 1% w / w of the formulation.

[0075] For administration by inhalation, the compounds can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of the present disclosure can be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be presented in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 20th ed., 2000).

[0076] The level of the compound in the formulation can vary within the full range accepted by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01 to 99.99% by weight of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. For example, the compound may be present at a level of about 1 to 80% by weight.

[0077] Combination and Combined Therapies The compounds of the present disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present disclosure or other drugs may be useful. Such other drug(s) may be administered simultaneously or sequentially with the compounds of the present disclosure. When the compounds of the present disclosure are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compounds of the present disclosure is contemplated. However, combination therapy may also include therapy in which the compounds of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used alone.

[0078] Accordingly, pharmaceutical compositions of the present disclosure include those that contain one or more other drugs, in addition to a compound of the present disclosure.

[0079] The above combinations include combinations of the compounds of the present disclosure with not only one other active agent, but also two or more other active agents. Similarly, the compounds of the present disclosure may be used in combination with other agents used to prevent, treat, control, ameliorate, or reduce the risk of diseases or conditions for which the compounds of the present disclosure are useful. Such other agents may be administered simultaneously or sequentially with the compounds of the present disclosure. When the compounds of the present disclosure are used simultaneously with one or more other agents, pharmaceutical compositions containing such other agents in addition to the compounds of the present disclosure can be used. Thus, pharmaceutical compositions of the present disclosure also include those containing one or more other active ingredients in addition to the compounds of the present disclosure. The weight ratio of the compounds of the present disclosure to the second active ingredient may vary and depends on the effective dosage of each ingredient. Generally, a therapeutically effective dose of each is used.

[0080] If the subject in need of treatment has or is at risk of having cancer, the subject may be treated with a compound of the present disclosure, optionally in combination with one or more other anti-cancer agents.

[0081] In some embodiments, compounds of the present disclosure are used in combination with a CDK 4 / 6 inhibitor. Examples of CDK 4 / 6 inhibitors suitable for the provided compositions and methods include, but are not limited to, abemaciclib (N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine); palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-pyrido[2,3-d]pyrimidin-7(8H)-one) and ribociclib (7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide), while CDK The 4 / 6 inhibitor trilaciclib (2'-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro-[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one) is in late-stage clinical trials. Another CDK 4 / 6 inhibitor useful in the methods of the invention is the CDK 2 / 4 / 6 inhibitor PF-06873600 (pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]).

[0082] In another embodiment, the compounds of the present disclosure are used in combination with a Raf family kinase inhibitor. Examples of Raf family kinase inhibitors suitable for the provided compositions and methods include encorafenib (LGX818): (S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)methylcarbamate, PLX-8394: N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropropan-2-yl pyrrolidine-1-sulfonamide, Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide, LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, sorafenib: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide, LY 3009120: 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido-[2,3-d]pyrimidin-6-yl)phenyl)urea, lifirafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-5-yl)methyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one, Tak-632: N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide, CEP-32496: 1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-( Examples include, but are not limited to, 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea, CCT196969: 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea, and R05126766: N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methylsulfamide;

[0083] In another embodiment, the compounds of the present disclosure are used in combination with a Src family kinase. Examples of Src family kinase inhibitors suitable for the provided compositions and methods include dasatinib (N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide), ponatinib (3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)propan-1-yl), benzodiazepine ... (methyl)phenyl)benzamide), vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine), bosutinib (4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)-propoxy)quinoline-3-carbonitrile), saracatinib (N-(5-chlorobenzo[d][1,3]dioxol-4-yl) -7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine), KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP1(1 In one embodiment, the Src inhibitor is dasatinib. In one embodiment, the Src inhibitor is saracatinib. In one embodiment, the Src inhibitor is ponatinib. In one embodiment, the Src inhibitor is vandetanib.In one embodiment, the Src inhibitor is KX-01.

[0084] In another embodiment, a compound of the present disclosure is used in combination with an SHP-2 inhibitor, including, but not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 (3(3S,4S)-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)pyrazin-2-yl)methanol), RMC-4360 (Revolution Medicines), TN0155 (Novartis), BBP-398 (BridgeBio), and ERAS-601 (Erasca).

[0085] In another embodiment, the compounds of the present disclosure are used in combination with an mTOR inhibitor. Examples of mTOR inhibitors suitable for the provided compositions and methods include everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib (INK128, 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine), Torin-1, 1-(4-(4-propionylpiperazin-1-yl)benzo[d]oxazol-2-amine), and rhabdomyosin (rhabdomyosin, ... )-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one, dactolisib (BEZ235), 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile, buparlisib (5-(2,6-dimorpholin-4-ylpyrimidin-4 -yl)-4-(trifluoromethyl)pyridin-2-amine), GDC-0941 (pictilisib), 4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyridin-2-yl)-4-methylpyridin-2-amine), These include, but are not limited to, bis(2,4-bis((S)-3-methylmorpholino)pyrido-[2,3-d]pyrimidin-2-yl)phenyl)urea), VS-5584 (SB2343) (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine), and bistusertib (AZD-2014, 3-(2,4-bis((S)-3-methylmorpholino)pyrido-[2,3-d]pyrimidin-7-yl)-N-methylbenzamide).

[0086] In another embodiment, a compound of the present disclosure is used in combination with a pan-ErbB family inhibitor. In one embodiment, the KRAS and pan-ErbB family inhibitor are the only active agents in the provided compositions and methods. In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan-ErbB family inhibitors suitable for the provided compositions and methods include afatinib, dacomitinib, canertinib, poziotinib, AV 412 (N-4-([3-(chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-1-butyn-1-yl]-6-quinazolinyl]-2-prepenamide), PF 6274484 N-4-([3-(chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 In another embodiment, the pan-ErbB family inhibitor is a reversible inhibitor.Examples of reversible pan-ErbB family inhibitors suitable for the provided compositions and methods include erlotinib, gefitinib, sapitinib, varlitinib, TAK-285 (N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide), AEE788(S)-(6-(4-((4-ethylpiperazin-1-ylmethyl)phenyl]-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), tarloxotinib, 3-[N-[4-(3-bromo-4-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl]carbamoyl]-N,N-dimethyl-N-(1-methyl-4-nitro-1H-imidazol-5-ylmethyl)-2(E)-propen-1-aminium bromide), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpropro[2,1-f][1,2,4]triazin-6-yl]carbamate dihydrochloride), and GW Examples include, but are not limited to, 583340 (N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[2-[2-(methylsulfonyl)ethylaminomethyl]thiazol-4-yl]quinazolin-4-amine dihydrochloride).

[0087] In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, and the EGFR inhibitor and the HER2 inhibitor are selected from the group consisting of AG 1478 (N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine hydrochloride), AG 555 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2-propenamide), AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-propenamide), AG 825 (E-3-[3-benzothiazol-2-ylsulfanylmethyl)-4-hydroxy-5-methoxyphenyl]-2-cyano-2-propenamide), CP 724714 (2-methoxy-N-[(2E)-3-[4-[3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino]quinazolin-6-yl]-2-propen-1-yl]acetamide, BIBU 1361 (N-(3-chloro-4-fluorophenyl)-6-[4-(diethylaminomethyl)-piperidin-1-yl]pyrimido[5,4-d]pyrimidin-4-amine dihydrochloride), BIBU 1382, (N 8 -(3-chloro-4-fluorophenyl)-N 2 -(1-methyl-4-piperidinyl)pyrimidino[5,4-d]pyrimidin-4-amine dihydrochloride), JNJ 28871063 (5E-4-amino-6-[4-(benzyloxy)-3-chlorophenylamino]-pyrimidine-5-carbaldehyde N-[2-(4-morpholinyl)ethyl]oxime hydrochloride), PD 153035 (4-(3-bromophenylamino)-6,7-dimethoxyquinazoline hydrochloride), and PD 158780 (N 4 -(3-bromophenyl)-N 6 -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine).

[0088] In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, an anti-HER2 antibody, or a combination of an anti-EGFR antibody and an anti-HER2 antibody. Antibodies, such as monoclonal antibodies, antibody conjugates, and bispecific antibodies, that target EGFR and / or HER2 are well known, and several antibodies are commercially available for research and human clinical use. Examples of anti-EGFR antibodies suitable for the provided compositions and methods include necitumumab, panitumumab, and cetuximab. Examples of anti-HER2 antibodies suitable for the provided compositions and methods include pertuzumab, trastuzumab, and trastuzumab emtansine.

[0089] In some embodiments, compounds of the present disclosure are used in combination with immune checkpoint inhibitors. Examples of immune checkpoint inhibitors suitable for the provided compositions and methods include, but are not limited to, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors, such as pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi™), ipilimumab (Yervoy®), leratolimab, Opdualag, and dostarlimab (Jemperli).

[0090] The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds and salts may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used as pre- or post-operative adjuncts in combination with other treatments, such as radiation or surgical intervention.

[0091] Selected Embodiments Embodiment 1. A compound of Formula I or Formula II, or a salt thereof; and / or an isotopic variant thereof: TIFF2024540410000006.tif69128In formula, R xis selected from hydrogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R y is selected from hydrogen, C1-C4 alkyl, and halo; R z is selected from hydrogen, C1-C4 alkyl, and halo; R 1 is a 4-8 membered saturated carbocyclic or heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2 is R 2a , R 2b , R 2c , R 2d , and R 2e selected from the group consisting of: R 3 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C7 cycloalkyl, CN, and C2-C3 alkynyl; R 2a is -NR 5 R 6 and; R 5 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 6 is -C1-C6 alkylene-S(O)2-CH=CHR 7 or R 5 and R 6together with the nitrogen to which they are attached form a 4- to 7-membered saturated heterocyclic group containing one ring and one nitrogen as the only heteroatom in the ring, said 4- to 7-membered saturated heterocyclic group being -(CH2) n -S(O)2-CH=CHR 7 is replaced by; R 7 is hydrogen, -C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -(CH2) m -NR 8 R 9 selected from the group consisting of: R 8 and R 9 is independently selected from the group consisting of -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen atom in the ring and optionally substituted by halo; n is 0 or 1; m is 1 or 2; R 2b is -NR 10 R 11 and; R 10 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 11 teeth, -(C1-C4 alkylene)-N(R 12 )-CN, and -(CH2) w -R 13 or selected from the group consisting of: R 10 and R 11together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said 4-8 membered saturated heterocyclic group being -(CH2) x -N(R 14 )-CN, a 4- to 6-membered saturated heterocyclic group containing one ring and one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen atom is substituted with cyano; and cyano, provided that when cyano is a substituent, R 10 and R 11 and the 4-8 membered saturated heterocyclic group they form together with the nitrogen to which they are attached contains a second nitrogen ring atom, and the cyano is connected to the 4-8 membered saturated heterocyclic group at the second ring nitrogen, and is substituted with one substituent selected from the group consisting of: R 12 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 13 is a 4-5 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, said nitrogen being substituted with cyano, and said heterocyclic group being optionally further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo; or R 13 is a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatom(s) in the ring, one of the nitrogens being substituted with cyano, and the heterocyclic group optionally being further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C cyanoalkyl, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bound to a heteroatom; or R13 is a 7-membered saturated heterocyclic group containing one nitrogen and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur as the only heteroatom(s) in the ring, wherein one of the nitrogen ring atom(s) is / are substituted with cyano, and the heterocyclic group is optionally further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C cyanoalkyl, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; R 14 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; w is 0, 1 or 2; x is 0 or 1; R 2c is -NR 15 R 16 and; R 15 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy, optionally substituted with one example, CN; and R 16 teeth, -(C1-C4 alkylene)-N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 , and -(CH2) y -R 21 or selected from the group consisting of: R 15 and R16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said heterocyclic group being -(CH2) q -N(R 17 )C(O)C(R 19 )=C(R 20 )R 18and, -C(O)C(R 19 )=C(R 20 )R 18 where -C(O)C(R 19 )=C(R 20 )R 18 is a substituent, R 15 and R 16 and the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen ring atom, and the -C(O)C(R 19 )=C(R 20 )R 18 is attached to the heterocyclic group at the second ring nitrogen, 19 )=C(R 20 )R 18 and and is substituted with one substituent selected from the group consisting of: R 17 is selected from the group consisting of hydrogen, —C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 18 is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)O-C1-C4 haloalkyl, -C(O)-C1-C4 alkyl, -C(O)-C1-C4 haloalkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(CH2) u -R 34 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, -S(O)2-C1-C4 haloalkyl, and R 35 and R 20 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; or R 18 and R 20can be taken together with the carbon to which they are attached to form a 4-5 membered carbocyclic or heterocyclic ring containing one heteroatom selected from N, O, and S, which carbocyclic or heterocyclic ring can be optionally substituted with, for example, methyl, halo, hydroxy, methoxy, or carbonyl; R 19 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 21 teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 the 4-5 membered saturated heterocyclic group is substituted by, wherein the heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, or is further substituted with two halo substituents; A 6-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is —C(O)C(R 19 )=C(R 20 )R 18 the 6-membered saturated heterocyclic group is substituted by, and the heterocyclic group is either unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or is further substituted with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) of the heterocyclic group is / are -C(O)C(R 19 )=C(R 20 )R 18 the 7-membered saturated heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or is further substituted with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom. Selected from; R 22 and R 23 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 34 is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, CH2-(C3-C6 heterocyclyl), and C2-C3 alkynyl; R 35 teeth, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. is a 5- to 6-membered heteroaryl group optionally substituted by 0, 1, 2, or 3 substituents independently selected from y is 0, 1 or 2; z is 1 or 2; q is 0 or 1; u is 0, 1 or 2; R 2d teeth, -NR 24 R 25 , -C(O)N(R 27 )-(C1-C4 alkylene)-C(O)CH=CHR 26 , and -O-(C1-C2 alkylene)-C(O)CH=CHR 26 selected from the group consisting of: R 24 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 25 is -(C1-C4 alkylene)-C(O)CH=CHR 26 or R 24 and R 25 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, the heterocyclic group being -(C0-C2 alkylene)-C(O)CH=CHR 26 and the heterocyclic group is optionally further substituted with C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 26 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 27 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2e is -NR 28 R 29 and; R 28is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 29 is -(CH2) t -R 30 and; R 30 teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C≡CR 31 the 4-5 membered saturated heterocyclic group is substituted by, which heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; A six-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is -C(O)C≡CR 31 the 6-membered saturated heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C cyanoalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atoms of the heterocyclic group is -C(O)C≡CR 31the 7-membered saturated heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom. Selected from; R 31 is -(CH2) v -NR 32 R 33 and -(CH2) p -R 36 selected from the group consisting of: R 32 and R 33 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; t is 0, 1 or 2; v is 1 or 2; p is 0, 1 or 2; R 36 is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; provided that when the compound is of formula I, R 2c teeth TIFF2024540410000007.tif25128; and with the further proviso that when the compound is of formula II, R 2c Ha-NR 15 R 16 Instead, R 15 and R 16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom in the ring, and the second nitrogen is substituted with -C(O)-CH=CH2.

[0092] Embodiment 2. The compound of embodiment 1, which is a compound of formula I or a salt thereof:

[0093] Embodiment 3. The compound of embodiment 1, wherein the compound is a compound of formula II or a salt thereof:

[0094] Embodiment 4.R y The compound of any one of embodiments 1-3, wherein is selected from hydrogen and halo.

[0095] Embodiment 5.R y The compound of any one of embodiments 1-3, wherein is selected from hydrogen, Me, F, and Cl.

[0096] Embodiment 6.R y The compound of any one of embodiments 1-3, wherein is selected from hydrogen, F, and Cl.

[0097] Embodiment 7.R y is H.

[0098] Embodiment 8.R z The compound of any one of embodiments 1-7, wherein is selected from hydrogen, Me, F, and Cl.

[0099] Embodiment 9.R z The compound of any one of embodiments 1-7, wherein is selected from hydrogen, Me, and F.

[0100] Embodiment 10.R z The compound of any one of embodiments 1-7, wherein is hydrogen.

[0101] Embodiment 11. A compound of formula I-1 or II-1, or a salt thereof; and / or an isotopic substitution thereof: TIFF2024540410000008.tif71128In formula, R xis selected from hydrogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R 1 is a 4-8 membered saturated carbocyclic or heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the carbocyclic or heterocyclic group is substituted with 0, 1, 2 or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2 is R 2a , R 2b , R 2c , R 2d , and R 2e selected from the group consisting of: R 3 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 2a is -NR 5 R 6 and; R 5 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 6 is -C1-C6 alkylene-S(O)2-CH=CHR 7 or R 5 and R 6 together with the nitrogen to which they are attached form a 4- to 7-membered saturated heterocyclic group containing one ring with one nitrogen as the only heteroatom in the ring, and the 4- to 7-membered saturated heterocyclic group is -(CH2) n -S(O)2-CH=CHR 7is replaced by; R 7 is hydrogen, -C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -(CH2) m -NR 8 R 9 selected from the group consisting of: R 8 and R 9 is independently selected from the group consisting of -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen atom in the ring and optionally substituted by halo; n is 0 or 1; m is 1 or 2; R 2b is -NR 10 R 11 and; R 10 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 11 teeth, -(C1-C4 alkylene)-N(R 12 )-CN, and -(CH2) w -R 13 or selected from the group consisting of: R 10 and R 11 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said 4-8 membered saturated heterocyclic group being -(CH2) x -N(R 14 )-CN, a 4- to 6-membered saturated heterocyclic group containing one ring and one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen atom is substituted with cyano; and cyano, provided that when cyano is a substituent, R 10 and R 11 and the 4-8 membered saturated heterocyclic group they form together with the nitrogen to which they are attached contains a second nitrogen ring atom, and the cyano is connected to the 4-8 membered saturated heterocyclic group at the second ring nitrogen, and is substituted with one substituent selected from the group consisting of: R 12 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 13 is a 4-5 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, said nitrogen being substituted with cyano, and said heterocyclic group being optionally further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo; or R 13 is a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatom(s) in the ring, one of the nitrogens being substituted with cyano, and the heterocyclic group optionally being further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C cyanoalkyl, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bound to a heteroatom; or R 13is a 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) is substituted with cyano, and the heterocyclic group is optionally further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C cyanoalkyl, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; R 14 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; w is 0, 1 or 2; x is 0 or 1; R 2c is -NR 15 R 16 and; R 15 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 16 teeth, -(C1-C4 alkylene)-N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 , and -(CH2) y -R 21 or selected from the group consisting of: R 15 and R16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said heterocyclic group being -(CH2) q -N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 and, -C(O)C(R19 )=C(R 20 )R 18 where -C(O)C(R 19 )=C(R 20 )R 18 is a substituent, R 15 and R 16 and the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen ring atom, and the -C(O)C(R 19 )=C(R 20 )R 18 is attached to the heterocyclic group at the second ring nitrogen, 19 )=C(R 20 )R 18 and and is substituted with one substituent selected from the group consisting of: R 17 is selected from the group consisting of hydrogen, —C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 18 is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)O-C1-C4 haloalkyl, -C(O)-C1-C4 alkyl, -C(O)-C1-C4 haloalkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(CH2) u -R 34 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, -S(O)2-C1-C4 haloalkyl, and R 35 selected from the group consisting of: R 19 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 20 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 21 teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 the 4-5 membered saturated heterocyclic group is substituted by, wherein the heterocyclic group is either unsubstituted or substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; A 6-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is —C(O)C(R 19 )=C(R 20 )R 18 the 6-membered saturated heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C cyanoalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) of the heterocyclic group is / are -C(O)C(R 19 )=C(R 20 )R 18 the 7-membered saturated heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom. Selected from; R22 and R 23 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 34 is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; R 35 teeth, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. is a 5- to 6-membered heteroaryl group optionally substituted by 0, 1, or 2 substituents independently selected from y is 0, 1 or 2; z is 1 or 2; q is 0 or 1; u is 0, 1 or 2; R 2d teeth, -NR 24 R 25 , -C(O)N(R 27 )-(C1-C4 alkylene)-C(O)CH=CHR 26 , and -O-(C1-C2 alkylene)-C(O)CH=CHR 26 selected from the group consisting of: R 24 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 25is -(C1-C4 alkylene)-C(O)CH=CHR 26 or R 24 and R 25 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, the heterocyclic group being -(C0-C2 alkylene)-C(O)CH=CHR 26 and the heterocyclic group is optionally further substituted with C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 26 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 27 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2e is -NR 28 R 29 and; R 28 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 29 is -(CH2) t -R 30 and; R 30 teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C≡CR 31 the 4-5 membered saturated heterocyclic group is substituted by, which heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; A six-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is -C(O)C≡CR 31 the 6-membered saturated heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C cyanoalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) of the heterocyclic group is / are -C(O)C≡CR 31 the 7-membered saturated heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom. Selected from; R 31 is -(CH2) v -NR 32 R 33 and -(CH2) p -R 36 selected from the group consisting of: R 32 and R 33 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; t is 0, 1 or 2; v is 1 or 2; p is 0, 1 or 2; R 36is a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; However, when the compound is of formula I-1, R 2c teeth TIFF2024540410000009.tif25128; and Further, with the proviso that when the compound is of formula II-1, R 2c Ha-NR 15 R 16 Instead, R 15 and R 16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom in the ring, and the second nitrogen is substituted with -C(O)-CH=CH2.

[0102] Embodiment 12. The compound of embodiment 11, which is a compound of formula I-1 or a salt thereof:

[0103] Embodiment 13. The compound of embodiment 11, which is a compound of formula II-1 or a salt thereof:

[0104] Embodiment 14.R x The compound of any one of embodiments 11-13, wherein is selected from hydrogen, hydroxy, and C1-C4 haloalkoxy.

[0105] Embodiment 15.R x The compound of any one of embodiments 11-13, wherein is selected from hydrogen, hydroxy, and —OCHF 2 .

[0106] Embodiment 16.R x The compound of any one of embodiments 11-13, wherein is selected from hydrogen and hydroxy.

[0107] Embodiment 17.R xThe compound of any one of embodiments 11-13, wherein is hydrogen.

[0108] Embodiment 18. A compound of formula I-2 or II-2, or a salt thereof; and / or an isotopic substitution thereof: TIFF2024540410000010.tif59128In formula, R 1 is a 4-8 membered saturated carbocyclic or heterocyclic group containing one nitrogen as the only heteroatom in the ring, optionally substituted with one or more substituents independently selected from C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 2 is R 2a , R 2b , R 2c , and R 2d selected from the group consisting of: R 3 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C3 alkynyl; R 4 is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C3 alkynyl; R 2a is -NR 5 R 6 and; R 5 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 6 is -C1-C6 alkylene-S(O)2-CH=CHR 7 or R 5 and R 6together with the nitrogen to which they are attached form a 4- to 7-membered saturated heterocyclic group containing one ring and one nitrogen as the only heteroatom in the ring, said 4- to 7-membered saturated heterocyclic group being -(CH2) n -S(O)2-CH=CHR 7 is replaced by; R 7 is hydrogen, -C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and -(CH2) m -NR 8 R 9 selected from the group consisting of: R 8 and R 9 is independently selected from the group consisting of -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen atom in the ring and optionally substituted by halo; n is 0 or 1; m is 1 or 2; R 2b is -NR 10 R 11 and; R 10 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; and R 11 teeth, -(C1-C4 alkylene)-N(R 12 )-CN, and -(CH2) w -R 13 or selected from the group consisting of: R 10 and R 11together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said 4-8 membered saturated heterocyclic group being -(CH2) x -N(R 14 )-CN and a 4- to 6-membered saturated heterocyclic group containing one ring and one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen atom is substituted with cyano; cyano, provided that when cyano is a substituent, R 10 and R 11 and the 4-8 membered saturated heterocyclic group they form together with the nitrogen to which they are attached contains a second nitrogen ring atom, and the cyano is connected to the 4-8 membered saturated heterocyclic group at the second ring nitrogen. and is substituted with one substituent selected from the group consisting of: R 12 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 13 is a 4-5 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, said nitrogen being substituted with cyano, and said heterocyclic group being optionally further substituted with C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo; or R 13 is a 6-membered saturated heterocyclic group containing one or two nitrogens as the only heteroatom(s) in the ring, one of the nitrogens being substituted with cyano, and the heterocyclic group being optionally further substituted with C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, or halo; or R 13is a seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, one of the nitrogen ring atom(s) being substituted with cyano, and the heterocyclic group being C1-C4 alkyl 、 optionally further substituted with C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo; R 14 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; w is 0, 1 or 2; x is 0 or 1; R 2c is -NR 15 R 16 and; R 15 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 16 teeth, -(C1-C4 alkylene)-N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 , and -(CH2) y -R 21 and R 21 is a 4- to 7-membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, and the nitrogen ring atom is —C(O)C(R 19 )=C(R 20 )R 18 the heterocyclic group is optionally further substituted with one substituent selected from the group consisting of C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, and halo, the -(CH) y -R 21 or selected from the group consisting of: R 15 and R 16together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said heterocyclic group being -(CH2) q -N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 and, -C(O)C(R 19 )=C(R 20 )R 18 where -C(O)C(R 19 )=C(R 20 )R 18 is a substituent, R 15 and R 16 and the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen ring atom, and the -C(O)C(R 19 )=C(R 20 )R 18 is attached to the heterocyclic group at the second ring nitrogen, 19 )=C(R 20 )R 18 and and is substituted with one substituent selected from the group consisting of: R 17 is selected from the group consisting of hydrogen, —C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 18 is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)O-C1-C4 haloalkyl, -C(O)-C1-C4 alkyl, -C(O)-C1-C4 haloalkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23, -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, -S(O)2-C1-C4 haloalkyl, and a 5-6 membered heteroaryl group optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 19 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 20 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; R 22 and R 23 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; y is 0, 1 or 2; z is 1 or 2; q is 0 or 1; R 2d teeth, -NR 24 R 25 , -C(O)N(R 27 )-(C1-C4 alkylene)-C(O)CH=CHR 26 , and -O-(C1-C2 alkylene)-C(O)CH=CHR 26 selected from the group consisting of: R 24 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 25 is -(C1-C4 alkylene)-C(O)CH=CHR 26 or R 24 and R 25together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, the heterocyclic group being -(C0-C2 alkylene)-C(O)CH=CHR 26 wherein the heterocyclic group is optionally further substituted with C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; R 26 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 27 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; However, when the compound is of formula I-2, R 2c teeth TIFF2024540410000011.tif25128, not TIFF2024540410000011.tif25128; and Further, with the proviso that when the compound is of formula II-2, R 2c Ha-NR 15 R 16 Instead, R 15 and R 16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom in the ring, and the second nitrogen is substituted with -C(O)-CH=CH2.

[0109] Embodiment 19. The compound of embodiment 18, which is a compound of formula I-2 or a salt thereof:

[0110] Embodiment 20. The compound of embodiment 18, which is a compound of formula II-2 or a salt thereof:

[0111] Embodiment 21.R 1 The compound of any one of embodiments 1-20, wherein the 4-8 membered saturated heterocyclic or carbocyclic group comprises a heterocyclic group.

[0112] Embodiment 22.R 1The compound of any one of embodiments 1-20, wherein the 4-8 membered saturated heterocyclic or carbocyclic group comprises a carbocyclic group.

[0113] Embodiment 23.R 1 The compound of any one of embodiments 1 to 20, wherein the 4-8 membered saturated heterocyclic or carbocyclic group of the formula (I) contains one ring.

[0114] Embodiment 24.R 1 The compound of any one of embodiments 1 to 20, wherein the 4-8 membered saturated heterocyclic or carbocyclic group of the formula (I) contains two rings.

[0115] Embodiment 25.R 1 The compound of any one of embodiments 1 to 20, wherein the 4-8 membered saturated heterocyclic or carbocyclic group is unsubstituted.

[0116] Embodiment 26.R 1 The compound of any one of embodiments 1-20, wherein the 4-8 membered saturated heterocyclic or carbocyclic group is substituted with one C1-C4 alkyl.

[0117] Embodiment 27.R 1 is a 4-8 membered saturated monocyclic carbocyclic or monocyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring, and the carbocyclic or heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0118] Embodiment 28.R 1is a 4-8 membered saturated bicyclic carbocyclic or bicyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring, and the carbocyclic or heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0119] Embodiment 29.R 1 is a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, and the heterocyclic group is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0120] Embodiment 30.R 1 is a 4-8 membered saturated carbocyclic group substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, spiro C3-C4 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy.

[0121] Embodiment 31.R 1 The compound of any one of embodiments 1-30, wherein is an unsubstituted 4-8 membered saturated carbocyclic or heterocyclic group containing one nitrogen as the only heteroatom in the ring.

[0122] Embodiment 32.R 1 The compound of any one of embodiments 1-30, wherein the carbocyclic or heterocyclic group is unsubstituted or substituted with one halo, hydroxy, or C1-C4 alkyl.

[0123] Embodiment 33.R 1The compound of any one of embodiments 1-30, wherein the carbocyclic or heterocyclic group is unsubstituted or substituted with one halo or hydroxy.

[0124] Embodiment 34.R 1 The compound of any one of embodiments 1-30, wherein the carbocyclic or heterocyclic group is unsubstituted or substituted with one fluoro.

[0125] Embodiment 35.R 1 The compound of any one of embodiments 1-30, wherein the carbocyclic or heterocyclic group is unsubstituted or substituted with one fluoro or hydroxy.

[0126] Embodiment 36.R 1 The compound of any one of embodiments 1-30, wherein the carbocyclic or heterocyclic group is substituted with one fluoro.

[0127] Embodiment 37.R 1 The compound of any one of embodiments 1-30, wherein the carbocyclic or heterocyclic group is substituted with one C1-C4 alkyl.

[0128] Embodiment 38.R 1 but, TIFF2024540410000012.tif22138.

[0129] Embodiment 39.R 1 but, TIFF2024540410000013.tif21128.

[0130] Embodiment 40.R 1 but, TIFF2024540410000014.tif22128.

[0131] Embodiment 41.R 1 but, TIFF2024540410000015.tif16128.

[0132] Embodiment 42.R 1 but, TIFF2024540410000016.tif22128.

[0133] Embodiment 43.R 3 and R 4 The compound of any one of embodiments 1-41, wherein is selected from the group consisting of hydrogen, methyl, ethyl, ethynyl, fluoro, and chloro.

[0134] Embodiment 44.R 3 and R 4 The compound of any one of embodiments 1-42, wherein is selected from the group consisting of hydrogen, fluoro, and chloro.

[0135] Embodiment 45.R 3 The compound of any one of embodiments 1-41, wherein is selected from the group consisting of hydrogen and fluoro.

[0136] Embodiment 46.R 3 The compound of any one of embodiments 1-41, wherein is hydrogen.

[0137] Embodiment 47.R 3 The compound of any one of embodiments 1-41, wherein is fluoro.

[0138] Embodiment 48.R 4 The compound of any one of embodiments 1-47, wherein is selected from the group consisting of hydrogen, methyl, ethyl, ethynyl, propynyl, difluoromethyl, CN, cyclopropyl, fluoro, and chloro.

[0139] Embodiment 49.R 4 The compound of any one of embodiments 1-47, wherein is selected from the group consisting of hydrogen, methyl, ethyl, ethynyl, fluoro, and chloro.

[0140] Embodiment 50.R 4 The compound of any one of embodiments 1-47, wherein is selected from the group consisting of hydrogen, fluoro, and chloro.

[0141] Embodiment 51.R 4 The compound of any one of embodiments 1-47, wherein is propynyl.

[0142] Embodiment 52.R 4 The compound of any one of embodiments 1-47, wherein is CN.

[0143] Embodiment 53.R 4 The compound of any one of embodiments 1-47, wherein is cyclopropyl.

[0144] Embodiment 54.R 4 The compound of any one of embodiments 1-47, wherein is difluoromethyl.

[0145] Embodiment 55.R 4 The compound of any one of embodiments 1-47, wherein is chloro.

[0146] Embodiment 56.R 4 The compound of any one of embodiments 1-47, wherein is fluoro.

[0147] Embodiment 57.R 4 The compound of any one of embodiments 1-47, wherein is methyl.

[0148] Embodiment 58.R 4 The compound of any one of embodiments 1-47, wherein is ethyl.

[0149] Embodiment 59.R4 The compound of any one of embodiments 1-47, wherein is ethynyl.

[0150] Embodiment 60.R 4 The compound of any one of embodiments 1-47, wherein is hydrogen.

[0151] Embodiment 61.R 2 But R 2a , R 2b , R 2c and R 2e 61. The compound of any one of embodiments 1-60, selected from the group consisting of:

[0152] Embodiment 62.R 2 But R 2a , R 2b , and R 2c 61. The compound of any one of embodiments 1-60, selected from the group consisting of:

[0153] Embodiment 63.R 2 But R 2c and R 2e 61. The compound of any one of embodiments 1-60, selected from the group consisting of:

[0154] Embodiment 64.R 2 But R 2a and R 2b 61. The compound of any one of embodiments 1-60, selected from the group consisting of:

[0155] Embodiment 65.R 2 R 2a 61. The compound of any one of embodiments 1-60, wherein

[0156] Embodiment 66.R 5 The compound of any one of embodiments 1-62, 64, and 65, wherein is methyl or ethyl.

[0157] Embodiment 67.R 5 The compound of any one of embodiments 1-62, 64, and 65, wherein is methyl.

[0158] Embodiment 68.R 6 -C1-C6 alkylene-S(O)2-CH=CHR 7 The compound of any one of embodiments 1-62 and 64-67, wherein

[0159] Embodiment 69.R 6 The compound of any one of embodiments 1-62 and 64-68, wherein the C1-C6 alkylene is linear.

[0160] Embodiment 70.R 6 The compound of any one of embodiments 1-62 and 64-68, wherein the C1-C6 alkylene is cyclic.

[0161] Embodiment 71.R 6 The compound of any one of embodiments 1-62 and 64-68, wherein C1-C6 alkylene is C1-C4 alkylene.

[0162] Embodiment 72.R 6 wherein the C1-C6 alkylene is -(CH2)2-, -(CH2)3-, -(CH2)4-, and The compound of any one of embodiments 1-62 and 64-68, selected from the group consisting of TIFF2024540410000017.tif8128.

[0163] Embodiment 73.R 5 and R 6 together with the nitrogen to which they are attached form a 4- to 7-membered saturated heterocyclic group containing one ring and one nitrogen as the only heteroatom in the ring, said 4- to 7-membered saturated heterocyclic group being -(CH2) n -S(O)2-CH=CHR 7 66. The compound of any one of embodiments 1-62, 64, and 65, substituted with:

[0164] Embodiment 74.R 5 and R 6 but together with the nitrogen to which they are attached, TIFF2024540410000018.tif19128, forming a 4- to 7-membered saturated heterocyclic group selected from the group consisting of -(CH2) n -S(O)2-CH=CHR 7 The compound of embodiment 73, substituted with:

[0165] Embodiment 75. A compound according to any one of embodiments 1 to 62 and 64 to 74, wherein n is 0.

[0166] Embodiment 76. A compound according to any one of embodiments 1 to 62 and 64 to 74, wherein n is 1.

[0167] Embodiment 77.R 7 The compound of any one of embodiments 1-62 and 64-76, wherein is hydrogen.

[0168] Embodiment 78.R 7 The compound of any one of embodiments 1-62 and 64-76, wherein is -C1-C4 alkyl.

[0169] Embodiment 79.R 7 Ga-(CH2) m -NR 8 R 9 The compound of any one of embodiments 1-62 and 64-76, wherein

[0170] Embodiment 80.R 8 and R 9 is independently -C1-C2 alkyl.

[0171] Embodiment 81.R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group containing a nitrogen as the only heteroatom in the ring, and optionally substituted with halo.

[0172] Embodiment 82.R8 and R 9 together with the nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic group containing two rings, the ring atoms containing one or two nitrogens as the only heteroatoms in the ring atoms, and optionally substituted by halo.

[0173] Embodiment 83.R 8 and R 9 83. Compounds according to embodiment 81 or 82, wherein the saturated heterocyclic group which is formed together with the nitrogen atom to which they are attached is substituted with -F.

[0174] Embodiment 84.R 7 is hydrogen, methyl, ethyl, -CH2N(CH3)2, -CH2N(CH2CH3)2, and The compound of any one of embodiments 1-62 and 64-76, selected from the group consisting of TIFF2024540410000019.tif10128.

[0175] Embodiment 85.R 2 R 2b 61. The compound of any one of embodiments 1-60, wherein

[0176] Embodiment 86.R 10 The compound of any one of embodiments 1-62, 64, and 66-85, wherein is methyl or ethyl.

[0177] Embodiment 87.R 10 The compound of any one of embodiments 1-62, 64, and 66-85, wherein is methyl.

[0178] Embodiment 88.R 11 -(C1-C4 alkylene)-N(R 12 )—CN.

[0179] Embodiment 89.R 11-(C1-C2 alkylene)-N(R 12 )—CN.

[0180] Embodiment 90.R 11 -(C3-C4 alkylene)-N(R 12 )—CN, and the C3-C4 alkylene is cyclic.

[0181] Embodiment 91.R 12 The compound of any one of embodiments 1-62, 64, and 66-90, wherein is hydrogen.

[0182] Embodiment 92.R 12 The compound of any one of embodiments 1-62, 64, and 66-90, wherein is methyl.

[0183] Embodiment 93.R 11 but, The compound of any one of embodiments 1 to 63 and 66 to 87, wherein the compound is selected from the group consisting of TIFF2024540410000020.tif24128 and —CH2CH2N(CH3)CN.

[0184] Embodiment 94.R 11 But -(CH2) w -R 13 The compound of any one of embodiments 1-62, 64, and 66-87, wherein

[0185] Embodiment 95. A compound according to embodiment 94, wherein w is 0 or 1.

[0186] Embodiment 96.R 13is a 4-7 membered saturated heterocyclic group containing a nitrogen as the only heteroatom in the ring, wherein the nitrogen is substituted with cyano, and the heterocyclic group is optionally further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, or halo.

[0187] Embodiment 97.R 13 is a 4-7 membered saturated heterocyclic group containing a nitrogen as the only heteroatom in the ring, said nitrogen being substituted with cyano, and said heterocyclic group being optionally further substituted with C1-C4 alkyl, C1-C4 alkoxy, or halo.

[0188] Embodiment 98.R 13 wherein the heterocyclic group is not further substituted with hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo.

[0189] Embodiment 99.R 13 The compound of any one of embodiments 1-62, 64, 66-87, and 94-97, wherein the heterocyclic group is not further substituted with C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, or halo.

[0190] Embodiment 100.R 13 The compound of any one of embodiments 1-62, 64, 66-87, and 94-97, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 cyanoalkyl, C1-C4 alkyl, C1-C4 alkoxy, or halo.

[0191] Embodiment 101.R13 The compound of any one of embodiments 1-62, 64, 66-87, and 94-97, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, or halo.

[0192] Embodiment 102.R 13 The compound of any one of embodiments 1-62, 64, 66-87, and 94-97, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of methyl, methoxy, or fluoro.

[0193] Embodiment 103.R 11 but, The compound of any one of embodiments 1-62, 64, and 66-87, selected from the group consisting of: TIFF2024540410000021.tif99142.

[0194] Embodiment 104.R 10 and R 11 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said 4-8 membered saturated heterocyclic group being -(CH2) x -N(R 14 )-CN and a 4- to 6-membered saturated heterocyclic group containing one ring and one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen atom is substituted with cyano; cyano, provided that when cyano is a substituent, R 10 and R 11 wherein the 4-8 membered saturated heterocyclic group which they form together with the nitrogen to which they are attached contains a second nitrogen ring atom, and the cyano is connected to the 4-8 membered saturated heterocyclic group at the second ring nitrogen. The compound of any one of embodiments 1-62, 64, and 66-85, substituted with one substituent selected from the group consisting of:

[0195] Embodiment 105.R 10 and R 11 The compound of any one of embodiments 1-62, 64, 66-85, and 104, wherein the 4-8 membered saturated heterocyclic group that they form together with the nitrogen to which they are attached is a 4-7 membered saturated heterocyclic group.

[0196] Embodiment 106.R 10 and R 11 The compound of any one of embodiments 1-62, 64, 66-85, and 104, wherein the 4-8 membered saturated heterocyclic group that they form together with the nitrogen to which they are attached contains a single nitrogen ring atom.

[0197] Embodiment 107.R 10 and R 11 and 66-85, and 104, wherein the 4-8 membered saturated heterocyclic group formed by combining with the nitrogen to which they are attached contains two nitrogen ring atoms.

[0198] Embodiment 108.R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 8-membered saturated heterocyclic group, TIFF2024540410000022.tif23128; -(CH2) x -N(R 14 )-CN and a 4- to 6-membered saturated heterocyclic group containing one ring and one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen atom is substituted with cyano; cyano, provided that when cyano is a substituent, R 10 and R 11 wherein the 4-8 membered saturated heterocyclic group which they form together with the nitrogen to which they are attached contains a second nitrogen ring atom, and the cyano is connected to the 4-8 membered saturated heterocyclic group at the second ring nitrogen. The compound of any one of embodiments 1-62, 64, 66-85, and 104, substituted with one substituent selected from the group consisting of:

[0199] Embodiment 109.R 10 and R 11 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group -(CH2) x -N(R 14 )—CN.

[0200] Embodiment 110.R 14 is hydrogen or methyl.

[0201] Embodiment 111.-(CH2) x -N(R 14 110. The compound of embodiment 109, wherein the —CN group is selected from the group consisting of —CH 2 NHCN, —CH 2 N(CH 3 )CN, —NHCN, and —N(CH 3 )CN.

[0202] Embodiment 112.R 10 and R 11 are substituted with a 4-6 membered saturated heterocyclic group containing one ring and one nitrogen as the only heteroatom in the ring, and the nitrogen is substituted with cyano.

[0203] Embodiment 113.R 10 and R 11 together with the nitrogen to which they are attached form a 4- to 8-membered saturated heterocyclic group, The compound of any one of embodiments 1 to 62, 64, 66 to 85, and 104 to 108, wherein the compound is substituted with TIFF2024540410000023.tif22128.

[0204] Embodiment 114.R 10 and R 11The compound of any one of embodiments 1-62, 64, 66-85, 104, 105, 107, and 108, wherein the 4-8 membered saturated heterocyclic group that they form together with the nitrogen to which they are attached is substituted with cyano.

[0205] Embodiment 115.R 2 R 2c 61. The compound of any one of embodiments 1-60, wherein

[0206] Embodiment 116.R 2c Ga-NR 15 R 16 and R 15 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy, optionally substituted with one example of CN; and R 16 -(C1-C4 alkylene)-N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 and -(CH2) y -R 21 The compound of any one of embodiments 1-63, 66-84, and 86-115, selected from the group consisting of:

[0207] Embodiment 117.R 2c Ga-NR 15 R 16 and R 15 is H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; and R 16 -(C1-C4 alkylene)-N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 and -(CH2) y -R 21 The compound of any one of embodiments 1-63, 66-84, and 86-115, selected from the group consisting of:

[0208] Embodiment 118.R 15 The compound of any one of embodiments 1-63, 66-84, and 86-117, wherein is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy.

[0209] Embodiment 119.R 15 The compound of any one of embodiments 1-63, 66-84, and 86-117, wherein is selected from the group consisting of C1-C4 alkyl and C1-C4 alkoxy.

[0210] Embodiment 120.R 15 The compound of any one of embodiments 1-63, 66-84, and 86-117, wherein is selected from the group consisting of H, methyl, ethyl, -CH2-cyclopropyl, -CH2CH2CN, -CH2CHF2, and -CH2CH2OCH3.

[0211] Embodiment 121.R 15 The compound of any one of embodiments 1-63, 66-84, and 86-117, wherein is selected from the group consisting of methyl, ethyl, —CH 2 CHF 2 , and —CH 2 CH 2 OCH 3 .

[0212] Embodiment 122.R 15 The compound of any one of embodiments 1-63, 66-84, and 86-117, wherein is selected from the group consisting of methyl, ethyl, and —CH 2 CH 2 OCH 3 .

[0213] Embodiment 123.R 15 The compound of any one of embodiments 1-63, 66-84, and 86-117, wherein is methyl or ethyl.

[0214] Embodiment 124.R 15 The compound of any one of embodiments 1-63, 66-84, and 86-117, wherein is methyl.

[0215] Embodiment 125.R 16 -(C1-C4 alkylene)-N(R17 )C(O)C(R 19 )=C(R 20 )R 18 The compound of any one of embodiments 1-63, 66-84, and 86-124, wherein

[0216] Embodiment 126.R 16 The compound of any one of embodiments 1-63, 66-84, and 86-125, wherein the C1-C4 alkylene is linear.

[0217] Embodiment 127.R 16 The compound of any one of embodiments 1-63, 66-84, and 86-125, wherein the C1-C4 alkylene is branched.

[0218] Embodiment 128.R 16 The compound of any one of embodiments 1-63, 66-84, and 86-125, wherein the C1-C4 alkylene is cyclic.

[0219] Embodiment 129.R 16 C1-C4 alkylene is -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)-, -CH(CH3)CH2-, The compound of any one of embodiments 1-63, 66-84, and 86-125, selected from the group consisting of TIFF2024540410000024.tif10128.

[0220] Embodiment 130.R 16 The compound of any one of embodiments 1-63, 66-84, and 86-125, wherein C1-C4 alkylene is -CH2CH2-.

[0221] Embodiment 131.R 17 The compound of any one of embodiments 1-63, 66-84, and 86-130, wherein is selected from the group consisting of hydrogen and methyl.

[0222] Embodiment 132.R 17The compound of any one of embodiments 1-63, 66-84, and 86-131, wherein is hydrogen.

[0223] Embodiment 133.R 16 But -(CH2) y -R 21 The compound of any one of embodiments 1-63, 66-84, and 86-124, wherein

[0224] Embodiment 134. A compound according to any one of embodiments 1 to 63, 66 to 84, 86 to 124, and 133, wherein y is 0 or 1.

[0225] Embodiment 135. A compound according to any one of embodiments 1 to 63, 66 to 84, 86 to 124, and 133, wherein y is 0.

[0226] Embodiment 136. A compound according to any one of embodiments 1 to 63, 66 to 84, 86 to 124, and 133, wherein y is 1.

[0227] Embodiment 137.R 21 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, wherein the 4-7 membered saturated heterocyclic group comprises one ring.

[0228] Embodiment 138.R 21 The compound according to any one of embodiments 1-63, 66-84, 86-124, and 133-136, wherein the 4-7 membered saturated heterocyclic group contains 4 to 6 ring atoms.

[0229] Embodiment 139.R 21 but, A 4-5 membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the nitrogen ring atom is -C(O)C(R 19 )=C(R 20 )R 18the 4-5 membered saturated monocyclic heterocyclic group is substituted by, which heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, or is further substituted with two halo substituents; A 6-membered saturated monocyclic heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms is -C(O)C(R 19 )=C(R 20 )R 18 the 6-membered saturated monocyclic heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or is further substituted with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) is / are selected from -C(O)C(R 19 )=C(R 20 )R 18 the 7-membered saturated monocyclic heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or is further substituted with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom. The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, selected from:

[0230] Embodiment 140.R 21 but, A 4-5 membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the nitrogen ring atom is -C(O)C(R 19 )=C(R 20 )R 18 the 4-5 membered saturated monocyclic heterocyclic group is substituted by, which heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; A 6-membered saturated monocyclic heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms is -C(O)C(R 19 )=C(R 20 )R 18 the 6-membered saturated heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C cyanoalkyl, C-C haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated monocyclic heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) is / are selected from -C(O)C(R 19 )=C(R 20 )R 18and the heterocyclic group is either unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bound to a heteroatom. The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, selected from:

[0231] Embodiment 141.R 21 but, A 4-5 membered monocyclic saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 the 4-5 membered monocyclic saturated heterocyclic group is substituted by, and the heterocyclic group is either unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, or is further substituted with two halo substituents; A 6-membered monocyclic saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is —C(O)C(R 19 )=C(R 20 )R 18 the 6-membered monocyclic saturated heterocyclic group, which is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or with two halo substituents, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bound to a heteroatom; A seven-membered saturated bicyclic spirocyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the nitrogen ring atom is —C(O)C(R 19 )=C(R 20 )R 18 and the heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, or is further substituted with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom.

[0232] Embodiment 142.R 21 but, A 4-5 membered monocyclic saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 the 4-5 membered monocyclic saturated heterocyclic group is substituted by, wherein the heterocyclic group is either unsubstituted or substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo; A 6-membered monocyclic saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is —C(O)C(R 19 )=C(R 20 )R 18the 6-membered monocyclic saturated heterocyclic group, which is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bound to heteroatoms; A seven-membered saturated bicyclic spirocyclic heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the nitrogen ring atom is —C(O)C(R 19 )=C(R 20 )R 18 the seven-membered saturated bicyclic spirocyclic heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bound to a heteroatom. The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, selected from:

[0233] Embodiment 143.R 21 is a 4-5 membered monocyclic saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, and the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 and wherein the heterocyclic group is unsubstituted or is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, or is further substituted with two halo substituents.

[0234] Embodiment 144.R 21 is a 4-5 membered monocyclic saturated heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, and the nitrogen ring atom of the heterocyclic group is -C(O)C(R 19 )=C(R 20 )R 18 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, wherein the heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0235] Embodiment 145.R 21 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-144, wherein the heterocyclic group is not further substituted.

[0236] Embodiment 146.R 21 is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, or with two halo substituents.

[0237] Embodiment 147.R 21 is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0238] Embodiment 148.R 21is further substituted with one substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and halo.

[0239] Embodiment 149.R 21 is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0240] Embodiment 150.R 21 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-144, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of hydroxy, CN, Me, —CHCN, and F.

[0241] Embodiment 151.R 21 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-144, wherein the heterocyclic group is further substituted with two halo substituents.

[0242] Embodiment 152.R 21 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-144, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of Me and F.

[0243] Embodiment 153.R 21 The heterocyclic group of TIFF2024540410000025.tif48158, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18and wherein the heterocyclic group is unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo, or substituted with two halo.

[0244] Embodiment 154.R 21 The heterocyclic group of TIFF2024540410000026.tif30154, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, wherein the heterocyclic group is unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0245] Embodiment 155.R 21 The heterocyclic group of TIFF2024540410000027.tif17128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, wherein the heterocyclic group is unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0246] Embodiment 156.R 21 The heterocyclic group of TIFF2024540410000028.tif17128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of any one of embodiments 1-63, 66-84, 86-124, and 133-136, wherein the heterocyclic group is unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0247] Embodiment 157.R 21 The compound of any one of embodiments 153-156, wherein the heterocyclic group is not further substituted.

[0248] Embodiment 158.R 21 is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo, or is further substituted with two halo.

[0249] Embodiment 159.R 21 The compound of any one of embodiments 153-156, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0250] Embodiment 160.R 21 The compound of any one of embodiments 153-156, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of C1-C4 alkyl or halo.

[0251] Embodiment 161.R 21The compound of any one of embodiments 153-156, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of hydroxy, CN, Me, —CHCN, and F.

[0252] Embodiment 162.R 21 is further substituted with one substituent selected from the group consisting of Me and F, or is further substituted with two fluoro.

[0253] Embodiment 163.R 21 157. The compound of any one of embodiments 153-156, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of Me and F.

[0254] Embodiment 164.R 21 The heterocyclic group of TIFF2024540410000029.tif178156, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of embodiment 153, substituted with:

[0255] Embodiment 165.R 21 The heterocyclic group of TIFF2024540410000030.tif161154, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 155. The compound of embodiment 153 or 154, substituted with:

[0256] Embodiment 166.R 21 The heterocyclic group of TIFF2024540410000031.tif144153, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18The compound of any one of embodiments 153-155, substituted with:

[0257] Embodiment 167.R 21 The heterocyclic group of TIFF2024540410000032.tif52147, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of embodiment 153, substituted with:

[0258] Embodiment 168.R 21 The heterocyclic group of TIFF2024540410000033.tif16144, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 155. The compound of embodiment 153 or 154, substituted with:

[0259] Embodiment 169.R 21 The heterocyclic group of TIFF2024540410000034.tif15128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound according to any one of embodiments 153-156, substituted with:

[0260] Embodiment 170.R 21 The heterocyclic group of TIFF2024540410000035.tif17128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of embodiment 153, substituted with:

[0261] Embodiment 171.R 21 The heterocyclic group of TIFF2024540410000036.tif16128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound according to any one of embodiments 153-156, substituted with:

[0262] Embodiment 172.R 21 The heterocyclic group of TIFF2024540410000037.tif17128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of embodiment 153, substituted with:

[0263] Embodiment 173.R 21 The heterocyclic group of TIFF2024540410000038.tif15128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R 19 )=C(R 20 )R 18 The compound of any one of embodiments 153-156t, substituted with:

[0264] Embodiment 174.R 21 The heterocyclic group of TIFF2024540410000039.tif13128, wherein the ring nitrogen of the heterocyclic group is —C(O)C(R 19 )=C(R 20 )R 18 The compound according to any one of embodiments 153-156, substituted with:

[0265] Embodiment 175.R 16 but, TIFF2024540410000040.tif96154, wherein the azetidine, pyrrolidine, piperidine, and 5-azaspiro[2.4]heptane groups are unsubstituted or substituted with one or two halos selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0266] Embodiment 176.R 16 but, TIFF2024540410000041.tif95154, wherein the azetidine, pyrrolidine, piperidine, and 5-azaspiro[2.4]heptane groups are unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0267] Embodiment 177.R 16 but, TIFF2024540410000042.tif63147, wherein the azetidine, pyrrolidine, and 5-azaspiro[2.4]heptane groups are unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0268] Embodiment 178. A compound according to any one of embodiments 175 to 177, wherein the azetidine, pyrrolidine, piperidine and 5-azaspiro[2.4]heptane groups are not further substituted.

[0269] Embodiment 179. A compound according to embodiment 177, wherein the azetidine group, the pyrrolidine group and the 5-azaspiro[2.4]heptane group are not further substituted.

[0270] Embodiment 180. A compound according to embodiment 175, wherein the azetidine, pyrrolidine, and 5-azaspiro[2.4]heptane groups are further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo, or with two halo.

[0271] Embodiment 181. A compound according to any one of embodiments 175-177, wherein the azetidine group, the pyrrolidine group, and the 5-azaspiro[2.4]heptane group are further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0272] Embodiment 182. A compound according to embodiment 175, wherein the azetidine, pyrrolidine, and 5-azaspiro[2.4]heptane groups are further substituted with one substituent selected from the group consisting of hydroxy, CN, Me, —CH 2 CN, and F, or with two fluoro.

[0273] Embodiment 183. A compound according to any one of embodiments 175-177, wherein the azetidine group, the pyrrolidine group, and the 5-azaspiro[2.4]heptane group are further substituted with one substituent selected from the group consisting of hydroxy, CN, Me, —CH CN, and F.

[0274] Embodiment 184.R 16 but, TIFF2024540410000043.tif66151TIFF2024540410000044.tif229153TIFF2024540410000045.tif160151.

[0275] Embodiment 185.R 16 but, The compound of any one of embodiments 175-176e, wherein the compound is selected from the group consisting of: TIFF2024540410000046.tif217153TIFF2024540410000047.tif180151.

[0276] Embodiment 186.R 16 but, The compound of any one of embodiments 175-177, selected from the group consisting of: TIFF2024540410000048.tif217153TIFF2024540410000049.tif120151.

[0277] Embodiment 187.R 16 but, TIFF2024540410000050.tif100148.

[0278] Embodiment 188.R 16 but, 177. The compound of embodiment 175 or 176, selected from the group consisting of TIFF2024540410000051.tif65147.

[0279] Embodiment 189.R 16 but, The compound of any one of embodiments 175-177, selected from the group consisting of: TIFF2024540410000052.tif30128.

[0280] Embodiment 190.R 16 but, TIFF2024540410000053.tif32128.

[0281] Embodiment 191.R 16 but, The compound of any one of embodiments 175-177, selected from the group consisting of: TIFF2024540410000054.tif31128.

[0282] Embodiment 192.R 16 but, TIFF2024540410000055.tif32128.

[0283] Embodiment 193.R 16 but, The compound of any one of embodiments 175-177, selected from the group consisting of: TIFF2024540410000056.tif31128.

[0284] Embodiment 194.R 16 but, The compound of any one of embodiments 175 to 177, wherein the compound is TIFF2024540410000057.tif27128.

[0285] Embodiment 195.R 15 and R 16 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said heterocyclic group being -(CH2) q -N(R 17 )C(O)C(R 19 )=C(R 20 )R 18 and, -C(O)C(R 19 )=C(R 20 )R 18 where -C(O)C(R 19 )=C(R 20 )R 18 is a substituent, R 15 and R16 and the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen ring atom, and the -C(O)C(R 19 )=C(R 20 )R18 is attached to the heterocyclic group at the second ring nitrogen, 19 )=C(R 20 )R 18 and The compound of any one of embodiments 1-63, 66-84, and 86-115, substituted with one substituent selected from the group consisting of:

[0286] Embodiment 196.R 15 and R 16 196. Compounds according to embodiment 195, wherein the 4-8 membered saturated heterocyclic groups of the formula: together with the nitrogen to which they are attached comprise one ring.

[0287] Embodiment 197.R 15 and R 16 196. Compounds according to embodiment 195, wherein the 4-8 membered saturated heterocyclic group of the formula, together with the nitrogen to which it is attached, comprises two rings.

[0288] Embodiment 198.R 15 and R 16 together with the nitrogen to which they are attached, 196. The compound of embodiment 195, selected from the group consisting of: TIFF2024540410000058.tif23141.

[0289] Embodiment 199.R 15 and R 16 together with the nitrogen to which they are attached, 196. The compound of embodiment 195, selected from the group consisting of: TIFF2024540410000059.tif23128.

[0290] Embodiment 200.R 15 and R 16 together with the nitrogen to which they are attached form -(CH2) q -N(R 17 )C(O)C(R 19 )=C(R 20 )R 18The compound of any one of embodiments 195-199, substituted with:

[0291] Embodiment 201. The compound of any one of embodiments 1 to 63, 66 to 84, 86 to 115, and 118 to 200, wherein q is 0.

[0292] Embodiment 202.R 17 The compound of any one of embodiments 1-63, 66-84, 86-115, and 118-201, wherein is selected from the group consisting of hydrogen and C1-C4 alkyl.

[0293] Embodiment 203.R 17 The compound of any one of embodiments 1-63, 66-84, 86-115, and 118-201, wherein is selected from the group consisting of hydrogen and methyl.

[0294] Embodiment 204.R 17 The compound of any one of embodiments 1-63, 66-84, 86-115, and 118-201, wherein is hydrogen.

[0295] Embodiment 205.R 15 and R 16 together with the nitrogen to which they are attached form -C(O)C(R 19 )=C(R 20 )R 18 The compound of any one of embodiments 1-63, 66-84, 86-115, and 118-198, substituted with:

[0296] Embodiment 206.R 19 The compound of any one of embodiments 1-63, 66-84, and 86-205, wherein is hydrogen.

[0297] Embodiment 207.R 20 The compound of any one of embodiments 1-63, 66-84, and 86-206, wherein is selected from the group consisting of hydrogen and methyl.

[0298] Embodiment 208.R20 The compound of any one of embodiments 1-63, 66-84, and 86-206, wherein is hydrogen.

[0299] Embodiment 209.R 18 and R 20 But R 18 and R 20 and, together with the carbon to which they are attached, can together form a 4-5 membered carbocyclic or heterocyclic ring containing one heteroatom selected from N, O, and S, which carbocyclic or heterocyclic ring can be optionally substituted with one methyl, halo, hydroxy, methoxy, or carbonyl.

[0300] Embodiment 210.R 18 and R 20 may, together with the carbons to which they are attached, form a cyclobutyl or azetidine ring, and the cyclobutyl and azetidine may be optionally substituted with an example methyl.

[0301] Embodiment 211.R 18 is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(CH2) u -R 34 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, and R 35 The compound of any one of embodiments 1-63, 66-84, and 86-208, selected from the group consisting of:

[0302] Embodiment 212.R 22 and R 23is independently selected from methyl, ethyl, and methoxyethyl.

[0303] Embodiment 213.R 22 and R 23 is independently selected from methyl and ethyl.

[0304] Embodiment 214.R 18 is hydrogen, -COOH, -C(O)O-C1-C4 alkyl, -C(O)-C1-C4 alkyl, -C(O)NR 22 R 23 , -(CH2) z -NR 22 R 23 , -(C1-C2 alkyl)-(C1-C2 alkoxy), -S(O)2-C1-C4 alkyl, and a 5-6 membered heteroaryl group optionally substituted with C1-C4 alkyl; 22 and N 23 The compound of any one of embodiments 1-63, 66-84, and 86-208, wherein is independently selected from methyl and ethyl.

[0305] Embodiment 215.R 18 H, -(CH2) u -R 34 and R 35 The compound of any one of embodiments 1-63, 66-84, and 86-208, selected from the group consisting of:

[0306] Embodiment 216. A compound according to any one of embodiments 1 to 63, 66 to 84, 86 to 208, and 211 to 214, wherein u is 0 or 1.

[0307] Embodiment 217. A compound according to any one of embodiments 1 to 63, 66 to 84, 86 to 208, and 211 to 214, wherein u is 0.

[0308] Embodiment 218. A compound according to any one of embodiments 1 to 63, 66 to 84, 86 to 208 and 211 to 214, wherein u is 1.

[0309] Embodiment 219. The compound of any one of embodiments 1 to 63, 66 to 84, 86 to 208, and 211 to 214, wherein u is 2.

[0310] Embodiment 220.R 18 But, H, -R 34 , -CH2-R 34 and -R 35 The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-214, selected from:

[0311] Embodiment 221.R 18 But -R 34 , -CH2-R 34 and -R 35 The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-214, selected from:

[0312] Embodiment 222.R 34 is a 4-7 membered monocyclic heterocycle containing a nitrogen atom and zero, one, or two additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), and the monocyclic heterocycle is substituted with zero, one, two, three, or four substituents independently selected from halo, hydroxy, C-C alkyl, C-C aminoalkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C hydroxyalkyl, CH—(C-C heterocyclyl), and C-C alkynyl.

[0313] Embodiment 223.R 34is a 4-7 membered monocyclic heterocycle containing a nitrogen atom and zero, one, or two additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), and the monocyclic heterocycle is substituted with zero, one, two, three, or four substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0314] Embodiment 224.R 34 is substituted with zero or one methyl, ethyl, isopropyl, methoxyethyl, hydroxyethyl, or CH2-oxetanyl.

[0315] Embodiment 225.R 34 The compound according to any one of embodiments 1-63, 66-84, 86-208, and 211-223, wherein the monocyclic heterocycle is substituted with zero or one methyl.

[0316] Embodiment 226.R 34 is selected from azetidinyl, pyrrolidinyl, tetrahydrofuranyl, and morpholinyl substituted with zero or one methyl, ethyl, isopropyl, methoxyethyl, hydroxyethyl, or CH2-oxetanyl.

[0317] Embodiment 227.R 34 is selected from azetidinyl, pyrrolidinyl, and morpholinyl substituted with zero or one methyl, ethyl, isopropyl, methoxyethyl, hydroxyethyl, or -CH2-oxetanyl.

[0318] Embodiment 228.R 34 The compound according to any one of embodiments 1-63, 66-84, 86-208, and 211-223, wherein is selected from azetidinyl, pyrrolidinyl, and morpholinyl substituted with zero or one methyl.

[0319] Embodiment 229.R 34 Compounds according to one of embodiments 1-63, 66-84, 86-208, and 211-223, wherein is azetidinyl substituted with zero or one methyl, ethyl, isopropyl, methoxyethyl, hydroxyethyl, or CH2-oxetanyl.

[0320] Embodiment 230.R 34 The compound according to one of embodiments 1-63, 66-84, 86-208, and 211-223, wherein is azetidinyl substituted with zero or one methyl.

[0321] Embodiment 231.R 34 The compound according to any one of embodiments 1-63, 66-84, 86-208, and 211-223, wherein is pyrrolidinyl substituted with zero or one methyl.

[0322] Embodiment 232.R 34 The compound according to any one of embodiments 1-63, 66-84, 86-208, and 211-223, wherein is unsubstituted morpholinyl.

[0323] Embodiment 233.R 34 The compound according to any one of embodiments 1-63, 66-84, 86-208, and 211-223, wherein is morpholinyl substituted with zero or one methyl.

[0324] Embodiment 234.R 34 The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-233, wherein the point of attachment of is a carbon atom.

[0325] Embodiment 235.R 34 but, TIFF2024540410000060.tif110157.

[0326] Embodiment 236.R 34 but, TIFF2024540410000061.tif56159.

[0327] Embodiment 237.R 34 but, TIFF2024540410000062.tif19150.

[0328] Embodiment 238.R 34 but, TIFF2024540410000063.tif19128.

[0329] Embodiment 239.R 34 but, The compound of embodiment 234, which is TIFF2024540410000064.tif12128.

[0330] Embodiment 240.R 34 is a 4-10 membered heterocycle containing a nitrogen atom and zero, one, or two additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), wherein the 4-10 membered heterocycle is substituted with zero, one, two, three, or four substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0331] Embodiment 241.R 34is a 4-10 membered heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms independently selected from oxygen and sulfur (including sulfur dioxide), and is selected from the group consisting of a 4-8 membered monocyclic heterocycle, a 6-10 membered fused bicyclic heterocycle, a 6-10 membered bridged heterocycle, and a 6-10 membered spiro heterocycle, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0332] Embodiment 242.R 34 is a 4-8 membered monocyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0333] Embodiment 243.R 34 is a 6-10 membered fused bicyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0334] Embodiment 244.R 34 is a 6-10 membered bridged heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0335] Embodiment 245.R 34is a 6-10 membered spiroheterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0336] Embodiment 246.R 34However, azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azaadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[4.1.0]heptane Bicyclo[2.2.1]heptane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1]nonane, 3-oxa-8-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.2]octane, 7-oxa-2-azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octane, 9-oxa -3-Azabicyclo[3.3.1]nonane, 6-oxa-8-azabicyclo[3.2.2]nonane, 2-oxa-6-azaspiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide Cide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane, and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0337] Embodiment 247.R 34 is pyrrolidine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0338] Embodiment 248.R 34 is morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0339] Embodiment 249.R 34 The compound of any one of embodiments 240-248, wherein the point of attachment of is at a nitrogen atom of the heterocycle.

[0340] Embodiment 250.R 34 but, TIFF2024540410000065.tif157151, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0341] Embodiment 251.R 34 but, TIFF2024540410000066.tif40149, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0342] Embodiment 252.R 34 but, TIFF2024540410000067.tif40149, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0343] Embodiment 253.R 34 but, TIFF2024540410000068.tif40149, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0344] Embodiment 254.R 34 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; The compound of embodiment 250, which is TIFF2024540410000069.tif13128.

[0345] Embodiment 255.R 34 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; The compound of embodiment 250, which is TIFF2024540410000070.tif16128.

[0346] Embodiment 256.R 34 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; The compound of embodiment 250, which is TIFF2024540410000071.tif17128.

[0347] Embodiment 257.R 34 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; The compound of embodiment 250, which is TIFF2024540410000072.tif16128.

[0348] Embodiment 258.R 34 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; The compound of embodiment 250, which is TIFF2024540410000073.tif17128.

[0349] Embodiment 259.R34 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, —CHOCH, —CHCHOCH, —CHCHOCHCHOCH, —CHN(CH), and —CHCHN(CH).

[0350] Embodiment 260.R 34 is substituted with 0, 1, or 2 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, CHOCH, CHCHOCH, CHCHOCHCHOCH, CHN(CH), and CHCHN(CH).

[0351] Embodiment 261.R 34 The compound according to any one of embodiments 240-258, wherein the 4-10 membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from fluoro and methyl.

[0352] Embodiment 262.R 34 The compound according to any one of embodiments 240 to 258, wherein the 4-10 membered heterocycle is unsubstituted.

[0353] Embodiment 263.R 34 but, TIFF2024540410000074.tif70155TIFF2024540410000075.tif219156TIFF2024540410000076.tif55155.

[0354] Embodiment 264.R 34 but, The compound of any one of embodiments 240-250, selected from the group consisting of: TIFF2024540410000077.tif131151TIFF2024540410000078.tif213153.

[0355] Embodiment 265.R 34 But non-substitution The compound of any one of embodiments 240-250, wherein the compound is TIFF2024540410000079.tif69155.

[0356] Embodiment 266.R 34 But non-substitution The compound of any one of embodiments 240 to 250, wherein the compound is TIFF2024540410000080.tif40150.

[0357] Embodiment 267.R 34 But non-substitution The compound of any one of embodiments 240 to 250, wherein the compound is TIFF2024540410000081.tif16128.

[0358] Embodiment 268.R 34 But non-substitution The compound of any one of embodiments 240 to 250, which is TIFF2024540410000082.tif17128.

[0359] Embodiment 269.R 34 But non-substitution The compound of any one of embodiments 240 to 250, wherein the compound is TIFF2024540410000083.tif16128.

[0360] Embodiment 270.R 34 But non-substitution The compound of any one of embodiments 240 to 250, wherein the compound is TIFF2024540410000084.tif17128.

[0361] Embodiment 271. A compound according to any one of embodiments 240 to 270, wherein u is 1.

[0362] Embodiment 272.R 35 is a 5- to 6-membered heteroaryl group containing at least one nitrogen atom, and the heteroaryl is halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, substituted with 0, 1, 2, or 3 substituents independently selected from:

[0363] Embodiment 273.R 35 is a 5- to 6-membered heteroaryl group containing at least one nitrogen atom, and the heteroaryl is halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, substituted with 0, 1, or 2 substituents independently selected from:

[0364] Embodiment 274.R 35is selected from the group consisting of pyrimidinyl, pyrazinyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, substituted with 0, 1, 2, or 3 substituents independently selected from:

[0365] Embodiment 275.R 35 is selected from the group consisting of pyrimidinyl, pyrazinyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, each substituted with 0, 1, or 2 substituents independently selected from:

[0366] Embodiment 276.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein the aryl group is selected from the group consisting of pyrimidinyl, oxazolyl, 1,2,4-oxadiazolyl, imidazolyl, and 1,2,4-thiadiazolyl, each substituted with 0, 1, 2, or 3 substituents independently selected from:

[0367] Embodiment 277.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein the aryl group is selected from the group consisting of pyrimidinyl, oxazolyl, 1,2,4-oxadiazolyl, imidazolyl, and 1,2,4-thiadiazolyl, each substituted with 0, 1, or 2 substituents independently selected from:

[0368] Embodiment 278.R 35 but, TIFF2024540410000085.tif28157, each of which is substituted with 0, 1, 2, or 3 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl optionally substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl, and C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl.

[0369] Embodiment 279.R 35 but, TIFF2024540410000086.tif28157, each of which is substituted with zero, one, or two substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl, and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl.

[0370] Embodiment 280.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. each substituted with 0, 1, or 2 substituents independently selected from The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000087.tif14128.

[0371] Embodiment 281.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. each substituted with 0, 1, or 2 substituents independently selected from The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000088.tif14128.

[0372] Embodiment 282.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein R is a 6-membered heteroaryl group substituted with 0, 1, 2, or 3 substituents independently selected from:

[0373] Embodiment 283.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein R is a 6-membered heteroaryl group substituted with 0, 1, or 2 substituents independently selected from:

[0374] Embodiment 284.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, which is pyrimidinyl or pyridazinyl substituted with 0, 1, 2, or 3 substituents independently selected from:

[0375] Embodiment 285.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, which is pyrimidinyl or pyridazinyl substituted with 0, 1, or 2 substituents independently selected from:

[0376] Embodiment 286.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. and is substituted with 0, 1, 2, or 3 substituents independently selected from The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000089.tif14128.

[0377] Embodiment 287.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. and is substituted with 0, 1, or 2 substituents independently selected from The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000090.tif14128.

[0378] Embodiment 288.R 35 but, A 5-membered heteroaryl group containing at least one nitrogen atom, wherein the heteroaryl is halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, substituted with 0, 1, or 2 substituents independently selected from:

[0379] Embodiment 289.R 35 is a 5-membered heteroaryl group containing at least one nitrogen atom, said heteroaryl being halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, substituted with 0, 1, or 2 substituents independently selected from:

[0380] Embodiment 290.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein the compound is selected from the group consisting of oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each substituted with 0, 1, or 2 substituents independently selected from:

[0381] Embodiment 291.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein the compound is selected from the group consisting of oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each substituted with 0, 1, or 2 substituents independently selected from:

[0382] Embodiment 292.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. each substituted with 0, 1, or 2 substituents independently selected from The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000091.tif26128.

[0383] Embodiment 293.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. each substituted with 0, 1, or 2 substituents independently selected from The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000092.tif26128.

[0384] Embodiment 294.R 35 The heteroaryl group of C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-293, substituted with zero or one substituent selected from:

[0385] Embodiment 295.R 35is substituted with zero or one substituent selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl.

[0386] Embodiment 296.R 35 is substituted with zero or one substituent selected from fluoro, methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, —C(OH)(CH), oxetan-3-yl, 3-methyloxetan-3-yl, cyclobutyl, 1-fluorooxycyclobutyl, 1-hydroxycyclobutyl, cyclopropyl, 1-methylcyclopropyl, and 2-fluorocyclopropyl.

[0387] Embodiment 297.R 35 is substituted with zero or one substituent selected from methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, —C(OH)(CH), oxetan-3-yl, 3-methyloxetan-3-yl, cyclobutyl, cyclopropyl, 1-methylcyclopropyl, and 2-fluorocyclopropyl.

[0388] Embodiment 298.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000093.tif137159.

[0389] Embodiment 299.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000094.tif123155.

[0390] Embodiment 300.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000095.tif123155.

[0391] Embodiment 301.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000096.tif123156.

[0392] Embodiment 302.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000097.tif99149.

[0393] Embodiment 303.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000098.tif99149.

[0394] Embodiment 304.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, which is 1,2,4-oxadiazolyl substituted with one substituent selected from:

[0395] Embodiment 305.R 35 is 1,2,4-oxadiazolyl substituted with one substituent selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl.

[0396] Embodiment 306.R 35 but, halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo, hydroxy, and methyl. is substituted with one substituent selected from The compound of any one of embodiments 1 to 63, 66 to 84, 86 to 208, and 211 to 271, wherein the compound is TIFF2024540410000099.tif10128.

[0397] Embodiment 307.R 35 is substituted with one substituent selected from halo, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; C3-C6 heterocyclyl optionally substituted with one or two substituents independently selected from halo and methyl; and C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from halo and methyl. The compound of any one of embodiments 1 to 63, 66 to 84, 86 to 208, and 211 to 271, wherein the compound is TIFF2024540410000100.tif10128.

[0398] Embodiment 308. A compound according to embodiment 304 or 306, wherein oxadiazolyl is substituted with one substituent selected from methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, —C(OH)(CH 3 ) 2 , oxetan-3-yl, 3-methyloxetan-3-yl, cyclobutyl, 1-fluorocyclobutyl, 1-hydroxy-cyclobutyl, cyclopropyl, 1-methylcyclopropyl, and 2-fluorocyclopropyl.

[0399] Embodiment 309. A compound according to any one of embodiments 304 to 307, wherein oxadiazolyl is substituted with one substituent selected from methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, —C(OH)(CH3)2, oxetan-3-yl, 3-methyloxetan-3-yl, cyclobutyl, cyclopropyl, 1-methylcyclopropyl, and 2-fluorocyclopropyl.

[0400] Embodiment 310.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000101.tif79141.

[0401] Embodiment 311.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, selected from the group consisting of TIFF2024540410000102.tif78141.

[0402] Embodiment 312.R 35 is pyrimidinyl or pyridazinyl substituted with 1 or 2 substituents independently selected from methyl and fluoro.

[0403] Embodiment 313.R 35 The compound according to any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein is pyrimidinyl or pyridazinyl substituted with zero or one methyl.

[0404] Embodiment 314.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271 selected from TIFF2024540410000103.tif22154.

[0405] Embodiment 315.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271 selected from TIFF2024540410000104.tif19128.

[0406] Embodiment 316.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271 selected from TIFF2024540410000105.tif22135.

[0407] Embodiment 317.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271 selected from TIFF2024540410000106.tif19128.

[0408] Embodiment 318.R 35 but, The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271 selected from TIFF2024540410000107.tif17128.

[0409] Embodiment 319.R 35 The compound according to any one of embodiments 1-63, 66-84, 86-208, and 211-318, wherein the point of attachment of is on a carbon atom.

[0410] Embodiment 320.R 18 Ga-(CH2) u R 34 The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein

[0411] Embodiment 321.R 18 -CH2-R 34 The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-271, wherein

[0412] Embodiment 322.R 18 R 34 The compound of any one of embodiments 1-63, 66-84, 86-208, and 211-270, wherein

[0413] Embodiment 323.R 18 R 35The compound of any one of embodiments 1-63, 66-84, 86-208, and 272-318, wherein

[0414] Embodiment 324.R 18 The compound of any one of embodiments 1-63, 66-84, and 86-208, wherein

[0415] Embodiment 325.R 18 The compound of any one of embodiments 1-63, 66-84, and 86-208, wherein is not H.

[0416] Embodiment 326.R 18 is hydrogen, -COOH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)N(CH3)2, -C(O)-cyclopropyl, -CH2OCH3, -CH2N(CH3)2, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2-cyclopropyl, The compound of any one of embodiments 1-63, 66-84, and 86-208, selected from the group consisting of TIFF2024540410000108.tif227157.

[0417] Embodiment 327.R 18 is hydrogen, -COOH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)N(CH3)2, -C(O)-cyclopropyl, -CH2OCH3, -CH2N(CH3)2, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2-cyclopropyl, The compound of any one of embodiments 1-63, 66-84, and 86-208, selected from the group consisting of TIFF2024540410000109.tif115155.

[0418] Embodiment 328.R 18is hydrogen, -COOH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH(CH3)2, -C(O)N(CH3)2, -C(O)-cyclopropyl, -CH2OCH3, -CH2N(CH3)2, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2-cyclopropyl, The compound of any one of embodiments 1-63, 66-84, and 86-208, selected from the group consisting of: TIFF2024540410000110.tif120156.

[0419] Embodiment 329.R 18 is selected from the group consisting of hydrogen, —COOH, —C(O)OCH3, —C(O)OCH2CH3, —C(O)OCH(CH3)2, —C(O)N(CH3)2, —C(O)-cyclopropyl, —CHOCH3, —CH2N(CH3)2, —S(O)2CH3, —S(O)2CH2CH3, —S(O)2-cyclopropyl, oxazolyl, and 4-methyloxazolyl.

[0420] Embodiment 330.R 18 The compound of any one of embodiments 1-63, 66-84, and 86-208, wherein is not hydrogen.

[0421] Embodiment 331.R 18 The compound of any one of embodiments 1-63, 66-84, and 86-208, wherein is —C(O)OCH 3 .

[0422] Embodiment 332. The compound -C(O)C(R 19 )=C(R 20 )R 18 The compound according to any one of embodiments 1-63, 66-84, and 86-331, wherein the double bond in the moiety is in the E configuration.

[0423] Embodiment 333.R 2 R 2d 61. The compound of any one of embodiments 1-60, wherein

[0424] Embodiment 334.R 2d Ga-NR 24 R 25 The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-333, wherein

[0425] Embodiment 335.R 24 The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-334, wherein is methyl or ethyl.

[0426] Embodiment 336.R 24 The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-334, wherein is methyl.

[0427] Embodiment 337.R 25 -(C1-C4 alkylene)-C(O)CH=CHR 26 The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-336, wherein

[0428] Embodiment 338.R 25 C1-C4 alkylene is -CH2-, -CH2CH2-, -(CH2)3-, -(CH2)4-, -CH2CH(CH3)-, and The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-337, selected from the group consisting of TIFF2024540410000111.tif11128.

[0429] Embodiment 339.R 24 and R 25 together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, and the 4-8 membered saturated heterocyclic group is -(C0-C2 alkylene)-C(O)CH=CHR 26 The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-334, wherein the 4-8 membered saturated heterocyclic group is optionally further substituted with C1-C4 alkyl.

[0430] Embodiment 340.R 24 and R 25 together with the nitrogen to which they are attached, The compound of any one of embodiments 1-60, 66-84, 86-114, 116-334, and 339, selected from the group consisting of TIFF2024540410000112.tif43144.

[0431] Embodiment 341.R 24 and R 25 together with the nitrogen to which they are attached, The compound of any one of embodiments 1-60, 66-84, 86-114, 116-334, and 339, selected from the group consisting of TIFF2024540410000113.tif23129.

[0432] Embodiment 342.R 24 and R 25 and n is 0 or 1. The compound of any one of embodiments 1-60, 66-84, 86-114, 116-334, and 339-341, wherein the 4-8 membered saturated heterocyclic groups, together with the nitrogen to which they are attached, are not substituted with C1-C4 alkyl.

[0433] Embodiment 343.R 24 and R 25 The compound according to any one of embodiments 1-60, 66-84, 86-114, 116-334, and 339-341, wherein the 4-8 membered saturated heterocyclic groups, together with the nitrogen to which they are attached, are substituted with methyl.

[0434] Embodiment 344. -(C0-C2 alkylene)-C(O)CH=CHR 26 The compound of any one of embodiments 1-60, 66-84, 86-114, 116-334, and 339-343, wherein the C0-C2 alkylene group of the group is selected from a bond and methylene.

[0435] Embodiment 345. —(C0-C2 alkylene)—C(O)CH═CHR 26 The compound of any one of embodiments 1-60, 66-84, 86-114, 116-334, and 339-343, wherein the C0-C2 alkylene group of the group is a bond.

[0436] Embodiment 346.R 2d -C(O)N(R 27 )-(C1-C4 alkylene)-C(O)CH=CHR 26 The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-333, wherein

[0437] Embodiment 347.R 27 The compound of any one of embodiments 1-60, 66-84, 86-114, 116-333, and 335-346, wherein is hydrogen.

[0438] Embodiment 348.-C(O)N(R 27 )-(C1-C4 alkylene)-C(O)CH=CHR 26 The compound according to any one of embodiments 1-60, 66-84, 86-114, 116-333, and 335-347, wherein the group C1-C4 alkylene is methylene.

[0439] Embodiment 349.R 2d -O-(C1-C4 alkylene)-C(O)CH=CHR 26 The compound of any one of embodiments 1-60, 66-84, 86-114, and 116-333, wherein

[0440] Embodiment 350. —O—(C1-C4 alkylene)-C(O)CH═CHR 26 The compound according to any one of embodiments 1-60, 66-84, 86-114, 116-333, 335-345, and 347-349, wherein the group C1-C4 alkylene is methylene.

[0441] Embodiment 351.R 26The compound of any one of embodiments 1-60, 66-84, 86-114, 116-333, 335-345, and 347-350, wherein is hydrogen or methyl.

[0442] Embodiment 352.R 26 The compound of any one of embodiments 1-60, 66-84, 86-114, 116-333, 335-345, and 347-350, wherein is hydrogen.

[0443] Embodiment 353.R 26 The compound of any one of embodiments 1-60, 66-84, 86-114, 116-333, 335-345, and 347-350, wherein is methyl.

[0444] Embodiment 354.R 2 R 2e 61. The compound of any one of embodiments 1-60, wherein

[0445] Embodiment 355.R 28 is selected from the group consisting of C1-C4 alkyl and C1-C4 alkoxy.

[0446] Embodiment 356.R 28 is selected from the group consisting of methyl, ethyl, and —CH 2 CH 2 OCH 3 .

[0447] Embodiment 357.R 28 The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, and 334-354, wherein is methyl or ethyl.

[0448] Embodiment 358.R 28 The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, and 334-354, wherein is methyl.

[0449] Embodiment 359. A compound according to any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332, and 334 to 358, wherein t is 0 or 1.

[0450] Embodiment 360. The compound of any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332, and 334 to 358, wherein t is 1.

[0451] Embodiment 361. The compound of any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332, and 334 to 358, wherein t is 0.

[0452] Embodiment 362.R 30 is a 4-5 membered saturated monocyclic heterocyclic group containing one nitrogen atom as the only heteroatom in the ring, and the nitrogen ring atom of the heterocyclic group is -C(O)C≡CR 31 The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, and 334-361, wherein the heterocyclic group is unsubstituted or further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0453] Embodiment 363.R 30 The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, and 334-362, wherein the heterocyclic group is not further substituted.

[0454] Embodiment 364.R 30is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0455] Embodiment 365.R 30 The heterocyclic group of TIFF2024540410000114.tif15128, wherein the ring nitrogen of the heterocyclic group is selected from the group consisting of -C(O)C≡CR 31 and the heterocyclic group is unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0456] Embodiment 366.R 30 366. The compound according to embodiment 365, wherein the heterocyclic group is not further substituted.

[0457] Embodiment 367.R 30 Compounds according to embodiment 365, wherein the heterocyclic group is further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0458] Embodiment 368.R 29 but, TIFF2024540410000115.tif33128, wherein the azetidine and pyrrolidine groups are unsubstituted or substituted with one substituent selected from hydroxy, CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 haloalkoxy, and halo.

[0459] Embodiment 369. A compound according to embodiment 368, wherein the azetidine group and the pyrrolidine group are not further substituted.

[0460] Embodiment 370. A compound according to embodiment 368, wherein the azetidine group and the pyrrolidine group are further substituted with one substituent selected from the group consisting of hydroxy, CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and halo.

[0461] Embodiment 371. A compound according to any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332, and 334 to 370, wherein v is 1.

[0462] Embodiment 372. The compound of any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332, and 334 to 370, wherein v is 2.

[0463] Embodiment 373. A compound according to any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332 and 334 to 372, wherein p is 0 or 1.

[0464] Embodiment 374. The compound of any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332, and 334 to 372, wherein p is 0.

[0465] Embodiment 375. The compound of any one of embodiments 1 to 61, 63, 66 to 84, 86 to 114, 116 to 332, and 334 to 372, wherein p is 1.

[0466] Embodiment 376.R 31 But -CH2-NR 32 R 33 and -(CH2) p -R 36 The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, 334-370, and 373-375, selected from the group consisting of:

[0467] Embodiment 377.R 32 and R 33 is independently selected from methyl and ethyl.

[0468] Embodiment 378.R 31 But -(CH2) p -R 36 The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, and 334-370, and 373-375, wherein

[0469] Embodiment 379.R 31 But -CH2-NR 32 R 33 378. The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, 334-370, and 377, wherein

[0470] Embodiment 380.R 36is a 4-7 membered monocyclic heterocycle containing a nitrogen atom and optionally an oxygen atom as the only heteroatoms, and the monocyclic heterocycle is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0471] Embodiment 381.R 36 is a 4-7 membered monocyclic heterocycle containing a nitrogen atom as the only heteroatom, and the monocyclic heterocycle is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0472] Embodiment 382.R 36 382. Compounds according to any one of embodiments 380-381, wherein the monocyclic heterocycle of Formula (I) is substituted with 0, 1, or 2 substituents independently selected from methyl and hydroxy.

[0473] Embodiment 383.R 36 382. The compound according to embodiment 380 or 381, wherein the monocyclic heterocycle of is substituted with 0, 1 or 2 methyl.

[0474] Embodiment 384.R 36 382. Compounds according to embodiment 380 or 381, wherein the monocyclic heterocycle of Formula (I) is substituted with 0 or 1 substituents independently selected from methyl and hydroxy.

[0475] Embodiment 385.R 36382. The compound according to embodiment 380 or 381, wherein the monocyclic heterocycle is substituted with zero or one methyl.

[0476] Embodiment 386.R 36 385. Compounds according to embodiment 384, wherein is selected from azetidinyl, pyrrolidinyl, and morpholinyl substituted with 0, 1, or 2 substituents independently selected from methyl and hydroxy.

[0477] Embodiment 387.R 36 The compound according to embodiment 385, wherein is selected from azetidinyl, pyrrolidinyl, and morpholinyl substituted with zero or one methyl.

[0478] Embodiment 388.R 36 385. The compound according to embodiment 384, wherein is azetidinyl substituted with 0, 1, or 2 substituents independently selected from methyl and hydroxy.

[0479] Embodiment 389.R 36 The compound according to embodiment 385, wherein is azetidinyl substituted with zero or one methyl.

[0480] Embodiment 390.R 36 385. The compound according to embodiment 384, wherein is pyrrolidinyl substituted with 0, 1, or 2 substituents independently selected from methyl and hydroxy.

[0481] Embodiment 391.R 36 The compound according to embodiment 385, wherein is pyrrolidinyl substituted with one or two methyl.

[0482] Embodiment 392.R 36 The compound according to embodiment 385, wherein is pyrrolidinyl substituted with zero or one methyl.

[0483] Embodiment 393.R 36The compound according to embodiment 385, wherein is morpholinyl substituted with zero or one methyl.

[0484] Embodiment 394.R 36 The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, 334-378, and 380-393, wherein the point of attachment of is a carbon atom.

[0485] Embodiment 395.R 36 but, TIFF2024540410000116.tif79157.

[0486] Embodiment 396.R 36 but, TIFF2024540410000117.tif75154.

[0487] Embodiment 397.R 36 but, TIFF2024540410000118.tif19128.

[0488] Embodiment 398.R 36 but, TIFF2024540410000119.tif38129.

[0489] Embodiment 399.R 36 but, TIFF2024540410000120.tif20163.

[0490] Embodiment 400. The compound of any one of embodiments 380 to 399, wherein p is 0.

[0491] Embodiment 401.R 36is a 4-10 membered heterocycle containing a nitrogen atom and zero, one, or two additional heteroatoms selected from oxygen and sulfur (including sulfur dioxide), wherein the 4-10 membered heterocycle is substituted with zero, one, two, three, or four substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0492] Embodiment 402.R 36 is a 4-10 membered heterocycle containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from oxygen and sulfur (including sulfur dioxide), and is selected from the group consisting of a 4-8 membered monocyclic heterocycle, a 6-10 membered fused bicyclic heterocycle, a 6-10 membered bridged heterocycle, and a 6-10 membered spiro heterocycle, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0493] Embodiment 403.R 36 is a 4-8 membered monocyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0494] Embodiment 404.R 36is a 6-10 membered fused bicyclic heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0495] Embodiment 405.R 36 is a 6-10 membered bridged heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0496] Embodiment 406.R 36 is a 6-10 membered spiroheterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0497] Embodiment 407.R 36However, azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azaadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[4.1.0]heptane Bicyclo[2.2.1]heptane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1]nonane, 3-oxa-8-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.2]octane, 7-oxa-2-azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octane, 9-oxa -3-Azabicyclo[3.3.1]nonane, 6-oxa-8-azabicyclo[3.2.2]nonane, 2-oxa-6-azaspiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide Cide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane 3,3-dioxide, 2-thia-5-azabicyclo[2.2.1]heptane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.4]octane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2-thia-6-azaspiro[3.3]heptane, and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0498] Embodiment 408.R 36 is morpholine substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0499] Embodiment 409.R 36 The compound of any one of embodiments 401-408, wherein the point of attachment of is at a nitrogen atom of the heterocycle.

[0500] Embodiment 410.R 36 but, TIFF2024540410000121.tif158152, each substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0501] Embodiment 411.R 36 but, TIFF2024540410000122.tif18128, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl.

[0502] Embodiment 412.R 36 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; The compound of embodiment 410, which is TIFF2024540410000123.tif13128.

[0503] Embodiment 413.R 36 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C2-C3 alkynyl; The compound of embodiment 410, which is TIFF2024540410000124.tif17128.

[0504] Embodiment 414.R 36 is substituted with 0, 1, 2, 3, or 4 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, —CHOCH, —CHCHOCH, —CHCHOCHCHOCH, —CHN(CH), —CHCHN(CH).

[0505] Embodiment 415.R 36is substituted with 0, 1, or 2 substituents independently selected from fluoro, methyl, ethyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, —CHOCH, —CHCHOCH, —CHCHOCHCHOCH, —CHN(CH), —CHCHN(CH).

[0506] Embodiment 416.R 36 The compound according to any one of embodiments 401 to 413, wherein the 4-10 membered heterocycle is substituted with 0, 1, or 2 substituents independently selected from fluoro and methyl.

[0507] Embodiment 417.R 36 The compound according to any one of embodiments 401 to 413, wherein the 4-10 membered heterocycle is substituted with 0, 1, or 2 fluoro.

[0508] Embodiment 418.R 36 The compound according to any one of embodiments 401 to 413, wherein the 4-10 membered heterocycle is unsubstituted.

[0509] Embodiment 419.R 36 but, The compound of any one of embodiments 401 to 410, selected from the group consisting of: TIFF2024540410000125.tif206156TIFF2024540410000126.tif138153.

[0510] Embodiment 420.R 36 but, TIFF2024540410000127.tif68151 TIFF2024540410000128.tif215153 TIFF2024540410000129.tif58144.

[0511] Embodiment 421.R 36 But non-substitution The compound of any one of embodiments 401 to 410, wherein the compound is TIFF2024540410000130.tif69151.

[0512] Embodiment 422.R 36 But non-substitution The compound of any one of embodiments 401 to 410, wherein the compound is TIFF2024540410000131.tif69155.

[0513] Embodiment 423.R 36 but, The compound of any one of embodiments 401-410, selected from the group consisting of: TIFF2024540410000132.tif20128.

[0514] Embodiment 424.R 36 But non-substitution TIFF2024540410000133.tif17128 or unsubstituted The compound of any one of embodiments 401 to 410, wherein the compound is TIFF2024540410000134.tif13128.

[0515] Embodiment 425.R 36 But non-substitution The compound of any one of embodiments 401 to 410, wherein the compound is TIFF2024540410000135.tif17128.

[0516] Embodiment 426. A compound according to any one of embodiments 401 to 425, wherein p is 1.

[0517] Embodiment 427.R 31 but, The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, and 334-370, selected from the group consisting of: TIFF2024540410000136.tif93153.

[0518] Embodiment 428.R 31 but, The compound of any one of embodiments 1-61, 63, 66-84, 86-114, 116-332, and 334-370, selected from the group consisting of TIFF2024540410000137.tif19147.

[0519] Embodiment 429. TIFF2024540410000138.tif83155TIFF2024540410000139.tif210155TIFF2024540410000140.tif198155TIFF20245404 10000141.tif203155TIFF2024540410000142.tif218156TIFF2024540410000143.tif228156TIFF2024540410000144.ti f208157TIFF2024540410000145.tif212156TIFF2024540410000146.tif195157TIFF2024540410000147.tif194154TIFF 2024540410000148.tif228157TIFF2024540410000149.tif194157TIFF2024540410000150.tif190150TIFF20245404100 00151.tif232154TIFF2024540410000152.tif197157TIFF2024540410000153.tif198157TIFF2024540410000154.tif18 3153TIFF2024540410000155.tif218154TIFF2024540410000156.tif200154TIFF2024540410000157.tif226154TIFF202 4540410000158.tif201154TIFF2024540410000159.tif227154TIFF2024540410000160.tif225154TIFF2024540410000161.tif198154TIFF2024540410000162.tif157149 and all salts and isotopic substitutions thereof.

[0520] Embodiment 430. TIFF2024540410000163.tif38128TIFF2024540410000164.tif209155TIFF2024540410000165.tif188155TIFF20245404100 00166.tif197154TIFF2024540410000167.tif222155TIFF2024540410000168.tif192156TIFF2024540410000169.tif211152 TIFF2024540410000170.tif207156TIFF2024540410000171.tif197150TIFF2024540410000172.tif226156TIFF20245404100 00173.tif179155TIFF2024540410000174.tif197157TIFF2024540410000175.tif191156TIFF2024540410000176.tif192157 TIFF2024540410000177.tif189157TIFF2024540410000178.tif194149TIFF2024540410000179.tif190153TIFF2024540410 000180.tif222153TIFF2024540410000181.tif182154TIFF2024540410000182.tif232154TIFF2024540410000183.tif19615 4TIFF2024540410000184.tif225155TIFF2024540410000185.tif187154TIFF2024540410000186.tif221155TIFF2024540410000187.tif190154TIFF2024540410000188.tif74149 and all salts and isotopic substitutions thereof.

[0521] Embodiment 431. 20. The compound of any one of embodiments 1, 11, and 18, selected from the group consisting of TIFF2024540410000189.tif163157 and all salts and isotopic substitutions thereof.

[0522] Embodiment 432. 20. The compound of any one of embodiments 1, 11, and 18, selected from the group consisting of TIFF2024540410000190.tif224154 and all salts and isotopic substitutions thereof.

[0523] Embodiment 433. TIFF2024540410000191.tif96157TIFF2024540410000192.tif149155TIFF2024540410000193.tif194157TIFF2024540410000194.tif223156TIFF2024540410000195.tif223155TIFF2024540410000196.tif227155TIFF2024540410000197.tif115156 and all salts and isotopic substitutions thereof.

[0524] Embodiment 434. 20. The compound of any one of embodiments 1, 11, and 18, selected from the group consisting of TIFF2024540410000198.tif83153 and all salts and isotopic substitutions thereof.

[0525] Embodiment 435. 20. The compound of any one of embodiments 1, 11, and 18, selected from the group consisting of TIFF2024540410000199.tif170155 and all salts and isotopic substitutions thereof.

[0526] Embodiment 436. TIFF2024540410000200.tif233157TIFF2024540410000201.tif194157TIFF2024540410000202.tif222157 TIFF2024540410000203.tif186157TIFF2024540410000204.tif190157TIFF2024540410000205.tif227148 20. The compound of any one of embodiments 1, 11, and 18, selected from the group consisting of TIFF2024540410000206.tif194155TIFF2024540410000207.tif224154TIFF2024540410000208.tif220154TIFF2024540410000209.tif192155 and all salts and isotopic substitutions thereof.

[0527] Embodiment 437. 12. The compound of embodiment 1 or 11, selected from TIFF2024540410000210.tif213155TIFF2024540410000211.tif157155 and all salts and isotopic substitutions thereof.

[0528] Embodiment 438. 20. The compound of any one of embodiments 1, 11, and 18, selected from TIFF2024540410000212.tif231155TIFF2024540410000213.tif198154TIFF2024540410000214.tif185154TIFF2024540410000215.tif152159 and all salts and isotopic substitutions thereof.

[0529] Embodiment 439. A compound according to any one of embodiments 1 to 438 that is not a salt.

[0530] Embodiment 440. A compound according to any one of embodiments 1 to 438 which is a salt.

[0531] Embodiment 441. The compound of embodiment 440, wherein the salt is a formate salt.

[0532] Embodiment 442. A compound according to embodiment 440, wherein the salt is a trifluoroacetic acid salt.

[0533] Embodiment 443. The compound of embodiment 440, wherein the salt is a pharmaceutically acceptable salt.

[0534] Embodiment 444. A pharmaceutical formulation comprising the compound according to any one of embodiments 1 to 440, when the compound is a salt, and a pharmaceutically acceptable carrier, wherein the salt is a pharmaceutically acceptable salt.

[0535] Embodiment 445. A method for treating or inhibiting cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1 to 440, or the pharmaceutical formulation of embodiment 444, wherein if the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0536] Embodiment 446. The method of embodiment 445, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0537] Embodiment 447. The cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate carcinoma, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine corpus, squamous cell carcinoma and adenocarcinoma of the uterine cervix, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinoma. 446. The method of embodiment 445, wherein the cancer is selected from the group consisting of: mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, childhood Wilms' tumor, childhood acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, childhood neuroblastoma, and melanoma.

[0538] Embodiment 448. The method of any one of embodiments 445 to 447, wherein the cancer is a KRAS G12C-mediated cancer.

[0539] Embodiment 449. The method of any one of embodiments 445 to 447, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0540] Embodiment 450. The method of any one of embodiments 445-449, further comprising administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent.

[0541] Embodiment 451. A compound according to any one of embodiments 1 to 440 or a pharmaceutical formulation according to embodiment 444 for use as a medicament.

[0542] Embodiment 452. A compound according to any one of embodiments 1 to 440 or a pharmaceutical preparation according to embodiment 444, for use in treating or suppressing cancer, wherein, when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0543] Embodiment 453. The compound or pharmaceutical composition for use according to embodiment 452, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0544] Embodiment 454. The cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast carcinoma, esophageal carcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate cancer, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine corpus, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, and vasculitis. The compound or pharmaceutical composition for use according to embodiment 452 is selected from the group consisting of renal cortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

[0545] Embodiment 455. The compound or pharmaceutical composition for use according to any one of embodiments 452 to 454, wherein the cancer is a KRAS G12C-mediated cancer.

[0546] Embodiment 456. The compound or pharmaceutical composition for use according to any one of embodiments 452 to 454, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0547] Embodiment 457. A compound or pharmaceutical composition for use according to any one of embodiments 452 to 456, which is adapted to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent.

[0548] Embodiment 458. A compound or pharmaceutical composition for use according to any one of embodiments 452 to 457, adapted to be administered in a therapeutically effective amount.

[0549] Embodiment 459. A compound according to any one of embodiments 1 to 440 or a pharmaceutical preparation according to embodiment 444, for use in the manufacture of a medicament for treating or inhibiting cancer, wherein, when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0550] Embodiment 460. The compound or pharmaceutical composition for use according to embodiment 459, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0551] Embodiment 461. The cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate cancer, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine corpus, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, and vasculitis. The compound or pharmaceutical composition for use according to embodiment 459 is selected from the group consisting of renal cortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, childhood acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, childhood neuroblastoma, and melanoma.

[0552] Embodiment 462. A compound or pharmaceutical composition for use according to any one of embodiments 459 to 461, wherein the cancer is a KRAS G12C-mediated cancer.

[0553] Embodiment 463. The compound or pharmaceutical composition for use according to any one of embodiments 459 to 461, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0554] Embodiment 464. A compound or pharmaceutical composition for use according to any one of embodiments 459 to 463, which is adapted to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent.

[0555] Embodiment 465. The compound or pharmaceutical composition for use according to any one of embodiments 459 to 464, wherein the medicament comprises a therapeutically effective amount of the compound or composition.

[0556] Embodiment 466. Use of a compound according to any one of embodiments 1 to 440 or a pharmaceutical formulation according to embodiment 444 in the manufacture of a medicament for treating or inhibiting cancer, wherein, when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0557] Embodiment 467. The use according to embodiment 466, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0558] Embodiment 468. The cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate cancer, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine corpus, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinoma. 467. The use according to embodiment 466, wherein the cancer is selected from the group consisting of: mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, childhood Wilms' tumor, childhood acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, childhood neuroblastoma, and melanoma.

[0559] Embodiment 469. The use according to any one of embodiments 466 to 468, wherein the cancer is a KRAS G12C-mediated cancer.

[0560] Embodiment 470. The use of any one of embodiments 466 to 468, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0561] Embodiment 471. The use according to any one of embodiments 466 to 470, wherein the compound or pharmaceutical composition is adapted to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent.

[0562] Embodiment 472. The use according to any one of embodiments 466 to 471, wherein the medicament comprises a therapeutically effective amount of a compound or pharmaceutical composition.

[0563] Embodiment 473. Use of a compound according to any one of embodiments 1 to 440 or a pharmaceutical formulation according to embodiment 444 for treating or inhibiting cancer, wherein when the compound is a salt, the salt is a pharmaceutically acceptable salt.

[0564] Embodiment 474. The use according to embodiment 473, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

[0565] Embodiment 475. The cancer is selected from the group consisting of glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate cancer, ovarian serous cystadenocarcinoma, endometrial carcinoma of the uterine corpus, squamous cell carcinoma and adenocarcinoma of the uterine cervix, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinoma. 474. The use according to embodiment 473, wherein the cancer is selected from the group consisting of: mesothelioma, adrenocortical carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, childhood Wilms' tumor, childhood acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, childhood neuroblastoma, and melanoma.

[0566] Embodiment 476. The use according to any one of embodiments 473 to 475, wherein the cancer is a KRAS G12C-mediated cancer.

[0567] Embodiment 477. The use of any one of embodiments 473 to 475, wherein the subject has been diagnosed with a KRAS G12C-mediated cancer.

[0568] Embodiment 478. The use according to any one of embodiments 473 to 477, wherein the compound or pharmaceutical composition is adapted to be administered together with a therapeutically effective amount of an additional chemotherapeutic agent.

[0569] Embodiment 479. The use according to any one of embodiments 473 to 478, comprising a therapeutically effective amount of the compound or composition.

[0570] General synthesis method The compounds of the present disclosure can be made in light of the disclosure of the examples provided below.

[0571] The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as MilliporeSigma, Bachem, or are prepared by methods known to those skilled in the art according to procedures described in such publications as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the ways in which the compounds of the present disclosure may be synthesized, and various modifications to these schemes may be made as will be suggested to those skilled in the art upon reading this disclosure. The starting materials and intermediates, and the end products of the reactions can be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0572] Unless otherwise specified, reactions described herein are carried out at atmospheric pressure, in a temperature range of about −78° C. to about 150° C., such as about 0° C. to about 125° C., or further, for example, at about room temperature (or ambient temperature), such as about 20° C. [Example]

[0573] The following preparations of compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (II), Formula (II-1) and Formula (II-2), and pharmaceutically acceptable salts thereof, are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0574] The following abbreviations are used in this section: TIFF2024540410000216.tif214112 All reagents were obtained from commercial suppliers and used without further purification unless otherwise stated.

[0575] Synthesis Example TIFF2024540410000217.tif54128 Example 1 (Method 1-A): Methyl (S,E)-4-((2-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)amino)-4-oxobut-2-enoate

[0576] TIFF2024540410000218.tif24128 Step 1: (S)-4-(benzyloxy)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine To a solution of 4-benzyloxy-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (400 mg, 1.13 mmol) in toluene (5 mL) was added (8-chloro-7-fluoro-1-naphthyl)trifluoromethanesulfonate (445.09 mg, 1.35 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (105.32 mg, 225.70 μmol), Tris(dibenzylideneacetone)dipalladium(0) (103.34 mg, 112.85 μmol), and cesium carbonate (1.47 g, 4.51 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 250*50mm*10μm; mobile phase: (water (0.1% TFA)-ACN; B%: 45%-75%, 10 min) to give (S)-4-(benzyloxy)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (260 mg, 36%, trifluoroacetate salt) as a yellow solid. LCMS rt = 0.765 min, m / z = 532.2 [M + H]+.

[0577] TIFF2024540410000219.tif24128 Step 2: (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol A mixture of (S)-4-(benzyloxy)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (250 mg, 386.36 μmol, trifluoroacetate salt) in trifluoroacetic acid (1 mL) was stirred at 60° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was quenched with a saturated solution of sodium carbonate (3 mL) at 0° C. and extracted with dichloromethane (3×15 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (200 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS rt = 0.644 min, m / z = 422.2 [M + H]+.

[0578] TIFF2024540410000220.tif24128 Step 3: (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate To a solution of (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (190 mg, 341.15 μmol) in dichloromethane (10 mL) was added triethylamine (138.08 mg, 1.36 mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate (240.63 mg, 852.88 μmol) at 0° C. The mixture was stirred at 25° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate (200 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS rt=0.762 min, m / z = 574.1 [M + H]+.

[0579] TIFF2024540410000221.tif38128 Step 4: (S)-tert-butyl (2-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)carbamate To a solution of (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate (100 mg, 173.92 μmol) in N,N-dimethylformaldehyde (1 mL) were added N-ethyl-N-isopropylpropan-2-amine (89.91 mg, 695.68 μmol) and tert-butyl N-[2-(methylamino)ethyl]carbamate (45.46 mg, 260.88 μmol) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (TFA)-ACN; B%: 15%-45%, 8 min) to give (S)-tert-butyl (2-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)carbamate (100 mg, 81%, trifluoroacetate salt) as a yellow solid. LCMS rt=1.585 min, m / z=598.3 [M + H]+.

[0580] TIFF2024540410000222.tif34128 Step 5: (S)-N 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 -methylethane-1,2-diamine A mixture of (S)-tert-butyl (2-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)carbamate (90 mg, 126.20 μmol, trifluoroacetate salt) in 4.0 M hydrochloric acid in ethyl acetate (1 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo to give (S)-N 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 -Methylethane-1,2-diamine (50 mg, crude, hydrochloride salt) was obtained as a yellow solid and used in the next step without further purification. LCMS rt=0.585 min, m / z=498.3 [M+H]+.

[0581] TIFF2024540410000223.tif54128 Step 6: Methyl (S,E)-4-((2-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)amino)-4-oxobut-2-enoate (S)-N in dichloromethane (1 mL) 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1To a solution of N-methylethane-1,2-diamine (40 mg, 80.16 μmol), (E)-4-methoxy-4-oxobut-2-enoic acid (5.21 mg, 40.08 μmol), N-ethyl-N-isopropylpropan-2-amine (20.72 mg, 160.31 μmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (38.26 mg, 60.12 μmol, 50% in ethyl acetate) were added at 0° C. The mixture was stirred at 25° C. for 0.5 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum and purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: (water (NH4HCO3)-ACN; B%: 40%-70%, 8 min) to give methyl (S,E)-4-((2-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)amino)-4-oxobut-2-enoate (4.13 mg, 17%) as a yellow oil: 1H NMR (400MHz, acetonitrile-d3) δ 7.92 (dd, J = 5.8, 9.0 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.56 - 7.39 (m, 3H), 7.38 - 7.25 (m, 1H), 6.87 (d, J = 15.4 Hz, 1H), 6.65 (d, J = 15.5 Hz, 1H), 4.38 - 4.30 (m, 1H), 4.24 - 4.10 (m, 2H), 3.89 - 3.80 (m, 1H), 3.79 - 3.69 (m, 4H), 3.66 - 3.49 (m, 4H), 3.31 - 3.21 (m, 1H), 3.18 (s, 3H), 3.15 - 3.01 (m, 2H), 2.69 (br d, J = 14.8 Hz, 1H), 2.63 (br s, 1H), 2.42 (s, 3H), 2.32 - 2.28 (m, 1H), 2.02 (br d, J = 8.1 Hz, 1H), 1.83 - 1.66 (m, 3H). LCMS room temperature = 3.162 min, m / z = 610.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 3.162 min, ESI+observed [M+H] = 610.3.

[0582] TIFF2024540410000224.tif50128 Example 2 (Method 1-A13): Methyl (E)-4-(3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate

[0583] TIFF2024540410000225.tif39128 Step 1: tert-Butyl 3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction was prepared in a similar manner to Step 4 of Example 1 (Method 1-A) using tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate in place of tert-butyl N-[2-(methylamino)ethyl]carbamate. The crude was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: (water (TFA)-ACN; B%: 15%-45%, 8min) to give tert-butyl 3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (14mg, 11 trifluoroacetate salt) as a white solid. LCMS rt=0.721min, m / z=624.3 [M + H]+.

[0584] TIFF2024540410000226.tif34128 Step 2: 7-(8-chloro-7-fluoronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine The Boc deprotection was prepared in a manner similar to Step 5 of Example 1 (Method 1-A). The mixture was concentrated to dryness in vacuo to give 7-(8-chloro-7-fluoronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (12 mg, crude, hydrochloride salt) as a white solid, which was used in the next step without further purification. LCMS rt = 0.603 min, m / z = 524.3 [M + H]+.

[0585] TIFF2024540410000227.tif49128 Step 3: Methyl (E)-4-(3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A). The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (FA)-ACN; B%: 1%-35%, 8 min) to give methyl (E)-4-(3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate (1.9 mg, 12%, formate salt) as a yellow oil: 1H NMR (400MHz, acetonitrile-d3) δ 7.89 (dd, J = 8.94, 5.84 Hz, 1 H) 7.69 (br d, J = 8.11 Hz, 1 H), 7.49 (td, J = 7.60, 3.04 Hz, 1 H), 7.44 - 7.36 (m, 2 H), 7.31 - 7.20 (m, 1 H), 6.73 - 6.65 (m, 1 H), 4.90 - 4.75 (m, 1 H), 4.49 - 4.40 (m, 1 H), 4.38 - 4.28 (m, 1 H), 4.22 (br d, J = 17.29 Hz, 1 H), 3.96 - 3.84 (m, 1 H), 3.78 - 3.70 (m, 5 H), 3.66 - 3.58 (m, 1 H), 3.56 - 3.43 (m, 2 H), 3.41 - 3.34 (m, 1 H), 3.18 - 3.04 (m, 3 H), 3.00 - 2.96 (m, 3 H), 2.64 - 2.57 (m, 5 H), 2.13 - 2.06 (m, 2 H), 1.87 - 1.81 (m, 1 H), 1.79 - 1.69 (m, 1 H), 1.64 - 1.40 (m, 2 H). LCMS room temperature = 2.196 min, m / z = 636.3 [M + H] + . LCMS (5-95% acetonitrile in water + 0.1% trifluoroacetic acid over 6 min) retention time 2.196 min, ESI+ found [M+H] = 636.3.

[0586] TIFF2024540410000228.tif46128 Example 3 (Method 1-A14): Methyl (E)-4-((R)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate

[0587] TIFF2024540410000229.tif36128 Step 1: (R)-tert-butyl 3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction was prepared in a similar manner to Step 4 of Example 1 (Method 1-A), using tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate instead of tert-butyl N-[2-(methylamino)ethyl]carbamate. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (TFA)-ACN; B%: 15%-50%, 8 min) to give (R)-tert-butyl 3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (20 mg, 16%, trifluoroacetate salt) as a white solid. LCMS rt=0.727 min, m / z = 624.3 [M + H]+.

[0588] TIFF2024540410000230.tif32128 Step 2: 7-(8-chloro-7-fluoronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine The Boc deprotection reaction was prepared in a manner similar to Step 5 of Example 1 (Method 1-A). The mixture was concentrated to dryness in vacuo to give 7-(8-chloro-7-fluoronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (17 mg, crude, hydrochloride salt) as a white solid, which was used in the next step without further purification. LCMS rt = 0.700 min, m / z = 524.3 [M + H]+.

[0589] TIFF2024540410000231.tif46128 Step 3: Methyl (E)-4-((R)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was prepared in the same manner as in Example 1 (Step 6 of Method 1-A). The residue was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (FA)-ACN; B%: 5%-40%, 8 min) to give methyl (E)-4-((R)-3-((7-(8-chloro-7-fluoronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate (5 mg, 23.38%) as a yellow oil: 1H NMR (400MHz, DMSO-d6) δ 8.04 (dd, J = 5.9, 9.0 Hz, 1H), 7.81 (br d, J = 7.9 Hz, 1H), 7.62 (t, J = 8.9 Hz, 1H), 7.55 (br d, J = 3.4 Hz, 1H), 7.50 - 7.38 (m, 1H), 7.37 - 7.22 (m, 1H), 6.88 - 6.56 (m, 1H), 5.00 - 4.65 (m, 1H), 4.40 - 4.03 (m, 3H), 3.98 - 3.87 (m, 1H), 3.86 - 3.60 (m, 9H), 3.19 - 3.04 (m, 3H), 3.03 - 2.94 (m, 3H), 2.65 - 2.54 (m, 5H), 2.28 - 1.94 (m, 2H), 1.88- 1.34 (m, 4H). LCMS room temperature = 2.179 min, m / z = 636.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.1% trifluoroacetic acid over 6 min) retention time 2.179 min, ESI+ found [M+H] = 636.3.

[0590] TIFF2024540410000232.tif45128 Example 4 (Method 1-A19): Methyl (E)-4-((2S,4S)-4-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-4-oxobut-2-enoate

[0591] TIFF2024540410000233.tif25128 Step 1: (2S,4S)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylate To a solution of tert-butyl (2S,4S)-4-amino-2-methyl-pyrrolidine-1-carboxylate (500 mg, 2.50 mmol) in tetrahydrofuran (5 mL) was added sodium hydroxide (2 M, 3.75 mL) and benzyl carbonochloridate (426.48 mg, 2.50 mmol) at 0 °C, and the mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give (2S,4S)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylate (600 mg, 71.8%) as a yellow oil: 1 H NMR (400MHz, DMSO-d6) δ 7.56-7.55 (m, 1H), 7.40 - 7.32 (m, 5H), 5.09 (s, 2H), 4.09 - 4.05 (m, 1H), 3.92-3.82 (m, 1H), 3.44 - 3.39 (m, 1H), 3.17-3.12 (m, 1H), 2.01-1.92 (m. 1H), 1.79-1.74 (m, 1H), 1.41 (s, 9H), 1.20-1.16 (m, 3H).

[0592] TIFF2024540410000234.tif25128 Step 2: (2S,4S)-tert-butyl 4-(((benzyloxy)carbonyl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate To a solution of (2S,4S)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylate (600 mg, 1.79 mmol) in N,N-dimethylformaldehyde (7 mL) was added sodium hydride (143.52 mg, 3.59 mmol, 60%) at 0° C. and stirred at 0° C. for 0.5 hours. Iodomethane (382.00 mg, 2.69 mmol) was added to the above solution and stirred at 25° C. for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give (2S,4S)-tert-butyl 4-(((benzyloxy)carbonyl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (500 mg, 80%) as a yellow gum: 1 H NMR (400MHz, DMSO-d6) δ 7.40 - 7.35 (m, 5H), 5.11 (s, 2H), 4.76 - 4.72 (m, 1H), 3.93-3.88 (m, 1H) 3.43 - 3.39 (m, 1H), 3.25-3.20 (m, 1H), 2.79 (s, 3H), 2.25-2.18 (m. 1H), 1.70-1.67 (m, 1H), 1.41 (s, 9H), 1.20-1.16 (m, 3H).

[0593] TIFF2024540410000235.tif19128Step 3: (2S,4S)-tert-butyl 2-methyl-4-(methylamino)pyrrolidine-1-carboxylate To a solution of (2S,4S)-tert-butyl 4-(((benzyloxy)carbonyl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (500 mg, 1.43 mmol) in ethyl acetate (6 mL) was added 10% palladium on carbon (10 mg, 10% purity). The mixture was then degassed, purged with hydrogen three times, and stirred under hydrogen at 25° C. for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give (2S,4S)-tert-butyl 2-methyl-4-(methylamino)pyrrolidine-1-carboxylate (280 mg, crude) as a colorless oil, which was used in the next step without further purification. LCMS rt=0.250 min, m / z = 241.2 [M + H]+.

[0594] TIFF2024540410000236.tif40128 Step 4: (2S,4S)-tert-butyl 4-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate The substitution reaction was prepared in a manner similar to Step 4 of Example 1 (Method 1-A) using (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate instead of (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate. The crude product was purified by reverse-phase HPLC (Phenomenex Luna 80*30 mm*3 μm column; 10%-50% acetonitrile in 1% TFA in water, 8 min gradient) to give (2S,4S)-tert-butyl 4-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate (160 mg, 31%) as a yellow gum. LCMS rt=0.726 min, m / z=620.3 [M + H]+.

[0595] TIFF2024540410000237.tif34128 Step 5: 7-(8-chloronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((3S,5S)-5-methylpyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine The Boc deprotection was prepared in a manner similar to Step 5 of Example 1 (Method 1-A). The mixture was concentrated to dryness in vacuo to afford 7-(8-chloronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((3S,5S)-5-methylpyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (140 mg, crude, hydrochloride salt) as a yellow gum, which was used in the next step without further purification. LCMS rt = 0.477 min, m / z = 520.3 [M + H]+.

[0596] TIFF2024540410000238.tif45128 Step 6: Methyl (E)-4-((2S,4S)-4-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A). The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 μm; mobile phase: (water (ammonium bicarbonate)-ACN; B%: 50%-80%, 10 min) to give methyl (E)-4-((2S,4S)-4-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-4-oxobut-2-enoate (14.35 mg, 23%) as a yellow oil: 1H NMR (400 MHz, acetonitrile-d3) δ 7.88 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.31 - 7.21 (m, 1H), 6.80 - 6.66 (m, 1H), 5.09 - 4.97 (m, 1H), 4.47 - 4.31 (m, 2H), 4.26 (br d, J = 17.3 Hz, 1H), 4.21 - 4.08 (m, 1H), 4.01 - 3.89 (m, 1H), 3.82 - 3.71 (m, 4H), 3.68 - 3.50 (m, 2H), 3.32 - 3.16 (m, 1H), 3.15 - 3.00 (m, 2H), 2.98 - 2.93 (m, 3H), 2.69 - 2.58 (m, 2H), 2.42 (d, J = 2.4 Hz, 3H) 2.37 - 2.29 (m, 2H), 2.01 (br d, J = 7.1 Hz, 1H), 1.88 - 1.67 (m, 4H), 1.36 - 1.22 (m, 3H). LCMS room temperature = 3.707 min, m / z = 632.3 [M + H]+. LCMS (5-95% acetonitrile in water + 10 mM ammonium bicarbonate over 6 min) retention time 3.707 min, ESI+ observed [M+H] = 632.3.

[0597] TIFF2024540410000239.tif49128 Example 5 (Method 1-A12): (E)-1-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-methoxybut-2-en-1-one

[0598] TIFF2024540410000240.tif36128 Step 1: tert-Butyl 3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction was prepared in a manner similar to Step 4 of Example 1 (Method 1-A), using (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate instead of (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate and tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate instead of tert-butyl (2-(methylamino)ethyl)carbamate. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give tert-butyl 3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (500 mg, 37%) as a yellow solid. LCMS rt = 0.720 min, m / z = 606.31 [M + H] + .

[0599] TIFF2024540410000241.tif34128 Step 2: 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-pyrrolidin-3-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine The Boc deprotection was prepared in a manner similar to Step 5 of Example 1 (Method 1-A). The reaction mixture was concentrated to dryness in vacuo to give 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-pyrrolidin-3-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine (160 mg, crude, hydrochloride salt) as a red solid, which was used in the next step without further purification. LCMS rt = 0.520 min, m / z = 506.26 [M + H] + .

[0600] TIFF2024540410000242.tif49128 Step 3: (E)-1-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-methoxybut-2-en-1-one The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A), except that (E)-4-methoxybut-2-enoic acid was used instead of (E)-4-methoxy-4-oxobut-2-enoic acid. The resulting residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: (water (NH4HCO3)-ACN; B%: 40%-70%, 8 min) to give (E)-1-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-methoxybut-2-en-1-one (2.23 mg, 4%) as a yellow oil: 1H NMR (400MHz, Acetonitrile-d3) δ ppm 7.80 - 7.75 (m, 1 H), 7.63 - 7.57 (m, 1 H), 7.50 - 7.38 (m, 2 H), 7.35 - 7.29 (m, 1 H), 7.27 - 7.22 (m, 1 H), 6.75 - 6.63 (m, 1 H), 6.37 - 6.24 (m, 1 H), 4.81 - 4.61 (m, 1 H), 4.28 - 4.11 (m, 2 H), 4.08 - 3.94 (m, 3 H), 3.86 - 3.57 (m, 3 H), 3.52 - 3.40 (m, 2H), 3.35 - 3.24 (m, 4 H), 3.08 - 2.93 (m, 1 H), 2.96 - 2.86 (m, 4 H), 2.57 - 2.46 (m, 2 H), 2.32 - 2.27 (m, 3 H), 2.20 - 2.15 (m, 2 H), 2.08 - 1.97 (m, 2 H), 1.94 - 1.88 (m, 1 H), 1.71 - 1.53 (m, 3 H). LCMS room temperature = 3.206 min, m / z = 604.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 3.206 min, ESI+observed [M+H] = 604.3.

[0601] TIFF2024540410000243.tif46128 Example 6 (Method 1-A2): Methyl (E)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was carried out in a manner similar to Step 6 of Example 1 (Method 1-A) by reacting 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-pyrrolidin-3-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine (prepared in Step 2 of Example 5) with (S)-N1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 The mixture was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (0.1% TFA)-ACN; B%: 25%-55%, 8 min) to give methyl (E)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate (9.68 mg, 12%, trifluoroacetate salt) as a yellow oil: 1 H NMR (400MHz, acetonitrile-d3) δ 7.87 (d, J = 8.2 Hz, 1H), 7.73 (br d, J = 8.0 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.44 - 7.39 (m, 1H), 7.37 - 7.22 (m, 2H), 6.74 - 6.68 (m, 1H), 5.15 - 5.01 (m, 1H), 4.75 - 4.59 (m, 2H), 4.34 (br d, J = 17.8 Hz, 2H), 3.98 - 3.84 (m, 2H), 3.76 (d, J = 4.3 Hz, 3H), 3.73 - 3.52 (m, 4H), 3.48 - 3.26 (m, 2H), 3.19 - 3.04 (m, 5H), 2.92 (br s, 3H), 2.71 (br d, J = 15.4 Hz, 1H), 2.39 - 2.17 (m, 3H), 2.16 - 1.98 (m, 3H) LCMS room temperature = 2.162 min, m / z = 618.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.1% trifluoroacetic acid over 6 min) retention time 2.162 min, ESI+ found [M+H] = 618.3.

[0602] TIFF2024540410000244.tif49128 Example 7 (Method 1-A10): Methyl (Z)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was prepared from 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-pyrrolidin-3-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine (prepared in Step 2 of Example 5) in a manner similar to Step 6 of Example 1 (Method 1-A), using (Z)-4-methoxy-4-oxobut-2-enoic acid instead of (E)-4-methoxy-4-oxobut-2-enoic acid. The residue was purified by reverse phase HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: (water (FA)-ACN; B%: 1%-40%, 8 min) to give methyl (Z)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate (4.87 mg, 7%, formate salt) as a yellow solid: 1H NMR (400MHz, acetonitrile-d3) δ ppm 8.29 (s, 1 H), 7.87 (d, J = 8.00 Hz, 1 H), 7.70 (br d, J = 8.25 Hz, 1 H), 7.63 - 7.48 (m, 2 H), 7.46 - 7.38 (m, 1 H), 7.37 - 7.27 (m, 1 H), 6.73 - 6.47 (m, 1 H), 6.20-5.97 (m, 1 H), 4.90 - 4.73 (m, 1 H), 4.52 - 4.40 (m, 1 H), 4.26 (br d, J = 17.39 Hz, 2 H), 3.98 - 3.82 (m, 1 H), 3.80 - 3.67 (m, 5 H), 3.66 - 3.49 (m, 2 H), 3.47 - 3.17 (m, 5 H), 3.16 - 3.03 (m, 3 H), 3.02 - 2.94 (m, 3 H), 2.87 (br d, J = 3.63 Hz, 2 H), 2.05 - 2.24 (m, 3 H), 1.88 (br s, 2 H), 1.42 - 1.64 (m, 1 H). LCMS room temperature = 2.054 min, m / z = 618.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.1% trifluoroacetic acid over 6 min) retention time 2.054 min, ESI+ found [M+H] = 618.3.

[0603] TIFF2024540410000245.tif37128 Example 8 (Method 1-A16): (E)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoic acid The amide coupling reaction was prepared from 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-pyrrolidin-3-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine (prepared in Step 2 of Example 5) in a manner similar to Step 6 of Example 1 (Method 1-A), using fumaric acid instead of (E)-4-methoxy-4-oxobut-2-enoic acid. The resulting residue was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (FA)-ACN; B%: 5%-45%, 8 min) to give (E)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoic acid (45 mg, 34%, formate salt) as a white solid: 1 H NMR (400MHz, DMSO-d6) δ ppm 7.93 (d, J = 8.19 Hz, 1 H), 7.71 - 7.83 (m, 1 H), 7.51 - 7.63 (m, 2 H), 7.46-7.42 (m, 1 H), 7.30 - 7.43 (m, 1 H), 7.22-7.18 (m, 1 H), 6.64-6.60 (m, 1 H), 4.68 - 4.95 (m, 1 H), 4.25 - 4.39 (m, 2 H), 4.11 - 4.24 (m, 3 H), 4.07-4.04 (m, 1 H), 3.83 - 3.98 (m, 3H), 3.72 - 3.80 (m, 3 H), 3.04 - 3.13 (m, 2 H), 2.93 - 3.03 (m, 4 H), 2.82 - 2.93 (m, 1 H), 2.59 (br s, 2 H), 2.12 - 2.23 (m, 1 H), 1.95 - 2.05 (m, 1 H), 1.58 - 1.84 (m, 3 H), 1.42 - 1.56 (m, 1 H). LCMS room temperature = 2.591 min, m / z = 604.2 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 2.591 min, ESI+observed [M+H] = 604.2.

[0604] TIFF2024540410000246.tif47128 Example 9 (Method 1-A21): (E)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(methylsulfonyl)prop-2-en-1-one

[0605] TIFF2024540410000247.tif17128 Step 1: (E)-3-Methylsulfonylprop-2-enoic acid A mixture of 2,3-dibromopropanoic acid (19.54 g, 84.28 mmol) and sodium ethanesulfinate (11.72 g, 126.43 mmol) in N,N-dimethylformaldehyde (30 mL) was stirred at 80° C. for 12 hours. The reaction mixture was concentrated to dryness under vacuum. The resulting residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 250*50 mm*10 μm; mobile phase: (water (TFA)-ACN; B%: 1%-20%, 10 min) to give (E)-3-methylsulfonylprop-2-enoic acid (8 g, 63%) as a yellow oil: 1 H NMR (400MHz, DMSO-d6) δ ppm 7.65-7.61 (d, J = 15.6 Hz, 1H), 6.64-6.60 (d, J = 15.6 Hz, 1H), 3.17(s, 3H).

[0606] TIFF2024540410000248.tif36128 Step 2: tert-Butyl (R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction of (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate was prepared in a manner similar to Step 4 of Example 1 (Method 1-A), using tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate instead of tert-butyl N-[2-(methylamino)ethyl]carbamate. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give tert-butyl (R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (270 mg, 32%) as a brown gum. LCMS rt=0.942 min, m / z = 606.3 [M + H]+.

[0607] TIFF2024540410000249.tif33128 Step 3: 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-[(3R)-pyrrolidin-3-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine The Boc deprotection was prepared in a manner similar to Step 5 of Example 1 (Method 1-A). The reaction mixture was concentrated in vacuo to give 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-[(3R)-pyrrolidin-3-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine (240 mg, crude, hydrochloride salt) as a brown gum, which was used in the next step without further purification. LCMS rt = 0.453 min, m / z = 506.3 [M + H]+.

[0608] TIFF2024540410000250.tif47128 Step 4: (E)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(methylsulfonyl)prop-2-en-1-one The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A), using (E)-3-methylsulfonylprop-2-enoic acid instead of (E)-4-methoxy-4-oxobut-2-enoic acid. The mixture was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: (water (NH4HCO3)-ACN; B%: 35%-55%, 8 min) to give (E)-1-((R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(methylsulfonyl)prop-2-en-1-one (6.29 mg, 10%) as a yellow solid: 1H NMR (400 MHz, acetonitrile-d3) δ 7.87 - 7.82 (m, 1H), 7.71 - 7.65 (m, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.22 - 7.11 (m, 1H), 4.92 - 4.71 (m, 1H), 4.41 - 4.29 (m, 1H), 4.27 - 4.20 (m, 1H), 4.19 - 4.06 (m, 1H), 3.98 - 3.85 (m, 1H), 3.68 (s, 2H), 3.66 - 3.58 (m, 1H), 3.57 - 3.49 (m, 1H), 3.48 - 3.36 (m, 1H), 3.28 - 3.04 (m, 3H), 3.03 - 3.00 (m, 3H), 2.99 - 2.94 (m, 3H), 2.72 - 2.56 (m, 2H), 2.47 - 2.36 (m, 4H), 2.11 - 1.98 (m, 2H), 1.86 - 1.55 (m, 4H). LCMS room temperature = 3.449 min, m / z = 638.2 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 3.449 min, ESI+ found [M+H] = 638.2.

[0609] TIFF2024540410000251.tif46128 Example 10 (Method 1-A7): Methyl (E)-4-((R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was carried out in a manner similar to Step 6 of Example 1 (Method 1-A) by reacting 7-(8-chloronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (prepared according to Step 3 of Example 9) with (S)-N 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 The residue was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: (water (FA)-ACN; B%: 5%-40%, 8 min) to give methyl (E)-4-((R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate (16.03 mg, 30%, formate salt) as a yellow solid: 1H NMR (400MHz, acetonitrile-d3) δ ppm 7.84 (d, J = 8.13 Hz, 1 H), 7.67 (d, J = 8.13 Hz, 1 H), 7.57 - 7.45 (m, 2 H,) 7.42 - 7.36 (m, 1 H), 7.34 - 7.27 (m, 1 H), 7.26 - 7.18 (m, 1 H), 6.74 - 6.62 (m, 1 H), 4.92 - 4.67 (m, 1 H), 4.41 - 4.29 (m, 1 H), 4.25 - 4.13 (m, 2 H), 3.96 - 3.79 (m, 1 H), 3.77 - 3.66 (m, 5 H), 3.63 - 3.32 (m, 3 H), 3.31 - 3.19 (m, 1 H), 3.18 - 3.01 (m, 3 H), 2.98 - 2.94 (m, 3 H), 2.79-2.74 (m, 1 H), 2.61-2.57 (m, 1 H), 2.39 - 2.29 (m, 3 H), 2.09 - 2.22 (m, 2 H), 1.50 - 1.86 (m, 4 H). LCMS room temperature = 2.114 min, m / z = 618.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.1% trifluoroacetic acid over 6 min) retention time 2.114 min, ESI+ found [M+H] = 618.3.

[0610] TIFF2024540410000252.tif46128 Example 11 (Method 1-A24): Isopropyl (E)-4-((R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was carried out in a manner similar to Step 6 of Example 1 (Method 1-A) by reacting 7-(8-chloronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((R)-pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (prepared according to Step 3 of Example 9) with (S)-N 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 The reaction mixture was prepared by substituting -methylethane-1,2-diamine and (E)-4-isopropoxy-4-oxobut-2-enoic acid for (E)-4-methoxy-4-oxobut-2-enoic acid. The reaction mixture was purified by reverse-phase HPLC (Phenomenex C18 75*30mm*3um column; 60%-90% acetonitrile in aqueous ammonium bicarbonate, 8 minute gradient) to give isopropyl (E)-4-((R)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate (12.14 mg, 13%) as a yellow solid: 1H NMR (400 MHz, acetonitrile-d3) δ 7.85 (d, J = 7.9 Hz, 1H), 7.68 (br d, J = 8.5 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.50 (dt, J = 2.8, 7.7 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.32 (br t, J = 6.3 Hz, 1H), 7.28 - 7.15 (m, 1H), 6.69 - 6.59 (m, 1H), 5.13 - 4.99 (m, 1H), 4.89 - 4.71 (m, 1H), 4.34 - 4.19 (m, 2H), 4.08 (td, J = 5.7, 10.8 Hz, 1H), 3.97 - 3.81 (m, 1H), 3.80 - 3.49 (m, 4H), 3.48 - 3.33 (m, 1H), 3.31 - 3.04 (m, 2H), 3.01 - 2.92 (m, 4H), 2.66 - 2.47 (m, 2H), 2.34 (br d, J = 4.1 Hz, 3H), 2.26 - 2.17 (m, 4H) 1.74 - 1.59 (m, 3H), 1.27 (dt, J = 2.0, 4.1 Hz, 6H). LCMS room temperature = 3.519 min, m / z = 646.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 3.519 min, ESI+ found [M+H] = 646.3.

[0611] TIFF2024540410000253.tif37128 Example 12 (Method 1-A3): Methyl (S,E)-4-((2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(ethyl)amino)ethyl)amino)-4-oxobut-2-enoate

[0612] TIFF2024540410000254.tif36128 Step 1: tert-Butyl (S)-(2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(ethyl)amino)ethyl)carbamate The substitution reaction of (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate was prepared in a similar manner to Step 4 of Example 1 (Method 1-A), using tert-butyl (2-(ethylamino)ethyl)carbamate instead of tert-butyl N-[2-(methylamino)ethyl]carbamate. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-80% ethyl acetate in petroleum ether) to give tert-butyl (S)-(2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(ethyl)amino)ethyl)carbamate (300 mg, 47%) as a white solid. LCMS rt = 0.701 min, m / z = 594.3 [M + H]+.

[0613] TIFF2024540410000255.tif36128 Step 2: N'-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N'-ethyl-ethane-1,2-diamine The Boc deprotection was prepared in a manner similar to Step 5 of Example 1 (Method 1-A). The resulting mixture was concentrated to dryness in vacuo to give N'-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N'-ethyl-ethane-1,2-diamine (200 mg, 80%) as a brown solid, which was used in the next step without further purification. LCMS rt = 1.125 min, m / z = 494.3 [M + H]+.

[0614] TIFF2024540410000256.tif37128 Step 3: Methyl (S,E)-4-((2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(ethyl)amino)ethyl)amino)-4-oxobut-2-enoate The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A). The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min) to give methyl (S,E)-4-((2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(ethyl)amino)ethyl)amino)-4-oxobut-2-enoate (31.13 mg, 24%) as a yellow solid: 1H NMR (400MHz, acetonitrile-d3) δ 7.95-7.65 (m, 1H), 7.63-7.21 (m, 5H), 7.01-6.81 (m, 1H), 6.75-6.52 (m, 1H), 4.47-4.05(m, 2H), 3.92-3.75 (m, 3H), 3.65-3.45 (m, 3H), 3.30-2.95 (m, 4H), 2.75-2.55 (m, 1H), 2.50-2.40 (m, 4H), 2.30-2.10 (m, 6H), 1.75-1.55 (m, 4H), 1.15-1.05 (m, 3H). LCMS room temperature = 3.292 min, m / z = 606.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 3.292 min, ESI+observed [M+H] = 606.3.

[0615] TIFF2024540410000257.tif37128 Example 13 (Method 1-A6): Methyl (E)-4-((2-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)amino)-4-oxobut-2-enoate

[0616] TIFF2024540410000258.tif33128 Step 1: tert-Butyl (2-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)carbamate The substitution reaction was prepared in a manner similar to Step 4 of Example 1 (Method 1-A) using 7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate in place of (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% methanol in dichloromethane) to give tert-butyl (2-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)carbamate (580 mg, 90%) as a brown oil. LCMS rt = 1.740 min, m / z = 606.3 [M + H]+.

[0617] TIFF2024540410000259.tif35128Step 2:N 1 -(7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 -methylethane-1,2-diamine The Boc deprotection was prepared in a similar manner to Step 5 of Example 1 (Method 1-A). The resulting mixture was concentrated to dryness under vacuum, and the crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: (water (TFA)-ACN; B%: 15%-45%, 10 min) to obtain N1-(7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N1-methylethane-1,2-diamine (160 mg, 27%, trifluoroacetate salt) as a yellow solid, which was used in the next step without further purification. LCMS RT = 0.599 min, m / z = 506.2 [M + H]+.

[0618] TIFF2024540410000260.tif37128 Step 3: Methyl (E)-4-((2-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)amino)-4-oxobut-2-enoate The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A). The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 min) to give methyl (E)-4-((2-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)amino)-4-oxobut-2-enoate (38 mg, 23%) as a pale yellow solid: 1H NMR (400MHz, acetonitrile-d3) δ 7.87 (dd, J = 8.2, 0.89 Hz, 1 H), 7.70 (d, J = 7.6 Hz, 1 H), 7.49 - 7.60 (m, 2 H), 7.40 - 7.45 (m, 1 H), 7.38 (br s, 1 H), 7.33 (dd, J = 7.6, 0.95 Hz, 1 H), 6.86 (d, J = 15.5 Hz, 1 H), 6.63 (d, J = 15.5 Hz, 1 H), 4.21 (d, 1 H), 3.96 - 4.01 (m, 2 H), 3.78 - 3.86 (m, 1 H), 3.76 (s, 3 H), 3.75-3.71 (d, 1 H), 3.49 - 3.64 (m, 4 H), 3.20 - 3.30 (m, 1 H), 3.16 (s, 3 H), 3.03 - 3.12 (m, 1 H), 2.95 - 3.02 (m, 2 H), 2.58 - 2.72 (m, 3 H), 1.72 - 1.95 (m, 6 H), 1.56 - 1.68 (m, 2 H). LCMS room temperature = 2.774 min, m / z = 618.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 2.774 min, ESI+observed [M+H] = 618.3.

[0619] TIFF2024540410000261.tif45128 Example 14 (Method 1-A5): Methyl (E)-4-((1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)amino)-4-oxobut-2-enoate

[0620] TIFF2024540410000262.tif37128 Step 1: tert-Butyl N-[1-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-yl]carbamate The substitution reaction was prepared in a manner similar to Step 4 of Example 1 (Method 1-A), using (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate in place of (S)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate and tert-butyl pyrrolidin-3-ylcarbamate in place of tert-butyl N-[2-(methylamino)ethyl]carbamate. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give tert-butyl N-[1-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-yl]carbamate (210 mg, 37%) as a brown solid, which was used in the next step without further purification. LCMS rt=0.667 min, m / z = 592.2 [M + H]+.

[0621] TIFF2024540410000263.tif38128 Step 2: 1-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-amine The Boc deprotection was prepared in a manner similar to Step 6 of Example 1 (Method 1-A). The resulting mixture was concentrated in vacuo to give 1-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-amine (80 mg, crude, hydrochloride salt) as a brown solid, which was used in the next step without further purification. LCMS rt = 0.556 min, m / z = 492.2 [M + H]+.

[0622] TIFF2024540410000264.tif45128 Step 3: Methyl (E)-4-((1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)amino)-4-oxobut-2-enoate The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A). The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: (water (10 mM NH4HCO3)-ACN; B%: 30%-60%, 8 min) to give methyl (E)-4-((1-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)amino)-4-oxobut-2-enoate (9.37 mg, 10%) as a white solid: 1H NMR (400MHz, acetonitrile-d3) δ 7.84 (d, J = 8.3 Hz, 1H), 7.66 (dd, J = 3.8, 7.8 Hz, 1H), 7.58 - 7.45 (m, 2H), 7.42 - 7.27 (m, 2H), 7.25 - 7.15 (m, 1H), 6.94 - 6.85 (m, 1H), 6.73 - 6.62 (m, 1H), 4.54 - 4.41 (m, 1H), 4.29 (dd, J = 5.0, 10.9 Hz, 1H), 4.16 - 4.05 (m, 2H), 4.00 - 3.76 (m, 3H), 3.74 (d, J = 2.4 Hz, 3H), 3.71 - 3.64 (m, 2H), 3.58 - 3.46 (m, 1H), 3.39 - 3.20 (m, 1H), 3.13 - 2.96 (m, 2H), 2.88 - 2.76 (m, 1H), 2.63 - 2.52 (m, 1H), 2.38 (s, 3H), 2.28 - 2.17 (m, 4H), 1.78 - 1.57 (m, 3H). LCMS room temperature = 3.143 min, m / z = 604.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 3.143 min, ESI+observed [M+H] = 604.3.

[0623] TIFF2024540410000265.tif46128 Example 15 (Method 1-A22): (E)-1-((S)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(methylsulfonyl)prop-2-en-1-one

[0624] TIFF2024540410000266.tif34128 Step 1: (S)-tert-butyl 3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction was prepared in a manner similar to Step 4 of Example 1 (Method 1-A), using tert-butyl (S)-3-(methylamino)pyrrolidine-1-carboxylate instead of tert-butyl N-[2-(methylamino)ethyl]carbamate. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% methanol in dichloromethane) to afford (S)-tert-butyl 3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (200 mg, 37%) as a brown oil. LCMS rt = 0.953 min, m / z = 606.3 [M + H]+.

[0625] TIFF2024540410000267.tif34128 Step 2: 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-[(3S)-pyrrolidin-3-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine The Boc deprotection was prepared in a manner similar to Step 5 of Example 1 (Method 1-A). The resulting mixture was concentrated to dryness in vacuo to give 7-(8-chloro-1-naphthyl)-N-methyl-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-N-[(3S)-pyrrolidin-3-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-amine (100 mg, 56%, hydrochloride salt) as a brown oil, which was used in the next step without further purification. LCMS rt = 0.896 min, m / z = 506.4 [M + H]+.

[0626] TIFF2024540410000268.tif45128 Step 3: (E)-1-((S)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(methylsulfonyl)prop-2-en-1-one The amide coupling reaction was prepared in a similar manner to Step 6 of Example 1 (Method 1-A), using (E)-3-(methylsulfonyl)acrylic acid instead of (E)-4-methoxy-4-oxobut-2-enoic acid. The crude product was purified by reverse-phase HPLC (neutral condition, column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: (water (NH4HCO3)-ACN; B%: 50%-80%, 10 min) to give (E)-1-((S)-3-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-3-(methylsulfonyl)prop-2-en-1-one (2.43 mg, 1.89%) as a brown solid: 1H NMR (400MHz, acetonitrile-d3) δ 7.90 (d, J = 8.11 Hz, 1 H), 7.76 - 7.71 (m, 1 H), 7.61 (dd, J = 7.39, 0.83 Hz, 1 H), 7.55 (td, J = 7.81, 4.29 Hz, 1 H), 7.46 (d, J = 7.75 Hz, 1 H), 7.43 - 7.35 (m, 2 H), 7.24 - 7.17 (m, 1 H), 4.98 - 4.78 (m, 1 H), 4.44 (br s, 1 H), 4.36 - 4.23 (m, 2 H), 4.16 - 3.59 (m, 5 H), 3.58 - 3.41 (m, 2 H), 1.91 - 1.74 (m, 3 H), 3.40 - 3.10 (m, 4 H), 3.09 - 3.05 (m, 3 H), 3.04 - 3.00 (m, 3 H), 2.64 (br s, 1 H), 2.57 (br s, 3 H), 2.25 - 2.05 (m, 3 H) LCMS room temperature = 2.056 min, m / z = 638.2 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 2.056 min, ESI+observed [M+H] = 638.2.

[0627] TIFF2024540410000269.tif61128 Example 16 (Method 1-A4): Methyl (S,E)-4-(3-(((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was carried out in a manner similar to Step 6 of Example 1 (Method 1-A), by reacting (S)-N-(azetidin-3-ylmethyl)-7-(8-chloronaphthalen-1-yl)-N-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with (S)-N 1-(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (FA)-ACN; B%: 5%-35%, 8 min) to give methyl (S,E)-4-(3-(((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)methyl)azetidin-1-yl)-4-oxobut-2-enoate (7.43 mg, 4%, formate salt) as a pale yellow solid: 1 H NMR (400 MHz, acetonitrile-d3) δ 7.90 - 7.79 (m, 1H), 7.67 (br d, J = 7.6 Hz, 1H), 7.60 - 7.46 (m, 2H), 7.44 - 7.35 (m, 1H), 7.34 - 7.27 (m, 1H), 7.02 - 6.90 (m, 1H), 6.69 - 6.59 (m, 1H), 4.39 - 4.24 (m, 2H), 4.23 - 4.16 (m, 1H), 4.14 - 3.95 (m, 4H), 3.82 - 3.75 (m, 1H), 3.75 - 3.65 (m, 4H), 3.64 - 3.48 (m, 2H), 3.29 - 3.14 (m, 2H), 3.10 (d, J = 2.0 Hz, 3H), 3.09 - 3.01 (m, 2H), 3.00 - 2.93 (m, 1H), 2.63 (br d, J = 14.6 Hz, 1H), 2.56 - 2.48 (m, 1H), 2.36 (s, 3H), 2.13 - 2.08 (m, 1H), 1.79 - 1.60 (m, 3H). LCMS room temperature = 2.101 min, m / z = 618.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 2.101 min, ESI+observed [M+H] = 618.3.

[0628] TIFF2024540410000270.tif46128 Example 17 (Method 1-A18): Methyl (E)-4-((2R,4R)-4-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-4-oxobut-2-enoate 7-(8-Chloronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((3R,5R)-5-methylpyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine was prepared in a manner similar to that described in Example 4, using tert-butyl (2R,4R)-4-amino-2-methyl-pyrrolidine-1-carboxylate instead of tert-butyl (2S,4S)-4-amino-2-methyl-pyrrolidine-1-carboxylate. The amide coupling reaction was carried out in a manner similar to Step 6 of Example 1 (Method 1-A) by reacting 7-(8-chloronaphthalen-1-yl)-N-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-N-((3R,5R)-5-methylpyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with (S)-N 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: (water (NH4HCO3)-ACN; B%: 50%-80%, 10 min)) to give methyl (E)-4-((2R,4R)-4-((7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-4-oxobut-2-enoate (10.49 mg, 18.47%) as a white solid: 1 H NMR (400 MHz, acetonitrile-d3) δ 7.85 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.43 - 7.37 (m, 1H), 7.36 - 7.31 (m, 1H), 7.30 - 7.19 (m, 1H), 6.77 - 6.64 (m, 1H), 5.10 - 4.91 (m, 1H), 4.45 - 4.27 (m, 2H), 4.26 - 4.08 (m, 2H), 4.07 - 4.00 (m, 1H). 3.80 - 3.69 (m, 4H), 3.64 - 3.49 (m, 2H), 3.26 - 3.02 (m, 3H), 2.97 - 2.93 (m, 3H), 2.73 - 2.56 (m, 2H), 2.45 - 2.39 (m, 3H), 2.33 - 2.25 (m, 2H), 2.02 - 1.99 (m, 1H), 1.87 - 1.64 (m, 4H), 1.32 - 1.18 (m, 3H). LCMS room temperature = 2.172 min, m / z = 632.3 [M + H]+. LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 2.172 min, ESI+ found [M+H] = 632.3.

[0629] TIFF2024540410000271.tif49128 Example 18 (Method 1-A23): Isopropyl (R,E)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate

[0630] TIFF2024540410000272.tif39128 Step 1: tert-Butyl (R)-3-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate The substitution reaction was prepared in a manner similar to Step 4 of Example 1 (Method 1-A), using tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate instead of tert-butyl N-[2-(methylamino)ethyl]carbamate. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 10-100% ethyl acetate in petroleum ether) to afford tert-butyl (R)-3-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidine-1-carboxylate (900 mg, 44.31%) as a yellow oil. LCMS rt = 0.707 min, m / z = 632.3 [M + H]+.

[0631] TIFF2024540410000273.tif34128 Step 2: (R)-7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine The Boc deprotection was prepared in the same manner as in Step 5 of Example 1 (Method 1-A). The reaction mixture was concentrated under vacuum, and the crude product was purified by reverse-phase HPLC (Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: (water (TFA)-ACN; B%: 20%-50%, 10 min) to give (R)-7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (200 mg, 21.74%, trifluoroacetate salt) as a yellow oil, which was used in the next step without further purification. LCMS RT = 0.721 min, m / z = 532.3 [M + H] + .

[0632] TIFF2024540410000274.tif49128 Step 3: Isopropyl (R,E)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate The amide coupling reaction was prepared in a manner similar to Step 6 of Example 1 (Method 1-A), using (E)-4-isopropoxy-4-oxobut-2-enoic acid instead of (E)-4-methoxy-4-oxobut-2-enoic acid. The crude product was purified by reverse-phase HPLC (Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (FA)-ACN]; B%: 15%-50%, 8 min) to give isopropyl (R,E)-4-(3-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)-4-oxobut-2-enoate (12.89 mg, 37%, formate salt) as a yellow solid: 1H NMR (400MHz, acetonitrile-d3) δ 7.90 - 7.86 (m, 1 H), 7.71 (dd, J = 8.07, 1.22 Hz, 1 H), 7.60 - 7.50 (m, 2 H), 7.46 - 7.40 (m, 1 H), 7.35 (t, J = 7.15 Hz, 1 H), 7.32 - 7.25 (m, 1 H), 6.73 - 6.63 (m, 1 H), 5.15 -4.96 (m, 1 H), 4.92 -4.75 (m, 1 H), 4.31 - 4.23 (m, 1 H), 4.15 - 4.07 (m, 2 H), 4.00 - 3.84 (m, 1 H), 3.81 - 3.73 (m, 1 H), 3.71 - 3.59 (m, 1 H), 3.58 -3.51 (m, 1 H), 3.50 - 3.39 (m, 1 H), 3.33 - 3.18 (m, 1 H), 3.17 - 3.08 (m, 3 H), 3.02 - 2.97 (m, 3 H), 2.71 -2.61 (m, 4 H), 2.32 - 2.10 (m, 2 H), 2.04 - 1.99 (m, 2 H), 1.94 - 1.83 (m, 4 H), 1.74 - 1.64 (m, 2 H), 1.33 - 1.28 (m, 6 H). LCMS room temperature = 2.274 min, m / z = 672.3 [M + H] + . LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 2.274 min, ESI+ found [M+H] = 672.3.

[0633] TIFF2024540410000275.tif44128 Example 19 (Method 1-A25): (R)-1-(3-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one The amide coupling reaction was carried out in a manner similar to Step 6 of Example 1 (Method 1-A), by reacting (R)-7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-N-methyl-N-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (Step 2 of Example 18) with (S)-N 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1 The residue was prepared by using -methylethane-1,2-diamine instead of methylethane-1,2-diamine, and acrylic acid instead of (E)-4-methoxy-4-oxobut-2-enoic acid. The residue was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: (water (NH4HCO3)-ACN; B%: 35%-65%, 8 min), to give (R)-1-(3-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one (66.75mg, 34%) as a yellow oil: 1H NMR (400 MHz, acetonitrile-d3) δ 7.90 - 7.86 (m, 1H), 7.74 - 7.68 (m, 1H), 7.60 - 7.50 (m, 2H), 7.45 - 7.39 (m, 1H), 7.38 - 7.32 (m, 1H), 6.65 - 6.50 (m, 1H), 6.28 - 6.18 (m, 1H), 5.71 - 5.62 (m, 1H), 4.91 - 4.73 (m, 1H), 4.31 - 4.21 (m, 1H), 4.09 - 4.03 (m, 2H), 3.96 - 3.67 (m, 3H), 3.66 - 3.50 (m, 2H), 3.47 - 3.36 (m, 1H), 3.34 - 3.22 (m, 1H), 3.21 - 3.14 (m, 1H), 3.13 - 3.04 (m, 2H), 3.01 - 2.98 (m, 3H), 2.70 - 2.59 (m, 3H), 2.14 - 2.06 (m, 2H), 1.94 - 1.73 (m, 6H), 1.70 - 1.59 (m, 2H). LCMS room temperature = 3.112 min, m / z = 586.3 [M + H] + . LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 3.112 min, ESI+ found [M+H] = 586.3.

[0634] TIFF2024540410000276.tif46128 Example 20 (Method 1-A26): Methyl (E)-4-((2S,4R)-4-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-4-oxobut-2-enoate 7-(8-chloronaphthalen-1-yl)-N-methyl-N-((3R,5S)-5-methylpyrrolidin-3-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine was prepared by the procedure described in Example 4, using tert-butyl (2S,4R)-4-amino-2-methyl-pyrrolidine-1-carboxylate instead of tert-butyl (2S,4S)-4-amino-2-methyl-pyrrolidine-1-carboxylate, to prepare 7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl Trifluoromethanesulfonate was used in place of (S)-7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl trifluoromethanesulfonate.

[0635] The amide coupling reaction was carried out in a manner similar to Step 6 of Example 1 (Method 1-A) by reacting 7-(8-chloronaphthalen-1-yl)-N-methyl-N-((3R,5S)-5-methylpyrrolidin-3-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with (S)-N 1 -(7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N 1The crude product was purified by reverse-phase HPLC (Phenomenex Luna 80*30 mm*3 μm; mobile phase: (water (FA)-ACN; B%: 10%-40%, 8 min) to give methyl (E)-4-((2S,4R)-4-((7-(8-chloronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)-2-methylpyrrolidin-1-yl)-4-oxobut-2-enoate (14.85 mg, 4%) as a yellow solid: 1 H NMR (400 MHz, acetonitrile-d3) δ 7.85 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.33 (br d, J = 7.2 Hz, 1H), 7.27 - 7.17 (m, 1H), 6.73 - 6.62 (m, 1H), 4.67 - 4.50 (m, 1H), 4.25-4.21 (m, 1H), 4.10 - 4.01 (m, 3H), 3.76 - 3.74 (m, 3H), 3.61 - 3.49 (m, 2H). 3.31 - 3.05 (m, 5H), 2.99 - 2.96 (m, 3H), 2.69 (br d, J = 7.2 Hz, 2H), 2.59 (br d, J = 15.3 Hz, 2H), 1.88 - 1.74 (m, 7H), 1.71 - 1.61 (m, 3H), 1.36 (br d, J = 5.7 Hz, 3H). LCMS room temperature = 2.292 min, m / z = 658.3 [M + H] + . LCMS (5-95% acetonitrile in water + 0.03% ammonium bicarbonate over 6 min) retention time 2.292 min, ESI+ found [M+H] = 658.3.

[0636] TIFF2024540410000277.tif49128 Example 21 (Method 1-A9): (S,E)-4-((2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)amino)-4-oxobut-2-enoic acid

[0637] TIFF2024540410000278.tif41128 Step 1: tert-Butyl (S)-(2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)carbamate The substitution reaction was prepared in a manner similar to Step 4 of Example 1 (Method 1-A). The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to afford tert-butyl (S)-(2-((7-(8-chloronaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)(methyl)amino)ethyl)carbamate (4 g, 87.19%) as a brown solid. LCMS rt = 0.841 min, m / z = 580.3 [M + H] + .

[0638] TIFF2024540410000279.tif36128 Step 2: N'-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N'-methyl-ethane-1,2-diamine The Boc deprotection was prepared in a similar manner to Step 5 of Example 1 (Method 1-A). The reaction mixture was concentrated to dryness in vacuo to give N'-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-N'-methyl-ethane-1,2-diamine (4 g, crude, hydrochloride salt) as a brown solid, which was used in the next step without further purification. LCMS rt = 0.671 min, m / z = 481.4 [M + H] + .

[0639] TIFF2024540410000280.tif49128 Step 3: (S,E)-4-((2-((7-(8-chloron...

Claims

1. A compound of formula I or formula II, or a salt thereof; and / or an isotopic variant thereof: During the ceremony, R ｘ is hydrogen, hydroxy, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, and C １ -C ４ haloalkoxy; R ｙ is hydrogen, C １ -C ４ selected from alkyl, and halo; R ｚ is hydrogen, C １ -C ４ selected from alkyl, and halo; R １ is a 4-8 membered saturated carbocyclic or heterocyclic group containing one nitrogen as the only heteroatom in the ring, said carbocyclic or heterocyclic group being selected from the group consisting of halo, hydroxy, C １ -C ４ Alkyl, Spiro C ３ -C ４ Cycloalkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ substituted with 0, 1, 2 or 3 substituents independently selected from haloalkoxy; R ２ is R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , and R ２ｅ selected from the group consisting of: R ３ is hydrogen, halo, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy, and C ２ -C ３ alkynyl; R ４ is hydrogen, halo, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy, C ３ -C ７ Cycloalkyl, CN, and C ２ -C ３ alkynyl; R ２ａ is -NR ５ R ６ and R ５ is H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; and R ６ is -C １ -C ６ Alkylene-S(O) ２ -CH=CHR ７ or R ５ and R ６ together with the nitrogen to which they are attached form a 4- to 7-membered saturated heterocyclic group containing one ring and one nitrogen as the only heteroatom in the ring, said 4- to 7-membered saturated heterocyclic group being -(CH ２ ) ｎ -S(O) ２ -CH=CHR ７ is substituted with; R ７ is hydrogen, -C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy, and -(CH ２ ) ｍ -NR ８ R ９ selected from the group consisting of: R ８ and R ９ are independently —H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; or R ８ and R ９ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen in a ring atom and optionally substituted by halo; n is 0 or 1; m is 1 or 2; R ２ｂ is -NR １０ R １１ and R １０ is H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; and R １１ teeth, -(C １ -C ４ alkylene)-N(R １２ )-CN, and -(CH ２ ) ｗ -R １３ or is selected from the group consisting of: R １０ and R １１ together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said 4-8 membered saturated heterocyclic group being -(EH ２ ) ｘ -N(R １４ )- a 4-6 membered saturated heterocyclic group containing one ring and one nitrogen as the only heteroatom in the ring, said nitrogen being substituted with cyano; cyano, provided that when cyano is a substituent, R １０ and R １１ wherein said 4-8 membered saturated heterocyclic group formed together with the nitrogen to which they are attached contains said second nitrogen ring atom, and said cyano is connected to said 4-8 membered saturated heterocyclic group at said second ring nitrogen. and is substituted with one substituent selected from the group consisting of: R １２ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy; R １３ is a 4-5 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, said nitrogen being substituted with cyano, and said heterocyclic group being selected from the group consisting of hydroxy, CN, C １ -C ４ Cyanoalkyl, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ may be further substituted with one substituent selected from the group consisting of haloalkoxy, or halo; or R １３ is a 6-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, one of said nitrogen atoms being substituted with cyano, and said heterocyclic group is selected from the group consisting of hydroxy, CN, C １ -C ４ Cyanoalkyl, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ may be further substituted with one substituent selected from the group consisting of haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; or R １３ is a seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, one of the nitrogen ring atom(s) being substituted with cyano, and the heterocyclic group is selected from the group consisting of hydroxy, CN, C １ -C ４ Cyanoalkyl, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ optionally further substituted with one substituent selected from the group consisting of haloalkoxy, or halo, provided that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; R １４ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy; w is 0, 1 or 2; x is 0 or 1; R ２ｃ is -NR １５ R １６ and R １５ is H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy, １ -C ４ The alkyl may be substituted with, for example, CN; and R １６ teeth, -(C １ -C ４ alkylene)-N(R １７ )C(O)C(R １９ ) = C(R ２０ ) R １８ and -(CH ２ ) ｙ -R ２１ or is selected from the group consisting of: R １５ and Ｒ１６ together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said heterocyclic group being - (CH ２ ) ｑ -N(R １７ )C(O)C(R １９ ) = C(R ２０ ) R １８ and, -C(O)C(R １９ ) = C(R ２０ ) R １８ where -C(O)C(R １９ ) = C(R ２０ ) R １８ is a substituent, R １５ and R １６ and the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing the second nitrogen ring atom, and the —C(O)C(R １９ ) = C(R ２０ ) R １８ is connected to the heterocyclic group at the second ring nitrogen, １９ ) = C(R ２０ ) R １８ and and is substituted with one substituent selected from the group consisting of: R １７ is hydrogen, -C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; R １８ represents hydrogen, —COOH, —C(O)O—C １ -C ４ Alkyl, —C(O)O—C １ -C ４ Haloalkyl, —C(O)—C １ -C ４ Alkyl, —C(O)—C １ -C ４ Haloalkyl, —C(O)NR ２２ R ２３ , -(CH ２ ) ｚ -NR ２２ R ２３ , -(CH ２ ) ｕ -R ３４ , -(C １ -C ２ alkyl)-(C １ -C ２ Alkoxy), -S(O) ２ -C １ -C ４ Alkyl, —S(O) ２ -C １ -C ４ haloalkyl, and R ３５ and R ２０ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; or R １８ and R ２０ can be taken together with the carbon to which they are attached to form a 4-5 membered carbocyclic or heterocyclic ring containing one heteroatom selected from N, O, and S, said carbocyclic or heterocyclic ring being optionally substituted with, for example, methyl, halo, hydroxy, methoxy, or carbonyl; R １９ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; R ２１ teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is —C(O)C(R １９ ) = C(R ２０ ) R １８ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ the aforementioned 4-5 membered saturated heterocyclic group which is further substituted with one substituent selected from the group consisting of haloalkoxy and halo, or with two halo substituents; A 6-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is —C(O)C(R １９ ) = C(R ２０ ) R １８ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ the 6-membered saturated heterocyclic groups which are further substituted with one substituent selected from the group consisting of haloalkoxy, or halo, or with two halo substituents, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atom(s) of the heterocyclic group is / are -C(O)C(R １９ ) = C(R ２０ ) R １８ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ the seven-membered saturated heterocyclic group, which is further substituted with one substituent selected from the group consisting of haloalkoxy, or halo, or with two halo substituents, provided that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not attached to a heteroatom; Selected from: R ２２ and R ２３ are independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; R ３４ is halo, hydroxy, C １ -C ４ Alkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy, C １ -C ４ Hydroxyalkyl, CH ２ -(C ３ -C ６ heterocyclyl), and C ２ -C ３ a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkynyl; R ３５ teeth, Halo, Hydroxy, C １ -C ４ Alkyl, C １ -C ４ Hydroxyalkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ haloalkoxy; C optionally substituted with 1 or 2 substituents independently selected from halo, hydroxy and methyl ３ -C ６ heterocyclyl; and C optionally substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl. ３ -C ６ cycloalkyl is a 5- to 6-membered heteroaryl group optionally substituted with 0, 1, 2, or 3 substituents independently selected from: y is 0, 1 or 2; z is 1 or 2; q is 0 or 1; u is 0, 1 or 2; R ２ｄ teeth, -NR ２４ R ２５ 、 -C(O)N(R ２７ )-(C １ -C ４ alkylene)-C(O)CH=CHR ２６ , and -O-(C １ -C ２ alkylene)-C(O)CH=CHR ２６ selected from the group consisting of: R ２４ is H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy; and R ２５ is -(C １ -C ４ alkylene)-C(O)CH=CHR ２６ or R ２４ and R ２５ together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, said heterocyclic group being -(C ０ -C ２ alkylene)-C(O)CH=CHR ２６ and the heterocyclic group is substituted with C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ may be further substituted with haloalkoxy; R ２６ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy; and R ２７ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; R ２ｅ is -NR ２８ R ２９ and R ２８ is H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy; and R ２９ is -(CH ２ ) ｔ -R ３０ and R ３０ teeth, A 4-5 membered saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, wherein the nitrogen ring atom of the heterocyclic group is -C(O)C≡CR ３１ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ the aforementioned 4-5 membered saturated heterocyclic group further substituted with one substituent selected from the group consisting of haloalkoxy and halo; a 6-membered saturated heterocyclic group containing one or two nitrogen atoms as the only heteroatom(s) in the ring, wherein one of the nitrogen atoms in the heterocyclic group is —C(O)C≡CR ３１ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ said 6-membered saturated heterocyclic group being further substituted with one substituent selected from the group consisting of haloalkoxy, or halo, with the proviso that said optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; and A seven-membered saturated heterocyclic group containing one nitrogen as the only heteroatom(s) in the ring and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein one of the nitrogen ring atoms of the heterocyclic group is -C(O)C≡CR ３１ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Cyanoalkyl, C １ -C ４ Haloalkyl, C １ -C ４ the seven-membered saturated heterocyclic group, further substituted with one substituent selected from the group consisting of haloalkoxy, or halo, with the proviso that the optional hydroxy, CN, cyanoalkyl, and halo substituents are not bonded to a heteroatom; Selected from: R ３１ is -(CH ２ ) ｖ -NR ３２ R ３３ and -(CH ２ ) ｐ -R ３６ selected from the group consisting of: R ３２ and R ３３ are independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, and C １ -C ４ haloalkoxy; t is 0, 1 or 2; v is 1 or 2; p is 0, 1 or 2; R ３６ is halo, hydroxy, C １ -C ４ Alkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy and C ２ -C ３ a 4-10 membered heterocycle substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkynyl; However, when the compound is of formula I, R ２ｃ teeth not; and with the further proviso that when the compound is of formula II, R ２ｃ Ha-NR １５ R １６ Instead, R １５ and R １６ together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group containing a second nitrogen as the only additional heteroatom in the ring, said second nitrogen being —C(O)—CH═CH ２ is replaced by .

2. 2. The compound of claim 1, which is a compound of formula I or a salt thereof, and / or an isotopic substitution thereof:

3. 10. The compound of claim 1, which is a compound of formula II or a salt thereof, and / or an isotopic substitution thereof:

4. R ｘ is hydrogen, hydroxy, and -OCHF ２ and R ｙ is selected from hydrogen, F and Cl, and R ｚ The compound according to any one of claims 1 to 3, or a salt thereof, and / or an isotopic substitution thereof, wherein is selected from hydrogen, Me, F, and Cl.

5. R ｘ , R ｙ , and R ｚ The compound according to any one of claims 1 to 3, or a salt thereof, and / or an isotope-substituted product thereof, wherein each of

6. R １ but, The compound according to any one of claims 1 to 5, or a salt thereof, and / or an isotope-substituted derivative thereof, selected from the group consisting of:

7. R １ but, The compound according to any one of claims 1 to 5, or a salt thereof, and / or an isotope-substituted derivative thereof.

8. (i) R ３ is selected from the group consisting of hydrogen and fluoro; or (ii) R ４ is selected from the group consisting of hydrogen, methyl, ethyl, ethynyl, propynyl, difluoromethyl, CN, cyclopropyl, fluoro and chloro; or Both (i) and (ii) above, The compound according to any one of claims 1 to 7, or a salt thereof, and / or an isotope-substituted derivative thereof.

9. R ３ is fluoro and R ４ The compound according to claim 8, wherein is ethynyl, or a salt thereof, and / or an isotopic substitution thereof.

10. R ２ｃ Ga-NR １５ R １６ and R １５ But H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, or C １ -C ４ haloalkoxy, １ -C ４ The alkyl may be substituted with, for example, CN; and R １６ But -(C １ -C ４ alkylene)-N(R １７ )C(O)C(R １９ ) = C(R ２０ ) R １８ and -(CH ２ ) ｙ -R ２１ The compound according to any one of claims 1 to 9, or a salt thereof, and / or an isotope-substituted derivative thereof, selected from the group consisting of:

11. R １５ is H, methyl, ethyl, -CH ２ -cyclopropyl, -CH ２ CH ２ CN, -CH ２ CHF ２ and -CH ２ CH ２ OCH ３ 11. The compound according to claim 10, selected from the group consisting of:

12. R １５ The compound according to claim 10, wherein is methyl, or a salt thereof, and / or an isotopic substitution thereof.

13. R １６ But -(CH ２ ) ｙ -R ２１ The compound according to any one of claims 10 to 12, or a salt thereof, and / or an isotope-substituted derivative thereof,

14. The compound according to any one of claims 10 to 13, wherein y is 0, or a salt thereof, and / or an isotope-substituted derivative thereof.

15. R ２１ is a 4-5 membered monocyclic saturated heterocyclic group containing one nitrogen as the only heteroatom in the ring, and the nitrogen ring atom of the heterocyclic group is -C(O)C(R １９ ) = C(R ２０ ) R １８ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ The compound according to any one of claims 10 to 14, or a salt thereof, and / or an isotopic substitution thereof, which is further substituted with one substituent selected from the group consisting of haloalkoxy and halo, or with two halo substituents.

16. R ２１ wherein the heterocyclic group is and the ring nitrogen of the heterocyclic group is selected from the group consisting of —C(O)C(R １９ ) = C(R ２０ ) R １８ and the heterocyclic group is not further substituted or is substituted with hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ The compound according to any one of claims 10 to 14, or a salt thereof, and / or an isotope-substituted derivative thereof, which is substituted with one substituent selected from haloalkoxy and halo, or substituted with two halos.

17. R １６ but, and wherein the azetidine, pyrrolidine, piperidine and 5-azaspiro[2.4]heptane groups are not further substituted or are selected from the group consisting of hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ The compound according to any one of claims 10 to 12, or a salt thereof, and / or an isotopic substitution thereof, which is substituted with one substituent selected from haloalkoxy and halo, or substituted with two halos.

18. R １６ but, 18. The compound according to claim 17, selected from the group consisting of:

19. R １５ and R １６ together with the nitrogen to which they are attached form a 4-8 membered saturated heterocyclic group optionally containing a second nitrogen as the only additional heteroatom in the ring, said heterocyclic group being -C(O)C(R １９ ) = C(R ２０ ) R １８ is substituted with, where R １５ and R １６ but the 4-8 membered saturated heterocyclic group they form together with the nitrogen to which they are attached contains the second nitrogen ring atom, and the —C(O)C(R １９ ) = C(R ２０ ) R １８ The compound according to any one of claims 1 to 9, or a salt thereof, and / or an isotopic substitution thereof, wherein: is attached to the heterocyclic group at the second ring nitrogen.

20. R １５ and R １６ together with the nitrogen to which they are attached form said 4-8 membered saturated heterocyclic group optionally containing a second nitrogen ring atom as the only additional heteroatom in the ring, said heterocyclic group being -(CH ２ ) ｑ -N(R １７ )C(O)C(R １９ ) = C(R ２０ ) R １８ The compound according to any one of claims 1 to 9, or a salt thereof, and / or an isotope-substituted derivative thereof, wherein

21. R １５ and R １６ together with the nitrogen to which they are attached form the 4-8 membered saturated heterocyclic group The compound according to any one of claims 1 to 9, or a salt thereof, and / or an isotope-substituted derivative thereof, selected from the group consisting of:

22. R １９ The compound according to any one of claims 1 to 21, or a salt thereof, and / or an isotope substitution thereof, wherein is hydrogen.

23. R ２０ The compound according to any one of claims 1 to 22, or a salt thereof, and / or an isotope substitution thereof, wherein is hydrogen.

24. R １８ The compound according to any one of claims 1 to 23, wherein is H, or a salt thereof, and / or an isotope substitution thereof.

25. R １８ But, -R ３４ or -CH ２ -R ３４ The compound according to any one of claims 1 to 23, or a salt thereof, and / or an isotope-substituted derivative thereof,

26. R ３４ azetidine, pyrrolidine, 2-azabicyclo[2.1.1]hexane, morpholine, 2-oxa-5-azabicyclo[4.1.0]heptane, 1,4-oxazepane, 2-oxa-6-azaadamantane, 5-oxa-8-azaspiro[2.6]nonane, 2-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane , 3-oxa-9-azabicyclo[3.3.1]nonane, 3,7-dioxa-9-azabicyclo[3.3.1]nonane, 3-oxa-7-azabicyclo[3.3.1]nonane, 3,9-dioxa-7-azabicyclo[3.3.1]nonane, 3-oxa-8-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.2]octane, 7-oxa-2-azabicyclo[3.3.1]nonane, 8-oxa-3-azabicyclo[3.2.1]octane, 9-oxa-3-azabicyclo[3.3.1]nonane, 6-oxa-8-azabicyclo[3.2.1]octane Cyclo[3.2.2]nonane, 2-oxa-6-azaspiro[3.3]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-thiazepane, 1,4-thiazepane 1,1-dioxide, 3-thia-6-azabicyclo[3.2.1]octane, 3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide, 3-thia-7-azabicyclo[3.3.1]nonane, 3-thia-6-azabicyclo[3.2.1] and hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, each of which is selected from halo, hydroxy, C １ -C ４ Alkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy and C ２ -C ３ 26. The compound according to claim 25, or a salt thereof, and / or an isotopic substitution thereof, each of which is substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkynyl.

27. R １８ But, -R ３５ The compound according to any one of claims 1 to 23, or a salt thereof, and / or an isotope-substituted derivative thereof,

28. R ３５ is selected from the group consisting of pyrimidinyl, pyrazinyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4-triazolyl, imidazolyl, 4H-1,2,4-triazolyl, 1,2,4-thiadiazolyl, and isoxazolyl, each of which is Halo, Hydroxy, C １ -C ４ Alkyl, C １ -C ４ Hydroxyalkyl, C １ -C ６ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ haloalkoxy; C optionally substituted with 1 or 2 substituents independently selected from halo, hydroxy and methyl ３ -C ６ heterocyclyl; and C optionally substituted with 1 or 2 substituents independently selected from halo, hydroxy, and methyl. ３ -C ６ cycloalkyl 28. The compound according to claim 27, or a salt thereof, and / or an isotopic substitution thereof, wherein the compound is substituted with 0, 1, 2, or 3 substituents independently selected from:

29. R １８ -COOH, -C(O)OCH ３ , —C(O)OCH ２ CH ３ , -C(O)OCH(CH ３ ) ２ , -C(O)N(CH ３ ) ２ , —C(O)-cyclopropyl, —CH ２ OCH ３ , -CH ２ N (CH ３ ) ２ , -S(O) ２ CH ３ , -S(O) ２ CH ２ CH ３ , -S(O) ２ -cyclopropyl, The compound according to any one of claims 1 to 23, or a salt thereof, and / or an isotopic substitution thereof, selected from the group consisting of:

30. R ２ is R ２ｅ 10. The compound according to any one of claims 1 to 9, or a salt thereof, and / or an isotope-substituted derivative thereof,

31. R ２８ The compound according to claim 30, wherein is methyl, or a salt thereof, and / or an isotopic substitution thereof.

32. 32. The compound according to claim 30 or 31, wherein t is 0 or 1; v is 1; and p is 0 or 1, or a salt thereof, and / or an isotopic substitution thereof.

33. R ２９ but, wherein the azetidine group and the pyrrolidine group are not further substituted or are selected from the group consisting of hydroxy, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Cyanoalkyl, C １ -C ４ The compound according to any one of claims 30 to 32, or a salt thereof, and / or an isotope-substituted product thereof, each of which is substituted with one substituent selected from haloalkoxy and halo.

34. R ３１ but, The compound according to any one of claims 30 to 33, or a salt thereof, and / or an isotope-substituted derivative thereof, selected from the group consisting of:

35. A compound selected from the following, or a salt thereof.

36. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1 to 35, wherein the salt is a pharmaceutically acceptable salt.

38. A pharmaceutical formulation comprising the compound according to any one of claims 1 to 37, or a salt thereof, and / or an isotopic substitution thereof, and a pharmaceutically acceptable carrier.

39. A compound according to any one of claims 1 to 37 or a pharmaceutical formulation according to claim 38 for use in the treatment or prevention of cancer.

40. 40. The compound or pharmaceutical composition for use according to claim 39, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, bile duct cancer, thyroid cancer, gallbladder cancer, uterine cancer, mesothelioma, cervical cancer, and bladder cancer.

41. The cancers include glioblastoma multiforme, low-grade glioma, squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, invasive breast cancer, esophageal cancer, gastric adenocarcinoma, small intestinal adenocarcinoma, colon adenocarcinoma, rectal adenocarcinoma, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, pancreatic adenocarcinoma, clear cell renal cell carcinoma, bladder urothelial carcinoma, prostate cancer, ovarian serous cystadenocarcinoma, endometrial cancer of the uterine corpus, cervical squamous cell carcinoma and cervical adenocarcinoma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, plasma cell myeloma, uterine carcinosarcoma, mesothelioma, adrenal gland sarcoma, and ovarian cancer.

40. The compound or pharmaceutical composition for use according to claim 39, wherein the compound or pharmaceutical composition is selected from the group consisting of interstitial carcinoma, brain low-grade glioma, diffuse large B-cell lymphoma, esophageal adenocarcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, pheochromocytoma and paraganglioma, sarcoma, testicular germ cell tumor, thymoma, uveal melanoma, metastatic colorectal cancer, bladder cancer, adenoid cystic carcinoma, myelodysplasia, breast cancer, thyroid cancer, glioma, esophageal / gastric cancer, pediatric Wilms' tumor, pediatric acute lymphocytic leukemia, chronic lymphocytic leukemia, mature B-cell malignancies, pediatric neuroblastoma, and melanoma.

42. 42. The compound or pharmaceutical composition for use according to any one of claims 39 to 41, wherein (i) the cancer is a KRAS G12C-mediated cancer, (ii) the subject has been diagnosed with a KRAS G12C-mediated cancer, or both (i) and (ii).

43. A compound or pharmaceutical composition for use according to any one of claims 39 to 42, adapted to be administered in a therapeutically effective amount.

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