EP4695262A1

EP4695262A1 - Pyrido[4,3-d]pyrimidine compounds

Info

Publication number: EP4695262A1
Application number: EP24720578.4A
Authority: EP
Inventors: Benjamin Joseph Burke; Jacob Cole DEFOREST; Asako Nagata; Simon Paul Planken; Jillian Elyse SPANGLER; Scott Channing Sutton; John Howard Tatlock; Hanna Maria WISNIEWSKA; Shouliang YANG
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 2023-04-10
Filing date: 2024-04-07
Publication date: 2026-02-18
Also published as: WO2024213979A1

Abstract

The invention relates to compounds of Formula (I)-(III) and pharmaceutically acceptable salts thereof to their use in medicine; to compositions containing them; to processes for their Intermediate; and to intermediates used in such processes. The compounds the present invention may be useful in the treatment, prevention, suppression and amelioration diseases, disorders and conditions such as cancers.

Description

Pyrido[4,3-d]pyrimidine Compounds

BACKGROUND OF THE INVENTION

The present invention relates to novel pyrido[4,3-d]pyrimidine compounds as Kirsten rat sarcoma viral oncogene homolog (KRAS) Inhibitors. The invention also relates to the Intermediate of the compounds and intermediates used in the Intermediate, compositions containing the compounds, and uses of the compounds for the treatment of KRAS related diseases such as cancers.

KRAS, HRAS (Harvey Rat sarcoma virus) and NRAS (Neuroblastoma RAS Viral Oncogene Homolog) belong to a group of GTPases that are critical in the survival and proliferation of cells through complex signaling cascades. Mutated RAS genes are found in approximately 30% of all cancers (Hyun et al 2021 Int. J. Mol. Sci. 22 (22), 12142). KRAS is the most frequently mutated RAS isoform in cancer cells (up to 85%), leading to development of cancers including non-small cell lung cancer (NSCLC), colorectal and pancreatic cancer that collectively and individually have significant unmet medical needs for affected patients. KRAS mutations are seen extensively in pancreatic ductal adenocarcinoma (PDAC). Mutations in KRAS have been observed in 30% of NSCLC cases, which is the major (80%) form of lung cancer. KRAS mutations seen in NSCLC include 39% of G12C, 18-21% of G 12V, and 17-18% of G12D. KRAS mutations occur in 35-45% of colon cancers, leading to drug resistance.

Inhibitors of KRAS have been sought for decades, with recent advances seeing approval of sotorasib and subsequent KRAS G12C targeting compounds in trials (Palmer et al 2021 NPJ Precision Oncology, 5, 98). Sotorasib specifically targets mutations in KRAS through covalent modification of mutant cysteine at position 12. For this reason, sotorasib and other currently known KRAS inhibitors that rely on the same mechanism of action may be narrow in treatment scope and be of limited use when considering other major KRAS mutations such as G12V and G12D.

Accordingly, there remains a need for new KRAS inhibitors that may be used for the treatment of a broader scope of cancers.

Summary of the Invention

The present invention provides, in part, compounds of Formula (I), Formula (II), and Formula (III), and pharmaceutically acceptable salts thereof. The compounds of the present invention may inhibit the activities of all KRAS G12C, KRAS G12D, and KRAS G12V receptors, and may be useful in the treatment, prevention, suppression, and amelioration of diseases such as cancers, disorders and conditions mediated by any of KRAS G12C, KRAS G12D, and KRAS G12V receptors, or a combination thereof. Also provided are pharmaceutical compositions, comprising the compounds or salts of the invention, alone or in combination with additional anticancer therapeutic agents. The present invention also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts and compositions of the invention, and methods of using the foregoing. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

According to an embodiment of the invention there is provided a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C3-C10 cycloalkyl or 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, wherein said C3-C10 cycloalkyl or said 4-12 membered heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkylidenyl, C1-C3 haloalkylidenyl, C1-C3 alkyl wherein when present two of the Ci-Csalkyl together with the carbon from which they attach may form a spirocyclic ring, C1-C3 alkoxy, -OC(O)NH₂, -OC(O)NHCH₃, -OC(O)N(CH₃)₂, wherein the C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkylidenyl or C1-C3 alkylidenyl, is each optionally substituted with one, two or three R¹² substituents;

R² is H or is selected from the group consisting of -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -(Ci-Ce alkylene)-SH, -(C1-C3 alkylene)-S-(Ci-Cs alkyl), -(C1-C3 alkylene)- (S=O)-(Ci-C3 alkyl), -(C1-C3 alkylene)-(SO2)-(Ci-Cs alkyl), Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce fluoroalkyl, C3-C6 fluorocycloalkyl, and Ci-Ce alkoxy, each optionally substituted with one, two or three substituents independently selected from the group consisting of - OH, -CN, -NH₂, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)₂, -SH, -(C1-C4 alkylene)-CN, -(C1-C4 alkylene)-OH, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; R³ is: wherein R⁷ and R⁸ are each independently H or C1-C3 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 alkoxy; alternatively R⁷ and R⁸ together with the C atoms to which they are attached form a Cs-Cs cycloalkyl or 3-8 membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S, wherein said cycloalkyl or heterocyclyalkyl is further optionally substituted with one, two or three substituents independently selected from the group consisting of -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C2-C3 alkynyl, C3-C5 cycloalkyl or together with the carbon to which it is attached C3-C5 spirocycloalkyl; and R³ is optionally further substituted with one, two or three substituents independently selected from the group consisting of -OH, -NH2, halogen, -CN or C1-C3 alkyl;

R⁴ is H, halogen, -CN, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 fluoroalkyl;

R⁵ is H, -OH, halogen, -NH2, CN, or selected from the group consisting of -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -(Ci-Ce alkylene)-SH, -(C1-C3 alkylene)-S-(Ci-Cs alkyl), -(C1-C3 alkylene)-(S=O)-(Ci-C₃ alkyl), -(C1-C3 alkylene)-(SO₂)-(Ci-C3 alkyl), Ci-C₆ alkyl, C3-C6 cycloalkyl, Ci-Ce fluoroalkyl, C3-C6 fluorocycloalkyl, and Ci-Ce alkoxy each is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, -NH2, -SH, -(C1-C4 alkylene)-CN, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; or alternatively, R⁵ and the carbon atom that R⁵ is attached to, and R² and the nitrogen atom that R² is attached to together form a 4-8 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, or heteroatom-containing groups selected from the group consisting of N(Ci-Ce alkyl), -(S=O)-, and -(SO2)-, wherein said 4-8 membered heterocycloalkyl is optionally substituted with one, two or three substituents selected from the group consisting of -OH, -OCH₃, -CN, halogen, C1-C3 alkyl, -(Ci-Ce alkylene)-CN, and -(Ci-Ce alkylene)-OH;

R⁶ at each occurrence is independently H, -OH, halogen, CN, or is selected from the group consisting of -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce fluoroalkyl, C3-C6 fluorocycloalkyl, and Ci-Ce alkoxy, each optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, -(C1-C4 alkylene)-CN, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy;

L is a linker comprising one, two or three members independently selected from the group consisting of -O-, -S-, -NR⁹-, and -CR¹⁰R¹¹;

R⁹, R¹⁰, and R¹¹ are each independently H or C1-C3 alkyl;

R¹² are each independently selected from the group consisting of -CN, -OH, -C1-C3 alkyl, C1-C3 alkoxy, -cyclopropyl, -oxetane, -C(O)NR⁹ R¹⁰, -S(O)2Rg, and halogen or alternately two of the R¹² together with the carbon they are attached form a C3-C6 cycloalkyl ring or a 3-6 membered heterocycloalkyl ring, and wherein the C1-C3 alkoxy is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -OCH3, and halogen;

X is O, N, or S;

I is 1 or 2; and x is 0,1 , or 2.

Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) is identical to the embodiment of Formula (I) provided above.

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

Detailed Description of the Invention

The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

E1 A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

E2 A compound of embodiment E1 , or a pharmaceutically acceptable salt thereof, wherein the linker L is -(O-CH2)-. E3 A compound of embodiment E1 or embodiment E2 or a pharmaceutically acceptable salt thereof, wherein R¹ is a 5-10 membered heterocycloalkyl substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, halogen, Ci-C₃ alkylidenyl, Ci-C₃ haloalkylidenyl, alkylidenylcyclopropyl, alkylidenyloxetane, Ci-C₃ alkyl wherein when present two of the Ci-C₃alkyl together with the carbon from which they attach may form a spirocyclic ring, Ci-C₃ alkoxy, - OC(O)NH₂, -OC(O)NHCH₃, -OC(O)N(CH₃)₂, wherein the C C₃ alkyl, C C₃ alkoxy, Ci-C₃ haloalkylidenyl or C1-C3 alkylidenyl, is each optionally substituted with one, two or three R¹² substituents.

E4 A compound of embodiment E1 or embodiment E2, or a pharmaceutically acceptable salt thereof, wherein R¹ is a 5-8 membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N and O, and said 5-8 membered heterocycloalkyl is substituted with one and only one C C₃ alkylidenyl or Ci-C₃ haloalkylidenyl, and is further optionally substituted with one, two or three R¹² substituents independently selected from the group consisting of -OH, -CN, halogen, C C₃ alkyl, Ci-C₃ alkoxy, -OC(O)NH₂, -OC(O)NHCH₃, -OC(O)N(CH₃)₂, wherein the Ci-C₃ alkoxy is optionally substituted with one, two or three R¹² substituents independently selected from the group consisting of -OH, -OCH₃ and halogen.

E5 A compound of embodiment E4, or a pharmaceutically acceptable salt thereof, wherein L-R¹ is selected from the group consisting of:

E6 A compound of embodiment E4, or a pharmaceutically acceptable salt thereof, wherein

L-R¹ is selected from the group consisting of:

E7 A compound of embodiment E4, or a pharmaceutically acceptable salt thereof, wherein

L-R¹ is selected from the group consisting of: E8 A compound of embodiment E4, or a pharmaceutically acceptable salt thereof, wherein

L-R¹ is selected from the group consisting of:

E9 A compound of any one of embodiments E1 to E8, or a pharmaceutically acceptable salt thereof, wherein R² is H or is selected from the group consisting of -(C1-C5 alkylene)-OH and C1-C5 alkyl, each optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, and halogen.

E10 A compound of any one of embodiments E1 to E9, or a pharmaceutically acceptable salt thereof, wherein benzene ring of R³ is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, and C2-C3 alkynyl.

E11 A compound of any one of embodiments E1 to E10, or a pharmaceutically acceptable salt thereof, wherein R³ is:

E12 A compound of embodiment E1 to E10, or a pharmaceutically acceptable salt thereof, wherein R³ is:

E13 A compound of any one of embodiments E1 to E12, or a pharmaceutically acceptable salt thereof, wherein R⁴ is -CN, Cl or F.

E14 A compound of any one of embodiments E1 to E13, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ at each occurrence are each independently selected from the group consisting of H, -OH, -CN, and halogen, or R⁵ and R⁶ at each occurrence is independently selected from the group consisting of -(C1-C5 alkylene)-OH and C1-C5 alkyl, each -(C1-C5 alkylene)-OH and C1-C5 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, and halogen.

E15 A compound of any one of embodiments E1 to E14, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (II): wherein Y is selected from the group consisting of CH2, O, N(Ci-Ce alkyl), S, (S=O), and (SO2), R¹³ at each occurrence is independently selected from the group consisting of - OH, -CN, halogen, C1-C3 alkyl, -(Ci-Ce alkylene)-CN, and -(Ci-Ce alkylene)-OH; and m and n are each independently 0, 1 , 2 or 3, y is 0, 1 , 2, or 3, and m plus n is 1 , 2, 3, 4, or 5.

E16 A compound of embodiment E15, or a pharmaceutically acceptable salt thereof, wherein I is 1 , n is 1 , m is 3, x is 0, and y is 0.

E17 A compound of embodiment E16, or a pharmaceutically acceptable salt thereof, wherein Y is -CH₂- or O.

E18 A compound of embodiment E17, or a pharmaceutically acceptable salt thereof, wherein Y is O.

E19 A compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (III):

E20 A compound of embodiment E1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

E21 A compound of embodiment E1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

E22 A compound of embodiment E1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

E23 A compound that is: or a pharmaceutically acceptable salt thereof.

E24 A compound that is:

E25 A pharmaceutically acceptable salt of a compound, wherein the compound is:

E26 A compound that is or a pharmaceutically acceptable salt thereof.

E27 A compound that is

E28 A pharmaceutically acceptable salt of a compound, wherein the compound is:

E29 A compound that is or a pharmaceutically acceptable salt thereof.

E30 A compound that is E31 A pharmaceutically acceptable salt of a compound, wherein the compound is:

E32 A compound that is or a pharmaceutically acceptable salt thereof.

E33 A compound that is

E34 A pharmaceutically acceptable salt of a compound, wherein the compound is:

E35 A compound that is or a pharmaceutically acceptable salt thereof. E36 A compound that is

E37 A pharmaceutically acceptable salt of a compound, wherein the compound is:

E38 A compound that is or a pharmaceutically acceptable salt thereof.

E39 A compound that is

E40 A pharmaceutically acceptable salt of a compound, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

E40b A compound that is E40c A pharmaceutically acceptable salt of a compound, wherein the compound is: E41 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

E42 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof.

E43 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, as a single agent.

E44 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, and further comprising administering a therapeutically effective amount of an additional anticancer therapeutic agent.

E45 A method for treating cancer of any one of embodiments E22 to E24, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

E46 A compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, for use as a medicament.

E47 A compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

E48 A compound for use in the treatment of cancer according to embodiment E27, wherein said cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

E49 Use of a compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. E50 Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer according to embodiment E29, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

E51 A method for the treatment of a disorder mediated by inhibition of KRAS G12C, KRAS G12D, and KRAS G12V receptors in a subject, comprising administering to the subject in need thereof a compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.

E52 A pharmaceutical combination comprising a compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical combination is a fixed or non-fixed combination.

E53 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E32 and at least one excipient.

Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or a pharmaceutically acceptable salt thereof.

Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds, stereoisomers of the compounds, hydrates of the compounds, and pharmaceutically acceptable salts of the stereoisomers described herein.

Definitions

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

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

“Compounds of the invention” include compounds of Formula (I) and the novel intermediates used in the Intermediate thereof. One of ordinary skill in the art will appreciate that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof, where they may be formed.

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

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

If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

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

The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=0) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different. Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art.

“Halogen” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

“Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -C=N (also depicted herein as “-CN”).

"Hydroxy" refers to an -OH group.

“Oxo” refers to a double bonded oxygen (=0). "Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 6 carbon atoms (“Ci-Ce alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

“Fluoroalkyl” refers to an alkyl group, as defined herein, wherein from one to all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF₃) and pentafluoroethyl (-C2F5).

“Alkylene” refers to a bivalent aliphatic hydrocarbon radical that has a specified number of carbon atoms. Alkylene groups may contain, but are not limited to, 1 to 6 carbon atoms (“Ci-Ce alkylene”), or 1 to 2 carbon atoms (“C1-C2 alkylene”). Examples include -(CH2)- (methylene) and -(CH2-CH2)- (ethylene).

“Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 6 carbon atoms (“Ci-Ce alkoxy”), or 1 to 3 carbon atoms (“C1-C3 alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and the like.

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

“Cycloalkyl” refers to a fully saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. Cycloalkyl groups may contain, but are not limited to, 3 to 10 carbon atoms (“C3-C10 cycloalkyl”), 3 to 8 carbon atoms (“Cs-Cs cycloalkyl”), 3 to 6 carbon atoms (“C3-C6 cycloalkyl”), 3 to 5 carbon atoms (“C3-C5 cycloalkyl”) or 3 to 4 carbon atoms (“C3-C4 cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

“Alkylidenyl” refers to linear or branched-chain monovalent hydrocarbon radical having formula =CR’R”, where R’ and R” may be independently selected from H or an alkyl group. Exemplary alkylidenyl radicals include, but are not limited to, methylidenyl (=CH2), ethylidenyl (=CHCHs), iso-propylidenyl (=C(CHs)2, and propylidenyl (=CH-CH2-CHs). “Haloalkylidenyl” refers to linear or branched-chain monovalent hydrocarbon radical having formula =CR’R”, where R’ or R” are as defined for Alkylidenyl and further comprises at least one halogen atom. Exemplary haloalkylidenyl radicals include, but are not limited to, fluoromethylidenyl (=CHF), difluoromethylidenyl (=CF2), fluoroethylidenyl (=CFCHs), and fluoropropylidenyl (=CF-CH2-CHs).

“Fluorocycloalkyl” refers to a cycloalkyl group, as defined herein, wherein from one to all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. Examples include, but are not limited to, fluorocyclcopropyl, fluorocyclcobutyl, fluorocyclcopentyl and fluorocycl cohexyl,

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

Heterocycloalkyl rings may be optionally substituted, unsubstituted or substituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a monocyclic, bicyclic, tricyclic, spirocyclic, bridged or fused ring attached thereto.

Heterocycloalkyl rings may include, but are not limited to, 4-12 membered heterocyclyl groups, for example 5-8 or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein. Examples of heterocycloalkyl ring group of the present invention may include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaazepanyl, thieazepanyl, a radical of hexahydro-1 H-pyrrolizine ring, a radical of 8-oxa-3-azabicyclo[3.2.1]octane ring, a radical of 3-azabicyclo[3.2.1]octane ring, a radical of 6-azabicyclo[3.2.1]octane ring, or a radical of 3-azabicyclo[3.2.0]heptane ring.

"Aryl" or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp² hybridization and in which the pi electrons are in conjugation. Aryl groups may contain, but are not limited to, 6 to 10 carbon atoms ("Ce-C aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

Similarly, "heteroaryl" or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in a ring in which all carbon atoms in the ring are of sp² hybridization and in which the pi electrons are in conjugation. Heteroaryl groups may contain, but are not limited to, 5 to 14 ring atoms (“5-14 membered heteroaryl”), 5 to 12 ring atoms (“5-12 membered heteroaryl”), 5 to 10 ring atoms (“5-10 membered heteroaryl”), 5 to 9 ring atoms (“5-9 membered heteroaryl”), or 5 to 6 ring atoms (“5- 6 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Thus, either 5- or 6-membered heteroaryl rings, alone or in a fused structure, may be attached to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyidinyl, pyrazolo[4,3-c]pyidinyl, pyrazolo[3,4-c]pyidinyl, pyrazolo[3,4-b]pyidinyl, isoindolyl, purinyl, indolininyl, imidazo[1 ,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1 ,5- a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, azaquinazolinyl, phthalazinyl, , (pyrido[3,2-d]pyrimidinyl, (pyrido[4,3-d]pyrimidinyl, (pyrido[3,4-d]pyrimidinyl, (pyrido[2,3- d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

“Amino” refers to a group -NH2, which is unsubstituted. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NRxRy, where each of Rx and Ry is defined as further described herein. For example, “alkylamino” refers to a group -NRxRy, wherein one of Rx and Ry is an alkyl moiety and the other is H, and “dialkylamino” refers to -NRxRy wherein both of Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(CI-C4 alkyl) or -N(CI-C4 alkyl)₂) . A wavy line “ - T ' used in a chemical structure in the present disclosure refers to the point of the attachment of a substituent.

The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.

“Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Salts

Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the invention that is suitable for administration to a subject or patient.

In addition, the compounds of Formula (l)-(lll) may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula (I); 2) purifying compounds of Formula (I); 3) separating enantiomers of compounds of Formula (I); or 4) separating diastereomers of compounds of Formula (I).

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

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

Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

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

Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures

(i) by reacting a compound of the invention with the desired acid or base;

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

(iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure.

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

Solvates

The compounds of the invention, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

In addition, the compounds of Formula (l)-(lll) may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula (I)- (III); 2) purifying compounds of Formula (l)-(lll); 3) separating enantiomers of compounds of Formula (I); or 4) separating diastereomers of compounds of Formula (l)-(lll). A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical

Solids by K. R Morris (Ed H. G. Brittain, Marcel Dekker, 1995) Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

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

Complexes

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drughost inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, for example, hydrogen bonded complex (cocrystal) may be formed with either a neutral molecule or with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17; 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64(8), 1269-1288, by Haleblian (August 1975).

Solid form

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COONa⁺, -COOK⁺, or -SOs'Na⁺) or non-ionic (such as -N-N⁺(CH₃)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4^th Edition (Edward Arnold, 1970).

Stereoisomers

Compounds of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds may include c/s and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers.

The pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl- arginine).

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

Conventional techniques for the Intermediate/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein).

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

Tautomerism

Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino/amino, keto/enol, or oxime/nitroso group, lactam/lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

It must be emphasized that while, for conciseness, the compounds of the invention have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention.

Isotopes

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. , ³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.

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

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

Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Intermediates using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.

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

Prodrugs

A compound of the invention may be administered in the form of a prodrug. Thus, certain derivatives of a compound of the invention which may have little or no pharmacological activity themselves may, when administered into or onto the body, be converted into a compound of the invention having the desired activity, for example by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘The Expanding Role of Prodrugs in Contemporary Drug Design and Development, Nature Reviews Drug Discovery, 17, 559-587 (2018) (J. Rautio et al.).

Prodrugs in accordance with the invention may, for example, be produced by replacing appropriate functionalities present in compounds of the invention with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in ‘Design of Prodrugs’ by H. Bundgaard (Elsevier, 1985).

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

Some specific examples of prodrugs in accordance with the invention include:

(i) when a compound of the invention contains a carboxylic acid functionality (- COOH), an ester thereof, such as a compound wherein the hydrogen of the carboxylic acid functionality of the compound is replaced by Ci-Cs alkyl (e.g., ethyl) or (Ci-Cs alkyl)C(=O)OCH₂- (e.g., ‘BuC(=O)OCH₂-);

(ii) when a compound of the invention contains an alcohol functionality (-OH), an ester thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by -CO(Ci-Cs alkyl) (e.g., methylcarbonyl) or the alcohol is esterified with an amino acid;

(iii) when a compound of the invention contains an alcohol functionality (-OH), an ether thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by (Ci-Cs alkyl)C(=O)OCH₂- or -CH₂OP(=O)(OH)₂;

(iv) when a compound of the invention contains an alcohol functionality (-OH), a phosphate thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by -P(=O)(OH)₂ or -P(=0)(ONa⁺)₂ or -P(=0)(O)₂Ca²⁺;

(v) when a compound of the invention contains a primary or secondary amino functionality (-NH₂ or -NHR where R H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is/are replaced by (Ci-Cw)alkanoyl, -COCH₂NH₂ or the amino group is derivatized with an amino acid; (vi) when a compound of the invention contains a primary or secondary amino functionality (-NH2 or -NHR where R H), an amine thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is/are replaced by -CH₂OP(=O)(OH)₂.

(vii) when a compound of the invention contains an alcohol functionality (-OH), replacement of the hydrogen of the alcohol functionality with a group selected the set below: wherein R, R’, R”, R’” are (Ci-Cs)alkyl or (Ci-Cs)alkoxy and can be linear, branched or cyclic. Some preferred prodrugs can be prepared through -OH on a Ce-C bicyclic aryl or a 4-12 membered bicyclic heteroaryl. Some more preferred prodrugs can be prepared through -OH on a naphthyl.

Certain compounds of the invention may themselves act as prodrugs of other compounds the invention It is also possible for two compounds of the invention to be joined together in the form of a prodrug. In certain circumstances, a prodrug of a compound of the invention may be created by internally linking two functional groups in a compound of the invention, for instance by forming a lactone.

Metabolites

Also included within the scope of the invention are active metabolites of compounds of the invention, that is, compounds formed in vivo upon administration of the drug, often by oxidation or dealkylation. Some examples of metabolites in accordance with the invention include, but are not limited to:

(i) where the compound of the invention contains an alkyl group, a hydroxyalkyl derivative thereof (-CH > -COH):

(ii) where the compound of the invention contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR’ -> -NHR or -NHR);

(iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (-NHR -> -NH₂);

(v) where the compound of the invention contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); (vi) where the compound of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH); and

(vii) where the compound contains a hydroxy or carboxylic acid group, the compound may be metabolized by conjugation, for example with glucuronic acid to form a glucuronide. Other routes of conjugative metabolism exist. These pathways are frequently known as Phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, may also be subject to conjugation.

Pharmaceutical Compositions

In another embodiment, the invention comprises pharmaceutical compositions. For pharmaceutical composition purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.

The term “excipient” is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders/binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

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

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

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

Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents.

In another embodiment, the invention comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable Intermediates (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents.

In another embodiment, the invention comprises a topical dosage form. "Topical administration" includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci. , vol. 88, pp. OSS- OSS, 1000.

Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1,1,2-tetrafluoroethane or 1,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

In another embodiment, the invention comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well- known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

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

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

Compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

Sustained-release Intermediates may be used. Suitable examples of sustained-release Intermediates include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

For example, the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsions comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the invention may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co-preci pitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the invention and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the invention are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al. Administration and Dosing

The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

As used herein, the terms, “subject, “individual” or “patient,” used interchangeably, refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following:

(1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and

(3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology or both).

Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

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

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

In another embodiment, the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.

The dosage regimen for the compounds of the invention or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg/kg (i.e. , mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein. In another embodiment, total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg. It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.

Therapeutic Methods and Uses

The compounds of the invention may inhibit the activities of one or more KRAS G12C, KRAS G12D, and KRAS G12V receptors, and may be useful in the treatment, prevention, suppression, and amelioration of diseases such as cancers, disorders and conditions mediated by any of KRAS G12C, KRAS G12D, and KRAS G12V receptors, or a combination thereof.

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

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

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

Co-administration

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

The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

A compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

Classes of additional chemotherapeutic agents, which can be administered in combination with a compound of this invention, include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists; IL-2 receptor agonist (recombinant cytokines or agonists for cytokine receptors); and anti-sense oligonucleotides or oligonucleotides derivatives that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth.

Other additional chemotherapy agents include not only taxanes or platinum agents but also HER2 targeted agents, e.g., trastuzumab.

In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, spindle poison plant alkaloids, MCT4 inhibitors; MAT2a inhibitors; alk/c-Met/ROS inhibitors (including crizotinib or lorlatinib); mTOR inhibitors (including temsirolimus or gedatolisib); src/abl inhibitors (including bosutinib); cyclin-dependent kinase (CDK) inhibitors (including palbociclib, PF-06873600); erb inhibitors (including dacomitinib); PARP inhibitors (including talazoparib); SMO inhibitors (including glasdegib); EGFR T790M inhibitors; PRMT5 inhibitors; TGFPR1 inhibitors; growth factor inhibitors; cell cycle inhibitors, biological response modifiers; enzyme inhibitors; and cytotoxics.

In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from an anti-angiogenesis agent, including for example tyrosine kinase I vascular endothelial growth factor (VEGF) receptor (VEGFR) inhibitors (including sunitinib, axitinib, sorafenib, and tivozanib), TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCp inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (Inlyta™), Sil 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenesis agents include vatalanib (CGP 79787), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), Sil 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdata (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer). Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia™). Yet further anti-angiogenesis agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril ™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Yet further anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Yet further anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).

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

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

In another embodiment, such additional anti-cancer therapeutic agents include docetaxel, paclitaxel, paclitaxel protein-bound particles, cisplatin, carboplatin, oxaliplatin, capecitabine, gemcitabine or vinorelbine.

In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from an epigenetic modulator, where examples include an inhibitor of EZH2 (including PF-06821497), SMARCA4, PBRM1, ARID1A, ARID2, ARID1 B, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1/2 or BCL6.

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

In another embodiment, combinations with pattern recognition receptors (PRRs) are contemplated. PRRs are receptors that are expressed by cells of the immune system and that recognize a variety of molecules associated with pathogens and/or cell damage or death. PRRs are involved in both the innate immune response and the adaptive immune response. PRR agonists may be used to stimulate the immune response in a subject. There are multiple classes of PRR molecules, including toll-like receptors (TLRs), RIG-l-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), and Stimulator of Interferon Genes (STING) protein.

The STING protein functions as both a cytosolic DNA sensor and an adaptor protein in Type 1 interferon signaling. The terms “STING” and “stimulator of interferon genes” refer to any form of the STING protein, as well as variants, isoforms, and species homologs that retain at least a part of the activity of STING. Unless indicated differently, such as by specific reference to human STING, STING includes all mammalian species of native sequence STING, e.g. human, monkey, and mouse STING is also known as - TMEM173.

“STING agonist” as used herein means, any molecule, which upon binding to STING, (1) stimulates or activates STING, (2) enhances, increases, promotes, induces, or prolongs an activity, function, or presence of STING, or (3) enhances, increases, promotes, or induces the expression of STING. STING agonists useful in the any of the treatment method, medicaments and uses of the present invention include, for example, nucleic acid ligands which bind STING.

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

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

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

In another embodiment, such additional anti-cancer therapeutic agents include antibodies that are agonists of 4-1 BB, 0X40, GITR, ICOS, or CD40.

In another embodiment the anti-cancer therapy may be a CAR-T-cell therapy.

Examples of a therapeutic antibody include: an anti-OX40 antibody, an anti-4-1 BB antibody, an anti-HER2 antibody (including an anti-HER2 antibody-drug conjugate (ADC)), a bispecific anti-CD471 anti-PD-L1 antibody, and a bispecific anti-P-cadherin I anti-CD3 antibody. Examples of cytotoxic agents that may be incorporated in an ADC include an anthracycline, an auristatin, a dolastatin, a combretastatin, a duocarmycin, a pyrrolobenzodiazepine dimer, an indolino-benzodiazepine dimer, an enediyne, a geldanamycin, a maytansine, a puromycin, a taxane, a vinca alkaloid, a camptothecin, a tubulysin, a hemiasterlin, a spliceostatin, a pladienolide, and stereoisomers, isosteres, analogs, or derivatives thereof. Exemplary immunomodulating agents that may be incorporated in an ADC include gancyclovier, etanercept, tacrolimus, sirolimus, voclosporin, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolgate mofetil, methotrextrate, glucocorticoid and its analogs, cytokines, stem cell growth factors, lymphotoxins, tumor necrosis factor (TNF), hematopoietic factors, interleukins (e.g., interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-15, IL-18, and IL-21), colony stimulating factors (e.g., granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF)), interferons (e.g., interferons-. alpha., -.beta, and -.gamma), the stem cell growth factor designated "S 1 factor," erythropoietin and thrombopoietin, or a combination thereof. Additional examples of therapeutic antibodies may include the following antigens where exemplary antibodies directed to the antigen are also included below (in brackets I parenthesis after the antigen). The antigens as follow may also be referred to as “target antigens” or the like herein. Target antigens for therapeutic antibodies herein include, for example: 4-1 BB (e.g. utomilumab); 5T4; A33; alpha-folate receptor 1 (e.g. mirvetuximab soravtansine); Alk-1 ; BCMA [e.g. see US9969809]; BTN1A1 (e.g. see WO2018222689); CA-125 (e.g. abagovomab); Carboanhydrase IX; CCR2; CCR4 (e.g. mogamulizumab); CCR5 (e.g. leronlimab); CCR8; CD3 [e.g. blinatumomab (CD3/CD19 bispecific), CD3/P-cadherin bispecific, CD3/BCMA bispecific] CD19 (e.g. blinatumomab, MOR208); CD20 (e.g. ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, ublituximab); CD22 (inotuzumab ozogamicin, moxetumomab pasudotox); CD25; CD28; CD30 (e.g. brentuximab vedotin); CD33 (e.g. gemtuzumab ozogamicin); CD38 (e.g. daratumumab, isatuximab), CD40; CD-40L; CD44v6; CD47 (e.g. Hu5F9-G4, CC-90002, SRF231, B6H12); CD52 (e.g. alemtuzumab); CD56; CD63; CD79 (e.g. polatuzumab vedotin); CD80; CD123; CD276 / B7-H3 (e.g. omburtamab); CDH17; CEA; ClhCG; CTLA-4 (e.g. ipilimumab, tremelimumab), CXCR4; desmoglein 4; DLL3 (e.g. rovalpituzumab tesirine); DLL4; E-cadherin; EDA; EDB; EFNA4; EGFR (e.g. cetuximab, depatuxizumab mafodotin, necitumumab, panitumumab); EGFRvlll; Endosialin; EpCAM (e.g. oportuzumab monatox); FAP; Fetal Acetylcholine Receptor; FLT3 (e.g. see WO2018/220584); GD2 (e.g. dinutuximab, 3F8); GD3; GITR; GloboH; GM1; GM2; HER2/neu [e.g. margetuximab, pertuzumab, trastuzumab; ado-trastuzumab emtansine, trastuzumab duocarmazine, [see US8828401]; HER3; HER4; ICOS; IL-10; ITG-AvB6; LAG-3 (e.g. relatlimab); Lewis-Y; LG; Ly-6; M-CSF [see US7326414]; MCSP; mesothelin; MUC1; MUC2; MUC3; MUC4; MUC5AC; MUC5B; MUC7; MUC16; Notchl; Notch3; Nectin-4 (e.g. enfortumab vedotin); 0X40 [see US7960515]; P-Cadherein [see WO2016/001810]; PCDHB2; PDGFRA (e.g. olaratumab); Plasma Cell Antigen; PolySA; PSCA; PSMA; PTK7 [see US9409995]; Ror1; SAS; SCRx6; SLAMF7 (e.g. elotuzumab); SHH; SIRPa (e.g. ED9, Effi-DEM); STEAP; TGF-beta; TIGIT; TIM- 3; TMPRSS3; TNF-alpha precursor; TROP-2 (e.g sacituzumab govitecan); TSPAN8; VEGF (e.g. bevacizumab, brolucizumab); VEGFR1 (e.g. ranibizumab); VEGFR2 (e.g. ramucirumab, ranibizumab); Wue-1.

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

Exemplary therapeutic proteins that may be included in an ADC include a toxin, a hormone, an enzyme, and a growth factor.

Exemplary biocompatible polymers that may be incorporated in an ADC include water- soluble polymers, such as polyethylene glycol (PEG) or its derivatives thereof and zwitterioncontaining biocompatible polymers (e.g., a phosphorylcholine containing polymer).

Exemplary biocompatible polymers that may be incorporated in an ADC include antisense oligonucleotides.

The invention also concerns the use of radiation in combination with any anti-cancer therapeutic agent administered herein. More specifically, compounds of the invention can be administered in combination with additional therapies, such as radiation therapy and/or chemotherapy.

These agents and compounds of the invention may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e. , dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

Kits

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

In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the invention in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises one or more compounds of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage and a container for the dosage.

Synthetic Methods Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature. For example, the following commercial starting materials are intermediates used in this application: CAS 2703745-57-5, 2703745-57-5, 82671-06-5, 630-25- 1, 1262409-55-1, 3470-50-6, 2820536-99-8, 2820537-74-2, 2871770-04-4, 2097518-76-6.

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

The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the Intermediate of compounds of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

In the Intermediate of compounds of the invention it is noted that some of the Intermediate methods useful for the Intermediate of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the Intermediate methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition. For example, if a compound contains an amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as /V-terf-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9- fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.

General Experimental Details

¹H and ¹⁹F Nuclear Magnetic Resonance (NMR) spectra were recorded on Bruker XWIN-NMR (400 or 700 MHz) spectrometer. ¹H and ¹⁹F resonances are reported in parts per million (ppm) downfield from tetramethylsilane. ¹H NMR data are reported as multiplicity (e.g. s, singlet; d, doublet; t, triplet; q, quartet; quint, quintuplet; dd, doublet of doublets; dt, doublet of triplets; br s, broad singlet). For spectra obtained in CDCI3, DMSO-cfe, and CD3OD, the residual protons (7.27, 2.50, and 3.31 ppm, respectively) were used as the internal reference. All observed coupling constants, J, are reported in Hertz (Hz). Exchangeable protons are not always observed.

Optical rotations were determined on a Jasco P-2000 or a Rudolph Autopol IV polarimeter. All final compounds were purified to > 95% purity, unless otherwise specified. When absolute stereochemistry is known, (R,S) labels are used. When absolute stereochemistry is not known, the software-generated names are modified to include (+)- and (-)-prefixes according to the optical rotations, and (R*/S*) labels are used to show relative configuration.

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

The nomenclature is written as described by IIIPAC (International Union of Pure and Applied Chemistry generated within Perkin Elmers Chemdraw 18.0.0.231. The naming convention provided with Perkin Elmers Chemdraw 18.0.0.231 is well known by those skilled in the art and it is believed that the naming convention provided with Perkin Elmers Chemdraw 18.0.0.231 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Abbreviations aq is aqueous;

Bn is benzyl;

Boc is tert-butoxycarbonyl;

BOC2O is di-ferf-butyl dicarbonate; br is broad; tBu is tert-butyl;

°C is degrees celcius;

CDC is deutero-chloroform;

5 is chemical shift; d is doublet; dd is doublet of doublets; ddd is doublet of doublet of doublets; dt is doublet of triplets;

DCM is dichloromethane; methylene chloride;

DIPEA is N-ethyldiisopropylamine, also known as N,N-diisopropylethylamine;

DMAP is 4-dimethylaminopyridine;

DMF is N,N-dimethylformamide;

DMSO is dimethyl sulfoxide;

DMSO-de is deuterodimethylsulfoxide; ee is enantiomeric excess;

ESI is electrospray ionization;

Et₂O is diethyl ether;

EtOAc is ethyl acetate;

EtOH is ethanol;

Et₃N is triethylamine; g is gram;

HPLC is high pressure liquid chromatography; h is hour(s); min is minutes;

L is liter;

LCMS is liquid chromatography mass spectrometry; m is multiplet;

M is molar; m-CPBA is 3-chloroperbenzoic acid;

MeOD_d4 is deuterated methanol; MeOH is methanol;

2-MeTHF is 2-methyl tetrahydrofuran; mg is milligram;

MHz is mega Hertz; min(s) is minute(s); mL is milliliter; mmol is millimole; mol is mole;

MOM is methoxymethyl ether group;

MS (m/z) is mass spectrum peak;

NMR is nuclear magnetic resonance;

Pd/C is palladium on carbon;

Pd(dppf)Ch is [1 ,1’-bis(diphenylphophino)ferrocene]dichloropalladium(ll); pH is power of hydrogen; ppm is parts per million; psi is pounds per square inch; q is quartet; r.b. is round bottom; rpm is revolutions per minute; rt is room temperature;

RT is retention time;

RuPhos Pd G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1'-biphenyl)[2-(2'-amino-1 ,T- biphenyl)]palladium(ll) methanesulfonate (CAS Number: 1445085-77-7); rxn is reaction; s is singlet;

SEMCI is 2-(trimethylsilyl)ethoxymethyl chloride;

SEM is 2-(trimethylsilyl)ethoxymethyl;

SFC is supercritical fluid chromatography; t is triplet;

TBAF is terf-butyl ammonium fluoride;

TFA is trifluoroacetic acid;

THF is tetrahydrofuran;

TLC is thin layer chromatography;

TMSCN is trimethylsilyl cyanide;

TsCI is p-toluenesulfonyl chloride; pL is microliter; and pmol is micromole.

The schemes described below are intended to provide a general description of the methodology employed in the Intermediate of the compounds of the present invention. Some of the compounds of the present invention contain a single chiral center. In the following schemes, the general methods for the Intermediate of the compounds are shown either in racemic or enantioenriched form. It will be apparent to one skilled in the art that all of the synthetic transformations may be conducted in a precisely similar manner whether the materials are enantioenriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature.

General Methods:

Unless stated otherwise, the variables in General Scheme 1 have the same meanings as defined herein.

General Scheme 1

Intermediate 9: 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-cf]pyrimidine

Diisopropyl amine (44.1 mL, 314 mmol) was dissolved in THF (300 mL) and the solution cooled to -78 °C. n-BuLi (114 mL of 2.5 M in hexanes, 286 mmol) was added over 15 min. The mixture was stirred for 45 min. and CAS: 82671-06-5 (30 g, 143 mmol) was added as a solution in THF (75 mL) over 6 min. The mixture was stirred for 30 min at -78 °C. CAS: 630-25-1 (69.8 g, 214 mmol) was added as a solution in THF (120 mL) over 10 min. The reaction was held at -78 °C for 2 h and the reaction was checked by LCMS. A new peak with M-H = 242 (product - CO2H) was observed (negative ion mode). The mixture was quenched by adding water (120 mL). After stirring for 10 min, at -78 °C, the cold bath was removed and 6 N HCI (90 mL) was added. The pH = 1 aqueous layer was extracted with EtOAc (x3). The combined organic extract was washed with brine (x2) and dried over MgSCU. Removal of the solvent afforded a solid that was stirred in heptane (250 mL) for 1 h to remove tetrachloroethylene byproduct. After filtration, the solid was washed with heptane (3 x 100 mL) and dried to afford 9a, 30.3 g (73%) as a cream colored solid. ¹⁹F NMR (376 MHz, DMSO) 8 -114.17. A solution of 9a (30.2 g, 104 mmol) was suspended in DCM (420 mL). Oxalyl chloride (25.0 mL, 300 mmol) was added followed by DMF (40 mg). After 2 h of stirring, solids were still present and bubbles could still be seen forming. So, the mixture was allowed to stir overnight (16 h). After stirring for 16 h at rt, the solids had dissolved and the mixture became a yellow solution. The solvents were removed in vacuo to afford 33.3 g of the acid chloride as a tan solid. In a separate 500 mL r.b. flask methylimidothiocarbamate sulfate (33.2 g, 177 mmol) was stirred with half-satd. Na2COs (80 mL) affording a clear solution. Et20 (60 mL) was added to this solution which was cooled to 10 °C. Then, the acid chloride of 9a added slowly as a solution in EtOAc (120 mL), monitoring the temperature with an internal thermometer. A very slight exotherm was observed and the ice bath was removed after the addition was complete. After warming to rt, the mixture was stirred for an 30 min, while monitoring the consumption of the acid chloride using neg. mode ionization and looking for no more 9a present (hydrolysis occurs during LCMS giving the acid). After the reaction was complete, clean product formation was observed and a new peak with M+H = 360 with multi-halogen pattern was observed. The mixture was partitioned between water (100 mL) and EtOAc (150 mL) and the aq. layer was extracted with EtOAc (x2). The combined organic extracts were washed with satd. NaHCOs (x1), dried over MgSO4 and concentrated to afford 35 g of 9b (93%) as a tan solid which was used in the next reaction without further purification. ¹H NMR (400 MHz, DMSO-d6) 5 9.03 (br s, 1 H), 9.53 (br s, 1 H), 2.40 (s, 3 H). 9b (14.7 g, 40.7 mmol) was dissolved in DMF (45 mL) and DIEA (14.2 mL, 81.4 mmol) was added. The reaction was heated to 95 °C under N2 for 3 h at which time LCMS analysis showed clean conversion to the cyclized product (9c) with M+H = 282, 284. After cooling to rt, the mixture solution was poured into an aqueous pH 5 buffer and 100 g ice and the resulting solution was adjusted to pH 3 using 6 N HCI. After addition to the cold aqueous solution, a pale-yellow solid precipitated from solution. This precipitate was collected in a Buchner funnel and washed with water (x3) to afford, after drying, 9.6 g of 9c (84%). ¹⁹F NMR (376 MHz, DMSO) 8 135.4. To a flask containing 9c (5.6 g, 20 mmol) was added DIEA (7.1 mL, 28.6 mmol) and the suspension was cooled to 0 °C under N2. POCI3 (30 mL, 320 mmol) was added in one portion and the ice bath was removed. The mixture was then heated to 90 °C for 4 h. LCMS analysis (sample dissolved in MeOH) showed two mono-methanol adducts with M+H = 294 with CI2 isotope pattern. The POCI3 was removed in vacuo chasing the excess POCI3 with a mixture of toluene and DCM (x2). After removing all the volatiles, the resulting orange solid was dry loaded on an 80 g ISCO silica column and purified using a gradient of 0 - 100% EtOAc in heptane, maintaining 100% EtOAc for 7 column volumes as the product bleeds off the column slowly. Concentration of the fractions afforded 5.7 g (92%) of Intermediate 9 as an orange solid. ¹³C NMR (101 MHz, DMSO-d6) 5 ppm 165.5, 157.2, 148.6, 146.7, 146.0, 143.2, 137.4, 137.3, 114.8, 12.9; ¹⁹F NMR (376 MHz, DMSO) 8 -135.5.

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

Intermediate 10

Intermediate 9 (1.25 g, 3.70 mmol) was suspended in CH3CN (24 mL) and DIEA (0.668 mL, 3.83 mmol) was added. The mixture was cooled to 0 °C and (S)-piperidin-2-yl methanol (421 mg, 3.65 mmol) was added as a solution in THF (18 mL). After 8 minutes, the first nitrogen-carbon bond was formed as observed by LCMS. LiOtBu (877 mg, 11.0 mmol) was added as a solution in THF (22 mL) and the mixture was warmed to 50 °C. After 4 h at 50 °C, LCMS analysis showed conversion to Intermediate 9. The reaction mixture was then diluted with 200 mL water and the product was extracted with DCM (50 mL x 4). The combined organic extract was dried over Na2SO4, filtered, and evaporated to afford Intermediate 10 as a crude solid. Purification was accomplished via flash chromatography eluting with a gradient of 0-10% MeOH in DCM to afford 1.13 g of Intermediate 10 (91%). ¹H NMR (CHLOROFORM-d, 400 MHz) d 4.8-4.9 (m, 1 H), 4.4-4.5 (m, 2H), 3.7-3.8 (m, 1 H), 2.97 (dt, 1 H, J=2.5, 12.8 Hz), 2.7-2.7 (m, 1 H), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1 H), 1.7-1.8 (m, 3H), 1.5-1.7 (m, 2H), MS: 341.1 [M+H]⁺.

Intermediate 11 : (8aS)-5-chloro-4-fluoro-2-(methylsulfanyl)-8a,9,12,13-tetrahydro-8H,11/7- [1 ,4]oxazepino[3',4':3,4][1 ,4]oxazepino[5,6,7-de]quinazoline

Intermediate 9 (450 mg, 1.51 mmol) was suspended in CH3CN (10 mL). DIPEA (276 uL, 1.59 mmol) was added and the suspension cooled to 0 °C under N2. In a separate vial, CAS 1262409- 55-1-HCI salt (232 mg, 1.39 mmol) was suspended in DCM (1 mL) and DIPEA (276 uL, 1.59 mmol) was added to dissolve the amine-HCI salt. THF (6 mL) was added to the resulting solution to give a milky mixture. This solution was added to the flask containing the cold solution of Intermediate 9. After about 45 m at 0 °C, LCMS analysis showed that the initial reaction was complete. LiOtBu (4.5 mL of 1 M in THF, 4.5 mmol) was added dropwise and the ice bath was removed. The ice bath was replaced with an oil bath and the reaction was heated at 50 °C for 30 min. LCMS analysis showed the cyclization step to be complete. The solution was cooled to rt and evaporated. Saturated aqueous NaHCOs (10 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The combined organic extract was dried over Na2SO4 and evaporated. The process described above was repeated a second time on the same scale with the same observations and results. The crude material from both reactions was combined and purified using flash chromatography eluting with a gradient of 0 - 100% EtOAc in heptane and using DCM to load the crude material onto the silica cartridge. Fractions containing the desired product were pooled and concentrated to afford 483 mg of Intermediate 11 (70%) as a tan solid. ¹H NMR (400 MHz, CHLOROFORM-d) 5 = 5.22 (ddd, J = 2.9, 6.8, 13.8 Hz, 1 H), 4.65 (dd, J = 4.6, 13.4 Hz, 1 H), 4.42 (d, J = 13.4 Hz, 1 H), 4.22 - 4.17 (m, 1 H), 4.09 - 3.98 (m, 2H), 3.72 (dd, J = 9.8, 12.6 Hz, 1 H), 3.43 - 3.24 (m, 2H), 2.62 (s, 3H), 2.26 - 2.12 (m, 1 H), 2.05 - 1.92 (m, 1 H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) 5 = -140.51 (s, 1 F).

Intermediate 12: 8-bromo-6-(methoxy methoxy)-3,4-dihydronaphthalen-1(2H)-one

CAS 3470-50-6 (100 g, 617 mmol) was dissolved in CH3CN (500 mL) and pyridine (73 g, 925 mmol) was added. Methoxyamine-HCI (77 g, 925 mmol) was added and the reaction stirred at rt for 2 h. Water (500 mL) was added followed by MTBE (500 mL). The layers were separated and the aq. layer was extracted with MTBE (500 mL) a second time. The combined organic extract was washed with water (300 mL x 3) and the organic extract was concentrated. A solvent swap into CH3CN was accomplished by adding CH3CN (300 mL x 3) and after the third treatment with CH3CN, the solution was concentrated to afford 12a (104 g, 88%) as a solid. ¹H NMR (CDCI3, 400 MHz) 5 7.86 (d, 1 H, J=8.6 Hz), 6.66 (dd, 1 H, J=2.6, 8.6 Hz), 6.58 (d, 1 H, J=2.5 Hz), 5.47 (br s, 1 H), 3.97 (s, 3H), 2.72 (t, 2H, J=6.6 Hz), 2.6-2.7 (m, 2H), 1.8-1.9 (m, 2H). 12a (104 g, 544 mmol) was dissolved in MTBE (520 mL). Et3N (110 g, 1.09 mol) was added followed by the slow addition of acetyl chloride (51.3 g, 654 mmol) via an addition funnel. The reaction was stirred at rt for 20 h. LCMS showed 97% purity of the acetate product. Water (520 mL) was added and the layers were separated. The aq. phase was extracted a second time with MTBE (520 mL). The combined organic extract was washed with water (300 mL) and the organic phase was concentrated. Heptane (730 mL) was added and the resulting mixture was concentrated to ca. 500 g upon which time a solid formed. The slurry was stirred at rt for 30 min. and then stirred at 0° C for 2 h. The solids were filtered and rinsed with cold heptane (200 mL). After drying 12b (109 g, 86%) was obtained. ¹H NMR (CDCI3, 400 MHz) 5 8.00 (d, 1 H, J=8.5 Hz), 6.9-6.9 (m, 2H), 3.98 (s, 3H), 2.7-2.8 (m, 4H), 2.30 (s, 3H), 1.85 (quin, 2H, J=6.4 Hz). 12b (109 g, 468 mmol) was dissolved in HOAc (544 mL). NBS (91.3 g, 513 mmol) was added and the head volume of the reaction was flushed with N₂. Pd(OAc)₂ (7.85 g, 35 mmol) was added and the reaction was stirred at rt for 20 h. After the bromination was complete, 10% Na₂SOs (109 mL) was added and solids formed while stirring for 1 h at rt. Water (550 mL) was added and the product was extracted into MTBE (1 L). The MTBE layer was washed with 15% Na₂COs (550 mL). The MTBE layer was next washed with satd. NaHCOs (550 mL x 2) and then with water (330 mL). The organic layer was filtered through a pad of celite and then concentrated to dryness. MTBE (110 mL) was added and the slurry was stirred for 15 min. Then, heptane (330 mL) was added and the mixture cooled to 0° C and stirred for 30 min. The solids were filtered and washed with cold heptane (220 mL). After drying, 12c (125 g, 86%) was obtained as a white solid. ¹H NMR (CDCh, 400 MHz) 5 7.30 (d, 1 H, J=2.4 Hz), 6.89 (d, 1 H, J=2.4 Hz), 4.03 (s, 3H), 2.75 (t, 2H, J=6.9 Hz), 2.6-2.6 (m, 2H), 2.28 (s, 3H), 1.7-1.8 (m, 2H). 12c (125 g, 400 mmol) was dissolved in 1 ,4-dioxane (1.3 L) and to this solution was added 2 N HCI (1.3 L). The mixture was heated and stirred at 100 °C for 3 h. LCMS analysis showed that the starting material was consumed. The reaction was concentrated to give a residue. The residue was filtered and the filter cake was washed with water (4 L) and dried in a vacuum oven. 12d (89% purity) was obtained as a solid and was used without further purification. 12d (7.1 g, 30 mmol) was dissolved in EtOAc (35 mL) and dimethoxymethane (22 g, 290 mmol) was added. T4P (n-butylphosphonic anhydride) (43 g of 50% in EtOAc, 60 mmol) was added and the heterogeneous reaction was heated to 50° C for 16 h. The reaction was cooled to rt and 20% K2CO3 (70 mL) was added. The product was extracted into EtOAc (35 mL x 2) and the combined organic extract was washed with 20% K2CO3 (35 mL) and water (35 mL). After drying and concentrating Intermediate 12 was obtained as a tan solid (8.4 g, 100%). ¹H NMR (CDCh, 400 MHz) 5 7.22 (d, 1 H, J=2.6 Hz), 6.84 (d, 1 H, J=2.4 Hz), 5.19 (s, 2H), 3.47 (s, 3H), 2.93 (t, 2H, J=6.1 Hz), 2.6-2.7 (m, 2H), 2.06 (quin, 2H, J=6.4 Hz).

Intermediate 13: 5-bromo-7-(methoxymethoxy)-4-methyl-1 ,2-dihydronaphthalene

I

To a 500 mL 3 neck flask equipped with a stir bar and an internal thermometer was added Intermediate 12 (10 g, 35 mmol), N-phenyltrifluoromethanesulfonamide (25 g, 70 mmol) and THF (175 mL). The solution was cooled to 0° C under N2. When internal temperature was at about 3° C, KHMDS (53 mL of 1 M in THF, 53 mmol) over 15 min. During the addition, the internal temperature was stable and did not warm above 7° C. After 25 m, the reaction was complete as determined by LCMS and satd. aq. Na2CCh (75 mL) was added followed by EtOAc (150 mL). The layers were separated and the aq. layer was further extracted with EtOAc (100 mL x 3). The combined organic extract was washed with brine and dried over Na2SO4. The crude product was purified via flash chromatography eluting with a slow gradient of 0 - 5% EtOAc in heptane over 30 min. Pure fractions were combined and evaporated to give a pale yellow oil which was stored at 4 C overnight. Further drying under high vacuum the next day at rt for 3 h afforded 13a with some EtOAc present. ¹H NMR (400 MHz, acetone) 5 = 7.21 (d, J = 2.4 Hz, 1 H), 7.04 - 6.98 (m, 1 H), 6.34 (t, J = 5.4 Hz, 1 H), 5.26 (s, 2H), 3.45 (s, 3H), 2.85 - 2.78 (m, 2H), 2.44 - 2.36 (m, 2H), ¹⁹F NMR (377 MHz, acetone) 5 = - 73.71 (s, 3F). A 500 mL 3-neck flask equipped with an internal thermometer and a stir bar was charged with 13a (14.6 g, 35.1 mmol). THF (207 mL) and NMP (11 mL) were added and the mixture was cooled in an ice bath. When internal temperature reached 3° C, Fe(acac)s (620 mg, 1.76 mmol) was added and a red solution formed. While keeping the temperature at 3° C, MeMgBr (7.0 mL of 3.0 M in diethylether, 21 mmol) was added over 7 min. During the addition, the internal temperature did not increase above 7° C and the color changed from red to orange-yellow. After 15 m at 3° C, the ice bath was removed and the reaction was allowed to come to rt. Since the reaction was not yet complete, it was cooled in an ice bath and more MeMgBr (7.0 mL of 3.0 M in ethyl ether, 21 mmol) was added over about 5 min. The color changed from light gray to light brown color. After 15 m at 3° C the ice bath was removed and the reaction was allowed to come to rt. The reaction was still not complete and needed one more charge of MeMgBr. It was cooled in the ice bath again, and MeMgBr (5.9 mL of 3.0 M in diethyl ether, 17.7 mmol) was added over 5 min. The color changed from light gray to light brown color. After 10 m, the ice bath was removed and the reaction was stirred at rt for 30 m longer. LCMS analysis showed the reaction to be complete. Aq. K2CO3 (50 mL of 2 M) was added followed by the addition of water (50 mL) and EtOAc (150 mL). After separation of the layers, the aq. layer was extracted with EtOAc (150 mL x 2) and the combined organic extract was dried over Na2SO4. The product was purified via flash chromatography eluting with a slow gradient of 0 - 2% EtOAc in heptane to afford Intermediate 13 (6.6 g, 63% over 2 steps). ¹H NMR (400 MHz, CDCI3) 5 = 7.17 (d, J = 2.6 Hz, 1 H), 6.86 - 6.81 (m, 1 H), 6.00 (ddd, J = 1.5, 3.7, 6.7 Hz, 1 H), 5.15 (s, 2H), 3.49 (s, 3H), 2.68 - 2.61 (m, 2H), 2.34 (q, J = 1.5 Hz, 3H), 2.11 - 2.05 (m, 2H).

Intermediate 14: (R)-8-bromo-6-(methoxymethoxy)-1 -methyl- 1 ,2,3,4-tetrahydronaphthalene

Intermediate 13 2. chiral SFC Intermediate 14

To a 10 mL vial was added (R,R)-[2-(4’-isopropyloxazolin-2’-yl)ferrocenyl]diphenylphosphine (Strem, CAS 541540-70-9, 273 mg, 5.5 mol%) and bis(1 ,5-cyclooctadiene)iridium(l) tetrakis[3,5- bis(trifluoromethyl)phenyl]borate (Strem, CAS 666826-16-0, 636 mg, 5 mol%) and DCE (5 mL). The solution was a deep red color. The vial was capped under N2 and stirred at 70° C (block temperature) for 4 h. After 4 h, the red solution was cooled to rt. To a separate bottle was added Intermediate 3 (2.83 g, 10 mmol) and HFIP (50 mL). To this solution was added the above catalyst solution in DCE (5 mL). The mixture was placed under 250 psi H2 with stirring at 25° C for 20 h. The starting material was consumed after 20 h. Analysis using chiral SFC showed the desired enantiomer as the major peak with dr = 83:17 (66% ee). The mixture was concentrated to give a red solid. Purification via flash chromatography eluting with a gradient of 0-10% EtOAc in heptane afforded 2.33 g (78%) of the enriched enantiomer. ¹H NMR (400 MHz, CDCh) 5 = 7.12 (d, J = 2.5 Hz, 1 H), 6.78 - 6.68 (m, 1 H), 5.12 (s, 2H), 3.47 (s, 3H), 3.17 (tq, J = 3.4, 6.9 Hz, 1 H), 2.85 - 2.65 (m, 2H), 1.96 - 1.69 (m, 4H), 1.23 (d, J = 7.0 Hz, 3H). This sample was submitted to preparative chiral SFC using 2 x Chiralpak AD-H SFC 5 urn, 21 mm x 250 mm columns ran in sequence and mobile phases: A CO2 and B: 1 :1 CH3CN : /PrOH. The run used 5% B isocratic, 110 bar, 80 mL/min and the major I desired peak elutes first. After concentration of the major peak, 1.67 g (59% overall) of Intermediate 14 was obtained as colorless oil, >98% purity, 99% ee, [OC]D²² +5.9° (c 0.3, MeOH).

Intermediate 15: (F?)-2-(3-(methoxymethoxy)-8-methyl-5, 6,7, 8-tetrahydronaphthalen-1-yl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane

Intermediate 14 Intermediate 15

To a solution of Intermediate 14 (18.1 g, 63.4 mmol) in toluene (150 mL) was added B2Pin2 (32.2 g, 127 mmol) and KOAc (21.8 g, 222 mmol). The rxn was degassed by bubbling argon through the solution for 30 min. To this was added Pd(dppf)CI2 (4.64 g, 6.34 mmol) and the reaction was heated in an oil bath set at 108° C for 16 h. The reaction was diluted with EtOAc and filtered. The filtrate was concentrated. The resulting black oil was taken up in DCM, silica gel was added, and the solvent was removed under vacuum. This was dry loaded onto a silica column (Isco Gold, 330g) and a gradient ran of 0-3.5% EtOAc in heptane, hold at 3.5% until impurity elutes (first) and then ramp to 5% EtOAc to elute the product. After concentration of the product fractions, 15.1 g (71%) of Intermediate 15 was obtained as a solid. ¹H NMR (400 MHz, CHLOROFORM-d) 5 = 7.25 (d, J = 2.6 Hz, 1 H), 6.81 (d, J = 2.6 Hz, 1 H), 5.17 - 5.12 (m, 2H), 3.66 - 3.56 (m, 1 H), 3.48 (s, 3H), 2.83 - 2.68 (m, 2H), 1.92 - 1.80 (m, 2H), 1.76 - 1.66 (m, 2H), 1.35 (d, J = 2.0 Hz, 12H), 1.18 (d, J = 7.0 Hz, 3H). Example 1 : (5R)-4-[(8aS)-4-fluoro-2-{[(7aS)-2-methylidenetetrahydro-1 H-pyrrolizin-7a(5/7)- yl]methoxy}-8a,9, 12,13-tetrahydro-8/7, 11 H-7, 10-dioxa-1 ,3,6,13a-tetraazanaphtho[1 ,8- ab]heptalen-5-yl]-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol

Argon was bubbled through a suspension of Intermediate 11 (9.74 g, 27.3 mmol), Intermediate 15 (9.07 g, 27.3 mmol) in dioxane (250 mL). K2CO3 (11.3 g, 81.9 mmol) was added as a solution in water (25 mL). To this was added cataCXium® A Pd G3 (2.01 g, 2.76 mmol) and argon was bubbled through the mixture for an additional 15 min. The rxn was heated to 90° C under argon for 16 h. LCMS analysis showed the reaction to be complete. The mixture was concentrated under vacuum and the resulting residue was taken up in DCM and filtered. The filtrate was concentrated and loaded onto silica gel and purified via flash chromatography eluting with a gradient of 0-55% EtOAc, holding at 55% EtOAc until the impurity and the product both elute. The pure fractions were combined and concentrated to afford 9.74 g (68%) of 34a as a tan solid. ¹H NMR (400 MHz, CDCI3) 5 = 6.84 (d, J = 2.5 Hz, 1 H), 6.82 (d, J = 2.5 Hz, 1 H), 5.29 - 5.21 (m, 1 H), 5.17 (d, J = 6.5 Hz, 1 H), 5.11 (d,J = 6.8 Hz, 1 H), 4.66 (dd,J = 4.6, 13.4 Hz, 1 H), 4.47 (d,J = 13.3 Hz, 1 H), 4.20 (dd,J = 3.6, 12.6 Hz, 1 H), 4.10 - 4.00 (m, 2H), 3.77 (dd,J = 9.7, 12.6 Hz, 1 H), 3.49 - 3.24 (m, 6H), 2.87 - 2.75 (m, 2H), 2.63 (s, 3H), 2.30 - 2.18 (m, 1 H), 2.04 - 1.80 (m, 3H), 1.79 - 1.67 (m, 1 H), 1.65 - 1.57 (m, 1 H), 0.88 (d,J = 7.1 Hz, 3H); ¹⁹F NMR (377 MHz, CDCh) 5 = -142.8; MS: 527.2 [M+H]⁺; [ot]_D ²² -64.4° (c 0.4, MeOH). A biphasic mixture of 34a (9.74 g, 18.5 mmol) in methyl ethyl ketone (360 mL) and satd. aq. NaHCOs (290 mL) was stirred vigorously. To this mixture was added Oxone (39.8 g, 64.7 mmol) in portions while keeping the bubbling under control. The rxn was stirred at rt for 0.5 h. LCMS showed complete conversion to the sulfone. The rxn was diluted with EtOAc (100 mL) and satd. aq. Na₂S20s (50 mL) was added. The layers were separated and the aqueous phase was extracted a second time with EtOAc (100 mL). The combined organic extract was washed with brine, dried over Na₂SO4, filtered, and concentrated to give 34b (10.3 g, 100%) as a yellow solid. This material was used without further purification. ¹H NMR (400 MHz, CDCh) 5 = 6.86 (d, J = 2.6 Hz, 1 H), 6.84 (d, J = 2.8 Hz, 1 H), 5.40 - 5.33 (m, 1 H), 5.18 (d, J = 7.1 Hz, 1 H), 5.12 (d, J = 6.6 Hz, 1 H), 4.74 (dd, J = 4.4, 13.5 Hz, 1 H), 4.53 (d, J = 13.4 Hz, 1 H), 4.27 - 4.16 (m, 2H), 4.04 (td, J = 5.0, 12.9 Hz, 1 H), 3.80 (dd, J = 9.1 , 12.4 Hz, 1 H), 3.45 (d, J = 17.1 Hz, 7H), 3.29 - 3.21 (m, 1 H), 2.90 - 2.76 (m, 2H), 2.35 - 2.23 (m, 1 H), 2.13 - 2.02 (m, 2H), 1.98 - 1.82 (m, 2H), 1.82 - 1.70 (m, 1 H), 1.68 - 1.60 (m, 1 H), 0.87 (d, J = 7.1 Hz, 3H), ¹⁹F NMR (377 MHz, CDCI₃) 5 = -139.2; MS 559.2 [M+H]⁺. A solution of 34b (10.3 g, 18.5 mmol) and Intermediate 16 (CAS 2820536-99-8) (4.15 g, 27.1 mmol) in CH3CN (300 mL) was cooled in an ice bath. To this was added LiOtBu (30 mL of 1 M in THF, 30 mmol) which gave a suspension. After stirring in the ice bath for 15 min, the rxn was removed from the ice bath and stirred at rt for 20 min. The reaction was complete and clean by LCMS and was neutralized with acetic acid (1.7 mL, 29.6 mmol) and the solution concentrated. The solids were taken up in DCM and silica gel was added. The solvents were removed under vacuum and compound was purified via flash chromatography eluting with a gradient of 0-10% MeOH in DCM containing 1.5% EtsN. The impurity started to elute at 1.8% MeOH and the gradient was held there until the impurity fully eluted. The product started to elute just after the impurity and showed up as 2 peaks on the ISCO chromatography instrument. The second product peak eluted after increasing the MeOH to 4%. The pure fractions were combined and concentrated to afford 9.95 g (85%) of the MOM protected intermediate as a pale yellow solid. ¹H NMR (400 MHz, METHANOL-d4)5 = 6.85 (d, J = 2.5 Hz, 1 H), 6.78 (d,J = 2.6 Hz, 1 H), 5.26 - 5.18 (m, 1 H), 5.18 - 5.12 (m, 2H), 4.98 (br d,J = 1.5 Hz, 2H), 4.71 (dd,J = 4.4, 13.4 Hz, 1 H), 4.55 (d,J = 13.5 Hz, 1 H), 4.34 - 4.26 (m, 3H), 4.17 (dd,J = 4.1 , 12.4 Hz, 1 H), 3.98 (td,J = 5.2, 12.8 Hz, 1 H), 3.79 - 3.68 (m, 2H), 3.54 (ddd,J = 4.2, 8.3,

12.7 Hz, 1 H), 3.46 - 3.38 (m, 4H), 3.34 - 3.32 (m, 1 H), 3.18 - 3.07 (m, 2H), 2.89 - 2.67 (m, 4H), 2.47 (br d, J = 15.5 Hz, 1 H), 2.25 - 2.10 (m, 2H), 2.04 - 1.80 (m, 6H), 1.79 - 1.60 (m, 2H), 0.87 (d, J = 7.0 Hz, 3H); MS: 632.3 [M+H]⁺. To a solution of the MOM protected intermediate (9.95 g,

15.8 mmol) in MeOH (113 mL) at 0° C was added acetyl chloride (7.1 mL, 86.9 mmol). The rxn was immediately warmed to rt and stirred at rt for 3 h. LCMS analysis showed complete MOM deprotection and the rxn was concentrated under vacuum. The resulting residue was taken up in DCM (200 mL) and washed with satd. aq. NaHCOs (200 mL). The aqueous layer was extracted a second time with DCM (50 mL) and the combined DCM extract was concentrated. Purification was accomplished using a 415 g C18 bonded flash silica column by first loading the compound onto a C18 bonded pre-cartridge. The reverse phase separation was accomplished using a gradient of 10-100% MeOH in water. The product eluted at 85% MeOH with two minor impurities eluting prior to the product. The pure fractions were combined and concentrated to a white solid. The solid was dissolved in a minimal amount of CH3CN, and water was added. The suspension was frozen in a dry ice bath and lyophilized overnight. This gave 8.2 g (85%) of Example 1 as a voluminous white solid. ¹H NMR (400 MHz, METHANOL-d4 ) 5 = 6.61 (d, J = 2.5 Hz, 1 H), 6.54 (d, J = 2.6 Hz, 1 H), 5.27 - 5.17 (m, 1 H), 4.98 (br d, J = 1.5 Hz, 2H), 4.71 (dd, J = 4.4, 13.5 Hz, 1 H), 4.55 (d, J = 13.4 Hz, 1 H), 4.34 - 4.24 (m, 3H), 4.16 (dd, J = 4.3, 12.4 Hz, 1 H), 3.97 (td, J = 5.2, 12.9 Hz, 1 H), 3.79 - 3.69 (m, 2H), 3.54 (ddd, J = 4.3, 8.3, 12.7 Hz, 1 H), 3.42 (ddd, J = 5.3, 10.5, 13.8 Hz, 1 H), 3.35 - 3.32 (m, 1 H, partially obscured by MeOD peak), 3.19 - 3.11 (m, 1 H), 3.11 - 3.02 (m, 1 H), 2.84 - 2.67 (m, 4H), 2.48 (br d, J = 16.0 Hz, 1 H), 2.26 - 2.11 (m, 2H), 2.07 - 1.78 (m, 6H), 1.78 - 1.56 (m, 2H), 0.85 (d, J = 7.0 Hz, 3H); ¹⁹F NMR (377 MHz, METHANOL-d4 ) 5 = -145.7; MS: 588.1 [M+H]⁺.

Example 2 and Example 3 were prepared according to the method to make Example 1 with non-critical modifications and commercial starting materials that one skilled in the art would appreciate.

Example 2: (R)-4-((S)-4-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)-8a,9, 12, 13-tetrahydro-8H, 11 H-7, 10-dioxa-1 ,3,6, 13a-tetraazanaphtho[1 ,8- ab]heptalen-5-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol.

¹H NMR (400 MHz, MeOD) 5 8.46 (s, 1 H), 6.86 (d, J = 82.8 Hz, 1 H), 6.61 (d, J = 2.4 Hz, 1 H),

6.53 (d, J = 2.5 Hz, 1 H), 5.22 (ddd, J = 13.6, 6.2, 2.6 Hz, 1 H), 4.73 (dd, J = 13.5, 4.4 Hz, 1 H),

4.53 (m, 3H), 4.33 (m, 1 H), 4.17 (dd, J = 12.4, 4.3 Hz, 1 H), 4.08 (d, J = 13.7 Hz, 1 H), 3.97 (m, 1 H), 3.74 (dd, J = 12.4, 10.0 Hz, 1 H), 3.67 (d, J = 14.2 Hz, 1 H), 3.55 (m, 1 H), 3.43 (m, 2H), 3.01 (m, 3H), 2.77 (m, 3H), 2.28 (m, 1 H), 2.14 (m, 2H), 2.02 (m, 3H), 1.88 (m, 2H), 1.70 (m, 2H), 0.84 (d, J = 7.0 Hz, 3H); MS: 606 [M+H]⁺.

Example 3: (R)-4-((S)-4-fluoro-2-(((S,E)-2-(fluoromethylene)tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)-8a,9, 12, 13-tetrahydro-8H, 11 H-7, 10-dioxa-1 ,3,6, 13a-tetraazanaphtho[1 ,8- ab]heptalen-5-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol

Example 3

¹H NMR (400 MHz, MeOD) 5 8.45 (s, 1 H), 6.81 (m, 1 H), 6.61 (d, J = 2.6 Hz, 1 H), 6.54 (d, J =

2.6 Hz, 1 H), 5.21 (ddd, J = 13.7, 6.3, 2.9 Hz, 1 H), 4.72 (dd, J = 13.5, 4.5 Hz, 1 H), 4.54 (m, 3H), 4.33 (m, 1 H), 4.17 (m, 2H), 3.97 (ddd, J = 12.7, 5.8, 4.7 Hz, 1 H), 3.83 (d, J = 14.7 Hz, 1 H), 3.74 (dd, J = 12.4, 9.9 Hz, 1 H), 3.55 (m, 1 H), 3.48 (m, 1 H), 3.42 (m, 1 H),3.03 (m, 2H), 2.89 (d, J = 15.6 Hz, 1 H), 2.77 (m, 2H), 2.63 (d, J = 15.7 Hz, 1 H), 2.27 (m, 1 H), 2.16 (m, 2H), 2.04 (m, 2H), 1.95 (m, 1 H), 1.86 (m, 2H), 1.68 (m, 2H), 0.84 (d, J = 7.0 Hz, 3H); MS: 606 [M+H]⁺.

Intermediate 17: ((3/?,5S)-5-methyl-1,4-oxazepan-3-yl)methanol

To a solution of (3S)-3-aminobutan-1-ol (1.76 g, 19.8 mmol) in MeOH (30 mL) was added benzaldehyde (2.10 g, 19.8 mmol). The mixture was stirred at rt for 1 h. The reaction was then cooled in an ice bath, and sodium borohydride (749 mg, 19.8 mmol) was added in portions to keep the bubbling under control. After 20 min, the reaction was removed from the ice bath and stirred at rt for 2 h. LCMS analysis showed the desired mass had formed. Water (20 mL) was added and the mixture was concentrated under vacuum. The white solid was taken up in water (40 mL) and extracted into DCM (2 X 40 mL). The combined DCM layers were dried over Na2SCU, filtered and concentrated to give 17a as a colorless oil which was taken to the next step without further purification. ¹H NMR (400 MHz, MeOD) 5 = 7.38 - 7.28 (m, 4H), 7.28 - 7.21 (m, 1 H), 3.84 - 3.79 (m, 1 H), 3.75 - 3.58 (m, 3H), 2.87 (sxt, J = 6.4 Hz, 1 H), 1.76 (tdd, J = 6.2, 7.8, 14.0 Hz, 1 H), 1.56 (qd, J = 5.8, 14.0 Hz, 1 H), 1.13 (d, J = 6.3 Hz, 3H); MS: 180.1 [M+H]⁺. A solution of 17a (3.28 g, 18.3 mmol) in toluene (30 mL) was treated with oxentan-3-one (1.52 g, 21.1 mmol) and the mixture was heated to 105° C for 3 h. The mixture was cooled to 35° C and sodium triacetoxyborohydride (6.21 g, 29.3 mmol) was added. The reaction was stirred for 16 h at 35° C. The reaction was quenched with 2 M Na2CC>3 (40 mL) and stirred vigorously at rt for 1 h. The layers were separated and the aqueous layer was extracted a second time with toluene. The combined toluene extract was concentrated under vacuum to give 4.1 g (96%) of 17b as a colorless oil. ¹H NMR (400 MHz, MeOD) 5 = 7.37 - 7.33 (m, 2H), 7.32 - 7.26 (m, 2H), 7.25 - 7.20 (m, 1 H), 4.68 - 4.63 (m, 1 H), 4.56 (t, J = 6.6 Hz,1 H), 4.45 - 4.35 (m, 2H), 4.30 - 4.20 (m, 1 H), 3.92 (d, J = 14.0 Hz, 1 H), 3.66 - 3.52 (m, 3H), 2.89 - 2.78 (m, 1 H), 1.79 (qd, J = 7.1 , 14.5 Hz, 1 H),1.41 (qd, J = 6.1 , 13.9 Hz, 1 H), 0.99 (d, J = 6.6 Hz, 3H); MS: 236.1 [M+H]⁺. To a solution of 17b (3.92 g, 16.6 mmol) in toluene (40 mL) was added dibutylhydrogenphosphate (3.8 g, 18 mmol). The rxn was heated to 108° C for 20 h. The reaction was cooled to rt and 2 N Na2COs (40 mL) was added. The mixture was stirred vigorously for 1 h and the layers were separated. The toluene layer was concentrated under vacuum to afford 3.61 g (92%) of a mixture containing 17c. Analysis of the crude mixture by ¹H NMR showed a 2.1 to 1 mixture of diatereomers. MS: 236.1 [M+H]⁺. The mixture was separated using chiral SFC: Chiralpak IG SFC 5um 30mm x 250mm; mobile phase A: CO2, mobile phase B: MeOH + 10 mm NH3; running 12% B isocratic, 120 bar, 120 mL/min. From this separation, 1.53 g of the undesired isomer was obtained [a]_D ²² -70.7° (c 0.1 , MeOH) along with 0.74 g (19%) of 17c, [a]_D ²² -14.8° (c 0.1 , MeOH), ¹H NMR (400 MHz, MeOD) 5 = 7.39 (d, J = 7.6 Hz, 2H), 7.30 - 7.23 (m, 2H), 7.20 - 7.13 (m, 1 H), 3.90 - 3.76 (m, 5H), 3.68 (ddd, J = 2.6, 9.8, 12.6 Hz, 1 H), 3.40 - 3.34 (m, 1 H), 3.29 - 3.21 (m, 2H), 3.20 - 3.12 (m, 1 H), 1.97 - 1.86 (m, 1 H), 1.75 (qdd, J = 2.6, 3.5, 15.0 Hz, 1 H), 1.12 (d, J = 6.6 Hz, 3H). To a solution of 17c (0.74 g, 3.13 mmol) in MeOH (20 mL) was added Pd(OH)2 (44 mg, 0.31 mmol). The reaction was stirred vigorously under H2 (1 atm) for 18 h. LCMS indicted that the benzyl deprotection was complete. The reaction was filtered and concentrated under vacuum to afford 433 mg (95%) of Intermediate 17 as a colorless oil that was used without further purification. ¹H NMR (DMSO-d6, 400 MHz) 5 8.9-9.1 (m, 1 H), 8.6-8.8 (m, 1 H), 5.2-5.4 (m, 1 H), 3.7-3.9 (m, 3H), 3.6-3.7 (m, 3H), 3.5-3.5 (m, 1 H), 2.0-2.2 (m, 1 H), 1.8-1.9 (m, 1 H), 1.34 (d, 3H, J=6.6 Hz), MS: 146 [M+H]⁺.

Intermediate 18: (5aS,10S)-2-chloro-1-fluoro-10-methyl-12-(methylthio)-5a,6,9,10-tetrahydro-

5/7, 8/7-4, 7-dioxa-3,10a,11 ,13-tetraazanaphtho[1 ,8-ab]heptalene

A mixture of Intermediate 9 (430 mg, 2.96 mmol) and Intermediate 17 (884 mg, 2.96 mmol) in CH3CN (50 mL) was cooled to 0° C. DIEA (2.06 mL, 11 .8 mmol) was added and the reaction was allowed to warm to rt. After 3h, the reaction was complete by LCMS. The CH3CN was removed under vacuum and the resulting bright orange solid was purified via flash chromatography (ISCO Gold, 80g, 0-5.5% MeOH in DCM, hold at 5.5% MeOH until the product elutes). A small amount of impurity eluted with the desired product mono-addition product. The fractions were concentrated and the mono-addition intermediate was taken on to the next step directly. The purified mono-addition intermediate (1.07 g, 2.62 mmol) was suspended in CH3CN (65 mL) and DBU (1.19 mL, 7.87 mmol) was added. The reaction was stirred at 50° C for 20 h. The CH3CN was removed under vacuum to give a thick oil which solidified upon standing. The solids were triturated with CH3CN by stirring the suspension at 50° C. After stirring the slurry for 1 h, it was cooled to rt. The solids were collected by filtration, washed with MTBE, and dried under vacuum to afford 614 mg (63%) of Intermediate 18 as a solid. ¹H NMR (400 MHz, DMSO) 5 4.62 (dd, J = 13.3, 4.9 Hz, 1 H), 4.45 (d, J = 13.1 Hz, 1 H), 4.37 - 4.23 (m, 2H), 4.12 (dd, J = 12.4, 3.8 Hz, 1H), 3.95 - 3.86 (m, 1H), 3.55 (dd, J = 12.2, 10.5 Hz, 1H), 2.55 (s, 3H), 2.26 (t, J = 10.6 Hz, 1 H), 2.05 - 1.92 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H); MS: 371 [M+H]⁺.

Intermediate 19: [(2Z,7aS)-2-(2-methoxyethylidene)tetrahydro-1H-pyrrolizin-7a(5H)- yl]methanol

Step 1 : Synthesis of ethyl (S)-2-(2-(tert-butoxy)-2-oxoethylidene)-5-oxotetrahydro-1H- pyrrolizine-7a(5H)-carboxylate (8a)

To a stirred solution of tert-butyl 2-(dimethoxyphosphoryl)acetate (2340 mg, 10.4 mmol) in THF (40 mL) was slowly added NaH (417 mg, 10.4 mmol) at 0 °C. The suspension was stirred at 0 °C for 10 min. Then ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolizine-7a(5/7)-carboxylate (CAS 2703745-57-5, 2000 mg, 9.47 mmol) in THF (5 mL) was added dropwise at 0 °C. The resulting mixture was warmed up to 25 °C gradually and stirred for another 2 h. LCMS showed the starting material was consumed and desired product was formed. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Biotage, 80 g silica gel, 0%-30% EtOAc in Petroleum ether) to give crude ethyl (S)-2-(2-(tert-butoxy)-2-oxoethylidene)- 5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (1870 mg, crude) as colorless oil. LCMS (ESI) m/z: 310.1 [M+H]⁺.

Step 2: Synthesis of (S)-2-(7a-(ethoxycarbonyl)-5-oxotetrahydro-1H-pyrrolizin-2(3H)- ylidene)acetic acid (8b)

To a solution of ethyl (S)-2-(2-(tert-butoxy)-2-oxoethylidene)-5-oxotetrahydro-1/7-pyrrolizine- 7a(5/-/)-carboxylate (700 mg, 2.26 mmol) in DCM (8 mL) was added HCI (6 mL, 4.0 M in dioxane). Then the mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and desired product was formed. The solution was concentrated under reduced pressure to give (S)-2-(7a-(ethoxycarbonyl)-5-oxotetrahydro-1H-pyrrolizin-2(3H)-ylidene)acetic acid (550 mg, crude) as light-yellow oil. LCMS (ESI) m/z: 254.1 [M+H]⁺.

Step 3: Synthesis of ethyl (S)-2-(2-hydroxyethylidene)-5-oxotetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate (8c)

To a solution of (S)-2-(7a-(ethoxycarbonyl)-5-oxotetrahydro-1/7-pyrrolizin-2(3/7)-ylidene)acetic acid (970 mg, 3.83 mmol) and NMM (774 mg, 7.65 mmol) in THF (33 mL) was added isobutyl chloroformate (784 mg, 5.74 mmol) in THF (4 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 40 min. Precipitation occurred and LCMS showed the mixed anhydride intermediate was formed. Solid was filtered. NaBH4 (247 mg, 6.53 mmol) in water (5 mL) was added to the filtrate at 0 °C. The resulting mixture was stirred at 0 °C for 15 min. LCMS showed the desired product was formed. The solution was concentrated under reduced pressure. The residue was purified by flash column chromotraghy (Biotage, 25 g silica gel, 0-100% EtOAc in Petroleum ether) to give ethyl (S)-2-(2-hydroxyethylidene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (220 mg, 24%, E/Z mixture) as colorless oil. ¹H NMR (400 MHz, CDCI3) 6 5.71 - 5.57 (m, 1H), 4.33 (d, J = 16.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.16 - 4.08 (m, 2H), 3.78 (d, J = 17.0 Hz, 1H), 3.24 (d, J = 15.7 Hz, 0.2H, minor isomer), 3.07 (d, J = 15.8 Hz, 0.8H, major isomer), 2.84 - 2.73 (m, 1 H), 2.67 - 2.57 (m, 1 H), 2.55 - 2.37 (m, 2H), 2.18 - 2.06 (m, 1 H), 1.28 (t, J = 7.1 Hz, 3H). LCMS (ESI) m/z 240.1 [M+H]⁺.

Step 4: Synthesis of ethyl (S)-2-(2-methoxyethylidene)-5-oxotetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate (8d)

To a solution of ethyl (S)-2-(2-hydroxyethylidene)-5-oxotetrahydro-1 H-pyrrolizine-7a(5/7)- carboxylate (180 mg, 0.752 mmol) and Ag2<D (872 mg, 3.76 mmol) in CH3CN (10 mL) was added iodomethane (1070 mg, 7.52 mmol). The reaction mixture was stirred at 25 °C for 16 h. LCMS showed -50% of the starting material remained and -50% of the desired product was formed. Another portion of Ag₂O (436 mg, 1.88 mmol) was added and the mixture was stirred for another 16 h. LCMS showed the starting material was consumed and desired product was formed. The mixture was filtered. The filtrate was concentrated under reduced pressure to give crude ethyl (S)-2-(2-methoxyethylidene)-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)- carboxylate (200 mg, crude, E/Z mixture) as a light yellow solid. ¹H NMR (400 MHz, CDCI3) 6 5.54 - 5.45 (m, 1 H), 4.31 - 4.21 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.86 - 3.77 (m, 2H), 3.71 (d, J = 15.6 Hz, 1 H), 3.24 (s, 3H), 3.15 (d, J = 16.7 Hz, 0.2H, minor isomer), 3.00 (d, J = 15.8 Hz, 0.8H, major isomer), 2.79 - 2.66 (m, 1 H), 2.61 - 2.50 (m, 1 H), 2.49 - 2.33 (m, 2H), 2.11 - 2.00 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H). LCMS (ESI) m/z: 254.1 [M+H]⁺. Step 5: Separation of ethyl (S,Z)-2-(2-methoxyethylidene)-5-oxotetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate (8e)

The E/Z mixture of ethyl (S)-2-(2-methoxyethylidene)-5-oxotetrahydro-1/7-pyrrolizine-7a(5/7)- carboxylate (200 mg, 0.79 mmol) was separated by chiral SFC (Apparatus: SFC 150; Column: Daicel CHIRALPAK IC, 250mm x 30 mm I. D. ,10pm; Mobile phase: CO₂/MeOH [0.2%NH₃ (7M Solution in MeOH)] = 90/10; Flow rate: 120 g/min; Wave length: UV 214 nm; Temperature: 35 °C) to give ethyl (S,Z)-2-(2-methoxyethylidene)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (91 mg, 46%, Rt: 2.406 min, Peak 1) as a light-yellow oil. ¹H NMR (400 MHz, CDCh) 5 5.63 - 5.52 (m, 1H), 4.32 (d, J = 16.0 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.87 (d, J = 6.5 Hz, 2H), 3.78 (d, J = 15.9 Hz, 1H), 3.31 (s, 3H), 3.07 (d, J = 15.8 Hz, 1H), 2.78 (dt, J = 16.7, 9.7 Hz, 1H), 2.61 (ddd, J = 13.2, 9.1, 1.8 Hz, 1H), 2.56 - 2.40 (m, 2H), 2.18 - 2.05 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H). LCMS (ESI) m/z: 254.1 [M+H]⁺.

Step 6: Synthesis of [(2Z,7aS)-2-(2-methoxyethylidene)tetrahydro-1H-pyrrolizin-7a(5H)- yl]methanol

(Intermediate 19)

To a solution of ethyl (S,Z)-2-(2-methoxyethylidene)-5-oxotetrahydro-1 H-pyrrolizine-7a(5/7)- carboxylate (80 mg, 0.32 mmol) in THF (3.2 mL) was added LAH (0.63 mL, 1 M in THF) at 0 °C under nitrogen. The resulting mixture was warmed to 70 °C and stirred at 70 °C for 1 h.

TLC (DCM/MeOH = 10:1, iodine stain) showed the starting material was consumed and a new point was observed. The mixture was quenched with Na2SO4.10 H₂O, and the suspension was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate concentrated to give crude (S,Z)-(2-(2-methoxyethylidene)tetrahydro-1H-pyrrolizin-7a(5/7)-yl)methanol (58 mg, 93 %) as yellow oil. ¹H NMR (400 MHz, CDCh) 5 5.52 - 5.42 (m, 1H), 3.88 - 3.81 (m, 2H), 3.68 (d, J = 15.6 Hz, 1 H), 3.36 - 3.21 (m, 6H), 3.15 - 3.05 (m, 1H), 2.67 (dt, J = 10.1, 7.1 Hz, 1 H), 2.50 (d, J = 16.1 Hz, 1H), 2.38 (d, J = 16.3 Hz, 1H), 1.93 - 1.78 (m, 3H), 1.72 - 1.65 (m, 1H). LCMS (ESI) m/z 198.3 [M+H]⁺.

Example 4: (R)-4-((8aS,13S)-4-fluoro-13-methyl-2-(((S)-2-methylenetetrahydro-1/7-pyrrolizin- 7a(5/-/)-yl)methoxy)-8a,9, 12,13-tetra hydro- 8/7, 11 H-7, 10-dioxa-1 ,3,6, 13a-tetraazanaphtho[1 ,8- ab]heptalen-5-yl)-5-methyl-5,6,7,8-tetrahydronaphthalen-2-ol; Example 4 was prepared from Intermediate 18 according to the method to make Example 1 with non-critical modifications that one skilled in the art would appreciate.

¹H NMR (400 MHz, MeOD) 6 6.61 (d, J = 2.5 Hz, 1 H), 6.53 (d, J = 2.5 Hz, 1 H), 5.12 (s, 2H), 4.68 (dd, J = 13.5, 4.8 Hz, 1 H), 4.54 - 4.34 (m, 4H), 4.33 - 4.26 (m, 1 H), 4.22 (dd, J = 12.5, 3.9 Hz, 1 H), 4.09 - 3.98 (m, 2H), 3.75 - 3.56 (m, 2H), 3.46 - 3.36 (m, 2H), 3.10 - 3.02 (m, 1 H), 3.01 - 2.93 (m, 1 H), 2.89 (d, J = 16.0 Hz, 1 H), 2.81 - 2.73 (m, 2H), 2.63 (d, J = 16.6 Hz, 1 H), 2.55 -

2.44 (m, 1 H), 2.29 - 2.19 (m, 1 H), 2.18 - 1.94 (m, 4H), 1.95 - 1.85 (m, 2H), 1.83 (d, J = 6.8 Hz, 3H), 1 .77 - 1 .69 (m, 1 H), 1 .67 - 1 .59 (m, 1 H), 0.84 (d, J = 7.0 Hz, 3H); MS: 602 [M+ H]⁺.

Additional compounds of the invention were prepared by modifications of the methods exemplified herein. Except where otherwise indicated, all compounds having chiral centers were prepared and/or isolated as a single enantiomer having a known relative configuration. Compounds marked “absolute stereochemistry unknown” were typically prepared from racemic intermediates and resolved into single enantiomers by an appropriate chiral preparative SFC method before characterization and testing. Examples and their corresponding characterization data are presented in Table 1 below.

Table 1 :

Binding affinity and kinetics measurements by SPR

The binding affinity and kinetics were measured by Surface Plasmon Resonance (SPR) using Biacore 8K or 8K+ (Cytiva, Marlborough, MA) instruments. Recombinant, C-terminal sitespecific biotinylated, wild-type (WT) KRASGDP (aa1-185), G12DGDP KRAS (aa1-185), G12CGDP KRAS (aa2-184), G12VGDP KRAS (aa2-184), WT HRASGDP (aa2-184) and WT NRASGDP (aa2- 185) proteins were purified in presence of 1 pM GDP.

The GDP-loaded KRAS proteins went through nucleotide exchange with GTPyS (a non- hydrolysable analog of GTP) in the presence of alkaline phosphatase beads to obtain WTGTPyS KRAS (aa1-185), G12DGTPyS KRAS (aa1-185), G12CGTPyS KRAS (aa2-184), G12VGTPyS KRAS (aa2-184), WT HRASGTPyS (aa2-184) and WT NRASGTPyS (aa2-185).

Binding measurements were performed in parallel sets of either WT/G12D/G12C/G12V KRAS or WT K/H/N RAS proteins in GDP and/or GTPyS-loaded forms. Biacore instrument was desorbed and docked with a Series S Sensor Chip SA. The proteins were diluted to 50 pg/mL with the assay buffer (50 mM HEPES, 150 mM NaCI, 10 pM GDP for GDP-loaded proteins or 10 pM GTPyS for GTPyS-loaded proteins, 5 mM MgCI2, 0.5 mM TCEP, 5 % glycerol, 0.02 % Tween-20, 2% DMSO, pH 7.2) and immobilized at a flow rate of 3 pL/min at 10 °C with a contact time of 3-10 min. to capture ~ 3000 - 4000 Rlls of proteins on the surface. The functionalized surface was then equilibrated with assay buffer for approximately 1 hour. Unfunctionalized SA surfaces with no immobilized protein served as reference for binding kinetic analysis. Compound binding kinetics were measured in either multi-cycle or single-cycle kinetic format.

Multi-cycle kinetic analysis (MCK): A 2-fold, 10-point serial dilution of test compounds was setup in a 96-well microplate (Greiner; Cat # 650101) with a top concentration of either 10 pM or 100 pM. Binding kinetics was measured at 10 °C by injecting serial dilution of compounds onto both reference and RAS immobilized channels at a flow rate of 100 pL/min and association time of 90 seconds. Compound dissociation was monitored for at least 400 seconds during each cycle. No additional regeneration was used. DMSO calibration curve was obtained before and after compound analysis by injecting 0-4% of DMSO in assay buffer. A suitable compound with known affinity and kinetics was tested once in every experiment as a positive control to assess activity of the captured protein on the surface.

Single-cycle kinetic analysis (SCK): A 3-fold, 6-point serial dilution of compounds was set-up in a deep 96-well microplate (Greiner Bio; Cat # 780201) with the highest concentration of 1 pM (concentration range: 0.004 - 1 pM). Binding kinetics was measured at 10 °C by injecting serial dilutions of compounds in increasing order onto reference as well as RAS immobilized channels at a flow rate of 100 pL/min and association time of 120 seconds. Compound dissociation was monitored for at least 3600 seconds. Two buffer blanks were also run in a single-cycle kinetics format before the compound run for double referencing. No additional regeneration was used. DMSO calibration curve was obtained before and after compound analysis by injecting 0-4% of DMSO in the assay buffer. A suitable compound with known affinity and kinetics was tested once in every experiment as a positive control to assess activity of the captured protein on the surface.

Both MCK and SCK data were processed and analyzed using Biacore Insight evaluation software (Cytiva, Marlborough, MA)). The double-referenced and solvent-corrected data was fit to 1 :1 Langmuir model to measure kinetic binding constant (KD), association rate (kon) and dissociation rate (koff). Dissociative half-life (t1/2) was calculated from the measured koff using standard equation (t1/2= 0.693/ koff). The adequateness of the fit was judged by c2 values and the randomness of residue distribution. The KrasGDP SPR and KRasGTPgS SPR binding assay results for Examples 1-14 are provided in Table 2 and Table 3 respectively. A geometric mean of binding constant KD was provided when an Example was tested more than once. A blank cell or “nd” indicates no data was obtained for that Example in that specific assay at time of writing.

The binding constant KD shows that the exemplified compounds have potent binding capabilities to one or more of KRAS G12C, KRAS G12D, and KRAS G12V receptors, and may be selective (at least 10 times more potent) over HRAS and NRAS receptors. Table 2: SPR binding assay results with GDP loaded proteins. KD values in nM.

Table 3. SPR binding assay results with GTPyS loaded proteins. KD values in nM.

KRAS Cell Titer Gio (CTG) Assay

The CellTiter-Glo® (CTG) Luminescent Cell Viability Assay is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells. The CTG is designed for use with multi-well formats, making it ideal for automated high-throughput screening (HTS), cell proliferation and cytotoxicity assays. The homogeneous assay procedure involves adding the single reagent (CellTiter-Glo® Reagent) directly to cells cultured in serum-supplemented medium. Cell washing, removal of medium and multiple pipetting steps are not required. The system detects as few as 15 cells per well in a 384- well format in 10 minutes after adding reagent and mixing.

Cells are grown in humidified 5% CO2 incubator at 37°C using the culture conditions outlined below. All cell culture media reagents were purchased from Gibco. Cell lines purchased from ATCC: H358 (non-small cell lung cancer cell line), SW620 (colorectal cancer cell line), PANC08.13 (RPMI1640 + 10%FBS + 10units/ml Insulin, pancreatic cancer cell line). Test and control compounds are dispensed as nanoliter drops according to desired final concentrations in 0.1 % DMSO using Echo Acoustic Dispenser onto 384 assay plates (Corning, Cat#3764) prior to cell seeding. Cells were seeded in 40pL volume per well at the following cell densities (cells per well): H358 (300), SW620 (750), PANC 08.13 (600). Cells are incubated in the presence of compound for 7-days. Viability is determined on Day 7 using CellTiter-Glo® (CTG) Luminescent Cell Viability Assay (Promega). CTG is added to a final volume of 20pl per well and incubated at room temperature for 15minutes before luminescence is captured using an EnVision Reader with LUM384 US protocol. Data is analyzed using Activity Base to determine compound response and will be represented either as a percent effect (PCTEFF) or percent control (PCTOCTL) as described: Zero percent effect control (ZPE) (Negative control) - 100% DMSO. Hundred percent effect (HPE) (Positive control) - 1uM Trametinib (GSK1120212, MEK inhibitor) (4nl of 10mM and 36nl of DMSO per well). The following equations/nomenclature are used (% Effect; PCTEFF) and (% of Control; PCTOCTL): PCTEFF: 100* (Raw_Data_Value - HPE I ZPE - HPE), PCTOCTL: 100 * Raw_Data_Value I User_Defined_Array), where the User_Defined_Array is either summarized HPE or ZPE.

The CTG assay results for some exemplified examples are provided in Table 4. A geometric mean of IC5o(nM) was provided when an Example was tested more than once. Cells with “nd” indicate compound not tested in that particular assay at time of writing.

The CTG assay shows that selective exemplified compounds of the present invention have demonstrated anticancer activities for pancreatic cancer, non-small cell lung cancer, and colorectal cancer.

Table 4: Cell proliferation (CTG) assay results. IC50 data (nM).

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

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

Claims

WE CLAIM:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

R² is H or is selected from the group consisting of -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -(Ci-Ce alkylene)-SH, -(C1-C3 alkylene)-S-(Ci-Cs alkyl), -(C1-C3 alkylene)- (S=O)-(Ci-Cs alkyl), -(C1-C3 alkylene)-(SO2)-(Ci-Cs alkyl), Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce fluoroalkyl, C3-C6 fluorocycloalkyl, and Ci-Ce alkoxy, each optionally substituted with one, two or three substituents independently selected from the group consisting of - OH, -CN, -NH₂, -NH(CI-C₃ alkyl), -N(CI-C₃ alkyl)₂, -SH, -(C1-C4 alkylene)-CN, -(C1-C4 alkylene)-OH, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; R³ is: wherein R⁷ and R⁸ are each independently H or C1-C3 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 alkoxy; alternatively R⁷ and R⁸ together with the C atoms to which they are attached form a Cs-Cs cycloalkyl or 3-8 membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N, O, and S, wherein said cycloalkyl or heterocyclyalkyl is further optionally substituted with one, two or three substituents independently selected from the group consisting of -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C2-C3 alkynyl, C3-C5 cycloalkyl or together with the carbon to which it is attached C3-C5 spirocycloalkyl; and R³ is optionally further substituted with one, two or three substituents independently selected from the group consisting of -OH, -NH2, halogen, -CN or C1-C3 alkyl;

R⁴ is H, halogen, -CN, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 fluoroalkyl;

R⁵ is H, -OH, halogen, -NH₂, CN, or selected from the group consisting of -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-CN, -(Ci-Ce alkylene)-SH, -(C1-C3 alkylene)-S-(Ci-Cs alkyl), -(C1-C3 alkylene)-(S=O)-(Ci-C₃ alkyl), -(C1-C3 alkylene)-(SO₂)-(Ci-C₃ alkyl), Ci-C₆ alkyl, C3-C6 cycloalkyl, Ci-Ce fluoroalkyl, C3-C6 fluorocycloalkyl, and Ci-Ce alkoxy each is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, -NH2, -SH, -(C1-C4 alkylene)-CN, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; or alternatively, R⁵ and the carbon atom that R⁵ is attached to, and R² and the nitrogen atom that R² is attached to together form a 4-8 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, or heteroatom-containing groups selected from the group consisting of N(Ci-Ce alkyl), -(S=O)-, and -(SO2)-, wherein said 4-8 membered heterocycloalkyl is optionally substituted with one, two or three substituents selected from the group consisting of -OH, -OCH3, -CN, halogen, C1-C3 alkyl, -(Ci-Ce alkylene)-CN, and -(Ci-Ce alkylene)-OH;

R⁹, R¹⁰, and R¹¹ are each independently H or C1-C3 alkyl;

X is O, N, or S;

I is 1 or 2; and x is 0,1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker L is -(O-CH2)-.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is a 5-10 membered heterocycloalkyl substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkylidenyl, C1-C3 haloalkylidenyl, alkylidenylcyclopropyl, alkylidenyloxetane, Ci-C₃ alkyl wherein when present two of the Ci-C₃alkyl together with the carbon from which they attach may form a spirocyclic ring, Ci-C₃ alkoxy, -OC(O)NH₂, -OC(O)NHCH₃, - OC(O)N(CH₃)₂, wherein the Ci-C₃ alkyl, Ci-C₃ alkoxy, C1-C3 haloalkylidenyl or C1-C3 alkylidenyl, is each optionally substituted with one, two or three R¹².

4. A compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is a 5-8 membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of N and O, and said 5-8 membered heterocycloalkyl is substituted with one and only one Ci-C₃ alkylidenyl or Ci-C₃ haloalkylidenyl, and is further optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, halogen, Ci-C₃ alkyl, Ci-C₃ alkoxy, -OC(O)NH₂, -OC(O)NHCH₃, - OC(O)N(CH₃)₂, wherein the Ci-C₃ alkoxy is optionally substituted with one, two or three R¹² substituents independently selected from the group consisting of -OH, -OCH₃ and halogen.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L-R¹ is selected from the group consisting of:

6. The compound of any of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L-R¹ is selected from the group consisting of:

7. The compound of any of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L-R¹ is selected from the group consisting of:

8. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein L-R¹ is selected from the group consisting of:

The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R² is H or is selected from the group consisting of -(C1-C5 alkylene)-OH and C1-C5 alkyl, each optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, and halogen.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein benzene ring of R³ is optionally substituted with one to three substituents independently selected from the group consisting of -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, and C2-C3 alkynyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R³ is:

12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R³ is

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁴ and -CN, Cl or F.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ at each occurrence are each independently H, -OH, -CN, halogen, or each independently selected from the group consisting of -(C1-C5 alkylene)- OH and C1-C5 alkyl, each optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, and halogen.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (II): wherein Y is selected from the group consisting of CH2, O, N(Ci-Ce alkyl), S, (S=O), and (SO2), R¹² at each occurrence is independently selected from the group consisting of H, halogen, -OH, -CN, C1-C3 alkyl, -(Ci-Ce alkylene)-CN, and -(Ci-Ce alkylene)-OH; and m and n are each independently 0, 1 , 2 or 3, y is 0,1 , 2, or 3, and m plus n is 1 , 2, 3, 4, or 5.

16. The compound of claim 15, wherein I is 1 , n is 1 , m is 3, x is 0, and y is 0.

17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein Y is -CH₂- or O.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein Y is O.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (III):

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

22. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

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

25. The method for treating cancer of claim 24, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

26. A method for the treatment of a disorder mediated by inhibition of KRAS G12C, KRAS G12D, and KRAS G12V receptors in a subject, comprising administering to the subject in need thereof a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.