WO2023209088A1

WO2023209088A1 - Bicyclic heteroaromatic compounds and their use in the treatment of cancer

Info

Publication number: WO2023209088A1
Application number: PCT/EP2023/061109
Authority: WO
Inventors: Scott Nathan MLYNARSKI
Original assignee: Astrazeneca Ab
Priority date: 2022-04-28
Filing date: 2023-04-27
Publication date: 2023-11-02

Abstract

The specification relates to compounds of Formula (I): (I) and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of cancer.

Description

BICYCLIC HETEROAROMATIC COMPOUNDS AND THEIR USE IN THE TREATMENT OF CANCER

This specification relates to certain heteroaromatic compounds and pharmaceutically acceptable salts thereof that inhibit TEAD, and their use in treating cancer. This specification also relates to processes and intermediate compounds involved in the preparation of the heteroaromatic compounds and to pharmaceutical compositions containing them.

Introduction

The Hippo pathway is a highly conserved signaling pathway that controls organ size and tissue maintenance through the regulation of gene expression programs involved in cell proliferation, survival, and differentiation (Dong et al., Cell 2007, 1120-33; Ma et al., Ann Rev Biochem 2018, 577- 604 and references therein). Hippo ultimately regulates the transcription coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) which bind to DNA-bound Transcriptional Enhanced Associate Domain proteins (TEAD1-4) to form bipartite transcription complexes that activate TEAD-dependent gene expression. The core of the Hippo pathway consists of a tightly regulated kinase signaling cascade. When Hippo signaling is active, the kinases LATS1/2 phosphorylate YAP/TAZ which causes these proteins to be sequestered in the cytoplasm or degraded by the proteasome. When Hippo signaling is inactive, LATS1/2 are inactivated resulting in YAP/TAZ to be dephosphorylated and subsequently translocated into the nucleus to interact with and activate TEAD-dependent transcription (Meng et al., Genes&Dev 2016, 1-17).

Hippo signaling is a well-established tumor suppressor pathway and data from The Cancer Genome Atlas show that the Hippo pathway is one of eight signaling pathways that are frequently altered in human cancer (Sanchez-Vega et al., Cell 2018, 321-337). Both genetic and epigenetic alterations of Hippo components can result in aberrant activation of YAP/TAZ and TEAD-dependent transcription and have been implicated in several human malignancies (Wang et al., 2018, 1304-1317). NF2 (aka Merlin) is encoded by the neurofibromatosis type 2 gene and is a key upstream regulator of the Hippo core kinase cascade consisting of STE20-like protein kinase 1 (STK3, aka MST2, and STK4, aka MST1), the large tumor suppressors (LATS1 and LATS2), and adaptor proteins Salvador homolog 1 (SAV1) and MOB kinase activators (MOB1A/MOB1B) (Tapon et al., Cell 2002, 467-478). Loss of function mutations or deletions in pathway components have been reported in several cancer types including mesothelioma, breast, liver, lung, prostate, gastric, and colorectal tumors (Poma et al., Scientific Reports 2018, volume 8, Article number: 10623; Zancanato et al., Cancer Cell 2016, 783- 803 and references therein). Because several Hippo pathway components are tumor suppressors where dysfunction results in aberrant TEAD-dependent transcription, targeting TEAD offers a potential opportunity for therapy.

The compounds of the specification provide an anti-cancer effect by, as a minimum, acting as TEAD inhibitors.

The compounds of the specification may also exhibit advantageous physical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability, lower plasma protein binding, and/or greater chemical stability), and/or favourable toxicity profiles (for example a decreased activity at hERG), and/or favourable metabolic or pharmacokinetic profiles, in comparison with other known TEAD inhibitors. Such compounds may therefore be especially suitable as therapeutic agents, particularly for the treatment of cancer.

General Description

According to one aspect of the specification there is provided a compound of Formula (I):

wherein:

X¹ and X² are independently selected from CH and N;

L is a covalent bond, O or CH?; either X³ is CH and X⁴ is selected from CR⁵ and N, or X³ is N and X⁴ is CR⁵;

R¹ is Ci-4 alkyl or C3-4 cycloalkyl;

R² is selected from H and R¹, wherein R¹ is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy;

R³, R⁴ and R⁵ are independently selected from H, C1-4 fluoroalkyl, C1-4 alkoxy, -S(Ci_₄ alkyl), -O(Ci_₄ fluoroalkyl), -S(Ci_₄ fluoroalkyl), F, Cl, C3-4 fluorocycloalkyl, R^j and R^k, wherein R^j is C3-4 cycloalkyl optionally substituted with -CN, C1-4 alkoxy or C1.4 fluoroalkyl and R^k is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy;

G is selected from

R⁶ is H, OH, F, -CN, C(=O)NH₂, N(CI-₄ al kyl )₂, Ci.₄ alkoxy, Ci-₄ fluoroalkyl, R¹⁰ or R¹¹;

R⁷ is H, Ci-4 alkoxy, R¹⁰ or R¹¹; either R⁸ and R⁹ are independently selected from H, R¹⁰ and R¹¹; or R⁸ and R⁹, together with the carbon atom to which they are attached, form a cyclopropane or cyclobutane ring; each R¹⁰ is independently C1.4 alkyl optionally substituted with Ci-₄ alkoxy, N(Ci.₄ alkyl)₂ or OH; each R¹¹ is independently C3-4 cycloalkyl optionally substituted with Ci-₄ alkoxy or OH;

J is selected from

R¹² is H or F;

R¹³ is H, CH₂F or CH₃; wherein a Ci-₄ fluoroalkyl is a saturated linear or branched hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom; and wherein a C3-4 fluorocycloalkyl is a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom; or a pharmaceutically acceptable salt thereof.

In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In a further aspect there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy.

In a further aspect there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

In a further aspect there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament.

In a further aspect there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

In a further aspect there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Definitions

So that the present specification may be more readily understood, certain terms are explicitly defined below. In addition, definitions are set forth as appropriate throughout the detailed description.

As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms.

In this specification the prefix C_x-y, as used in terms such as "C_x.v alkyl" and the like where x and y are integers, indicates the numerical range of carbon atoms that are present in the group. Examples of suitable C1-3 alkyl groups include methyl, ethyl, n-propyl, and i-propyl. Examples of suitable C1-4 alkyl groups include methyl, ethyl, n-propyl, and i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.

As used herein the term "cycloalkyl" refers to a saturated, cyclic hydrocarbon radical having the specified number of carbon atoms. Examples of C3-4 cycloalkyl groups are cyclopropyl and cyclobutyl.

As used herein the term "fluoroalkyl" refers to saturated linear or branched hydrocarbon radicals having the specified number of carbon atoms, wherein at least one hydrogen atom is substituted for a fluorine atom. Examples of suitable C1-4 fluoroalkyl groups include fluoromethyl (CFH2), difluoromethyl (CF2H), trifluoromethyl (CF3), 1,1-difluoroethyl (CF2CH3), 2,2,2-trifluoroethyl (CH2CF3) and 3-fluoropropyl (CH2CH2CH2F).

As used herein the term "fluorocycloalkyl" refers to saturated cyclic hydrocarbon radicals having the specified number of carbon atoms, wherein at least one hydrogen atom is substituted for a fluorine atom. Examples of suitable C3-4 fluorocycloalkyl groups include 2-fluorocyclopropyl, 2,2- difluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4- difluorocyclobutyl and 2,3,4-trifluorocyclobutyL

As used herein the term "alkoxy" refers to a saturated group comprising the specified number of carbon atoms and one oxygen atom. For the avoidance of doubt, the alkoxy group may be a straight chain or a branched chain. Examples of suitable C1.4 alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O”Pr) and i-propoxy (O'Pr), n-butoxy (O”Bu), i-butoxy (O'Bu), s-butoxy (O^sBu) and t- butoxy (C^Bu).

Unless specifically stated, the bonding of an atom or group may be any suitable atom of that group; for example, propyl includes prop-l-yl and prop-2-yl.

For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may comprise the same substituents or different substituents from within the given group.

For the avoidance of doubt, the use of "-L" in formulas of this specification denotes the point of

HN'^CH3 attachment between different groups. By way of illustration, denotes a methylamide group which is attached to a different group through the nitrogen atom.

Where any embodiment within this specification includes a group which is said to be "optionally substituted", then a further embodiment will include that embodiment wherein the said group is unsubstituted.

Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

Detailed Description In one aspect, this specification provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined above.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X¹ is CH.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X¹ is N.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X² is CH.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X² is N.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X¹ is CH and X² is CH, X¹ is N and X² is CH or X¹ is CH and X² is N.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X³ and X⁴ are both CH.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X³ is N and X⁴ is CH.

In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X³ is CH and X⁴ is N.

In embodiments, the compound of Formula (I) is a compound of Formula (II):

wherein R¹, R², R³, R⁴, R⁵, X³, L and G are as defined above, or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of Formula (I) is a compound of Formula (III):

In embodiments, the compound of Formula (I) is a compound of Formula (IV):

In embodiments, there is provided a compound of Formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein X³ is CH. In embodiments, there is provided a compound of Formula (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein X³ is N.

In embodiments, there is provided a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein R¹ is Ci-₄ alkyl, such as CH3.

In embodiments, there is provided a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein R² is H or CH3, such as H.

In embodiments, there is provided a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein L is a covalent bond.

In embodiments, there is provided a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein L is O. In embodiments, there is provided a compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein L is CHj.

In embodiments, the compound of Formula (I) is a compound of Formula (IA):

wherein:

X¹ is CH or N;

X² is CH or N;

R¹, R³, R⁴, R⁵ and G are as defined above; or a pharmaceutically acceptable salt thereof. In embodiments, the compound of Formula (I) is a compound of Formula (I IA):

wherein R¹, R³, R⁴, R⁵ and G are as defined above, or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of Formula (I) is a compound of Formula (I I IA):

In embodiments, the compound of Formula (I) is a compound of Formula (IVA):

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA) or a pharmaceutically acceptable salt thereof, wherein R³ is selected from H, F, Cl and C1-4 alkyl (such as CH₃).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA) or a pharmaceutically acceptable salt thereof, wherein R³ is H.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA) or a pharmaceutically acceptable salt thereof, wherein R⁴ is selected from H, C1-4 fluoroalkyl, C1-4 alkoxy, -S(Ci_₄ alkyl), -O(Ci-₄ fluoroalkyl), -S(Ci.₄ fluoroalkyl), F, Cl, C3-4 fluorocycloalkyl, R^j and R^k, wherein R^j is C3-4 cycloalkyl optionally substituted with -CN, C1-4 alkoxy or C1-4 fluoroalkyl (i.e. C3-4 cycloalkyl, C3-4 cycloalkyl substituted with -CN , C3-4 cycloalkyl substituted with C1-4 alkoxy, or C3-4 cycloalkyl substituted with C1-4 fluoroalkyl), and wherein R^k is C1-4 alkyl optionally substituted with - CN or C1-4 alkoxy (i.e. C1-4 alkyl, C1-4 alkyl substituted with -CN, or C1-4 alkyl substituted with C1-4 alkoxy).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁴ is C1-4 fluoroalkyl, -O(Ci_₄ fluoroalkyl) or - S(Ci-₄ fluoroalkyl).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁴ is CF2H, CF2CH3, CF3, OCF3, OCF2H or SCF3, such as CF3. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from H, F, Cl and C1-4 alkyl (such as CH₃).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁵ is H.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R³ and R⁵ are independently selected from H, Cl, F and C1-4 alkyl (such as CH3), and R⁴ is C1-4 fluoroalkyl (such as CF3, CF2CH3 or CF2H), -O(Ci_₄ fluoroalkyl) (such as OCF3 or OCF2H) and -S(Ci_₄ fluoroalkyl) (such as SCF3).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R³ and R⁵ are both H, and R⁴ is C1-4 fluoroalkyl (such as CF3, CF2CH3 or CF2H), -O(Ci_₄ fluoroalkyl) (such as OCF3 or OCF2H) and -S(Ci_₄ fluoroalkyl) (such as SCF3).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R³ is H, R⁴ is CF3 and R⁵ is H.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is selected from

wherein R⁶, R⁷ and J are as defined herein.

wherein R⁶ and J are as defined herein.

wherein R⁶, R¹² and R¹³ are as defined herein.

wherein R⁶ is as defined herein.

wherein R⁶, R⁷ and J are as defined herein.

wherein R⁶ and J are as defined herein. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is selected from

wherein R⁶, R¹² and R¹³ are as defined herein.

wherein R⁶ are as defined herein.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁶ is H, OH, F or R¹⁰.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁶ is H, OH, F, CH2OH or CH2OCH3.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁷ is C1-4 alkyl optionally substituted with OH, such as CH2OH.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁷ is H.

wherein R⁸, R⁹ and J are as defined herein. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is selected from

wherein R⁸,R⁹ R¹² and R¹³ are as defined herein.

wherein R⁸ and R⁹ are as defined herein.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁸ and R⁹ are independently selected from H, R¹⁰ and R¹¹, wherein R¹⁰ is C1-4 alkyl optionally substituted with C1-4 alkoxy or OH (i.e. C1-4 alkyl, C1-4 alkyl substituted with C1-4 alkoxy, or C1-4 alkyl substituted with OH), and wherein R¹¹ is C3-4 cycloalkyl optionally substituted with C1-4 alkoxy or OH (i.e. C3-4 cycloalkyl, C3-4 cycloalkyl substituted with C1-4 alkoxy, or C3-4 cycloalkyl substituted with OH).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁸ is H and R⁹ is C1-4 alkyl, such as CH3.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R⁸ and R⁹, together with the carbon atom to which they are attached, form a cyclopropane or cyclobutane ring.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein J is

wherein R¹² is H or F, and wherein R¹³ is H, CH?F or CH3.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein J is selected from

In embodiments, the compound of Formula (I) is a compound of Formula (IB):

wherein:

X³ is CH or N;

R¹ is Ci-4 alkyl;

R³ and R⁵ are independently selected from H, F, Cl and C1-4 alkyl;

R⁴ is Ci-4 fluoroalkyl, -O(Ci_₄ fluoroalkyl) or -S(Ci_₄ fluoroalkyl);

R⁶ is H, OH, F, -CN, C(=O)NH₂, N(CI-₄ al kyl )₂, C1-4 alkoxy, C1-4 fluoroalkyl, R¹⁰ or R¹¹; each R¹⁰ is independently Ci-₄ alkyl optionally substituted with C1-4 alkoxy, N(Ci.₄alkyl)₂ or OH; and

R¹¹ is C3-4 cycloalkyl optionally substituted with C1-4 alkoxy or OH, or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of Formula (IB) or a pharmaceutically acceptable salt thereof, wherein R¹ is CH3.

In embodiments, there is provided a compound of Formula (IB) or a pharmaceutically acceptable salt thereof, wherein X³ is CH.

In embodiments, there is provided a compound of Formula (IB) or a pharmaceutically acceptable salt thereof, wherein X³ is N.

In embodiments, there is provided a compound of Formula (IB) or a pharmaceutically acceptable salt thereof, wherein R³ and R⁵ are H, and optionally R⁴ is CF₂H, CF3, OCF3 or SCF3.

In embodiments, there is provided a compound of Formula (IB) or a pharmaceutically acceptable salt thereof, wherein R³ and R⁵ are H, and R⁴ is CF3. In embodiments, there is provided a compound of Formula (IB) or a pharmaceutically acceptable salt thereof, wherein R⁶ is H, OH, F, CH2OH or CH2OCH3, such as H.

In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(4- (trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from: (S)-4-((l-acryloylpyrrolidin-3-yl)amino)-6-methyl-l-(4-(trifluoromethyl)phenyl)pyrido[3,4- d]pyridazin-5(6H)-one, (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one, (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethoxy)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one, 5-(((3R,4S)-l-acryloyl-4-fluoropyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2- yl)pyrido[4,3-d]pyrimidin-4(3H)-one, and (S)-8-((l-acryloylpyrrolidin-3-yl)amino)-2-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-2,7-naphthyridin- l(2H)-one, or a pharmaceutically acceptable salt thereof.

A further feature is any of the embodiments described in the specification with the proviso that any of the specific Examples are individually disclaimed. A further feature is any of the embodiments described in the specification with the proviso that any one or more of the compounds selected from the above list of Examples of compounds of the specification are individually disclaimed.

The compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, diastereoisomers, conformers, rotamers and tautomers of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R).

In embodiments, there is provided a pharmaceutical composition which comprises a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.

The compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), and pharmaceutically acceptable salts thereof, may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi hydrate, a mono hydrate, a di hydrate, a tri hydrate or other stoichiometry of hydrate) and/or solvated forms. It is to be understood that the present specification encompasses any and all such solid forms of the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), and pharmaceutically acceptable salts thereof.

In further embodiments there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), which is obtainable by the methods described in the 'Examples" section hereinafter.

The present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopes of nitrogen include ¹⁵N.

A suitable pharmaceutically acceptable salt of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB) is, for example, an acid addition salt. An acid addition salt of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.

A further suitable pharmaceutically acceptable salt of a compound of Formula (I), (IA), (II), (I IA), (III), ( 11 IA), (IV), (IVA) or (IB) is, for example, a salt formed within a patient's body after administration of a compound of Formula (I), (IA), (II), ( I IA), (III), ( II IA), (IV), (IVA) or (IB) to the patient.

The compound of Formula (I), (IA), (II), (HA), (III), (I II A), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, may be prepared as a co-crystal solid form. It is to be understood that a pharmaceutically acceptable co-crystal of an compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or pharmaceutically acceptable salts thereof, form an aspect of the present specification.

In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

The term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a patient to which the composition would be administered. Such compositions can be sterile. A pharmaceutical composition according to the present specification will comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. For example, the composition may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). Such compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. An effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, will normally be present in the composition. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.

The pharmaceutical formulations of the compound of Formula (I) described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration.

The pharmaceutical formulations of the compound of Formula (I) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).

Pharmaceutical formulations suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents; fillers; lubricants; and surfactants. Liquid compositions may contain conventional additives such as suspending agents; emulsifying agents; and preservatives Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An exemplary oral composition would comprise a compound of Formula (I) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.

As a result of their TEAD inhibitory activity, the compounds of Formula (I), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by TEAD, including cancer.

In one aspect of the present specification there is provided a compound of Formula (I), (IA), (II), (IIA), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in therapy.

In one aspect of the present specification there is provided a compound of Formula (I), (IA), (II), (IIA), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

Where "cancer" is mentioned, this includes both non-metastatic cancer and also metastatic cancer, such that treating cancer involves treatment of both primary tumours and also tumour metastases. The term "therapy" is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

The term "prophylaxis" is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

The term "treatment" is used synonymously with "therapy". Similarly the term "treat" can be regarded as "applying therapy" where "therapy" is as defined herein.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in providing an inhibitory effect on TEAD.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by TEAD, such as cancer.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, gastric cancer, lung cancer, hepatocellular cancer (HCC), gastrointestinal stromal tumour (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, melanoma and mesothelioma (such as malignant pleural mesothelioma).

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of hippo mutationpositive cancer, such as NF2 mutation-positive or LATS1/2 mutation-positive cancer.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of hippo mutationpositive cancer, such as YAP1 and/or WWTR1 amplified cancer.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of hippo mutationpositive cancer, such as FAT1 mutant cancer. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer driven by YAP or TAZ fusions.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer that exhibits an elevated TEAD transcriptional signature. In further embodiments, the cancer that exhibits an elevated TEAD transcriptional signature is hepatocellular cancer (HCC), gastric cancer or prostate cancer.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of hippo mutationpositive mesothelioma, such as NF2 mutation-positive or LATS1/2 mutation-positive mesothelioma.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of hippo mutationpositive malignant pleural mesothelioma, such as NF2 mutation-positive or LATS1/2 mutationpositive malignant pleural mesothelioma.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of lung cancer.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of non-small cell lung cancer.

In embodiment there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof for use in the treatment of EGFR mutationpositive cancer (such as non-small cell lung cancer). In further embodiments, the EGFR mutationpositive cancer comprises at least one activating mutation in EGFR selected from exon 19 deletions and L858R substitution mutations. In still further embodiments, the EGFR mutation-positive cancer comprises an EGFR T790M resistance mutation.

In one aspect of the present specification there is provided the use of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament, such as a medicament for the treatment of cancer. In one aspect of the present specification there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (ll)₇ ( 11 A), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof.

Terms such as "treating" or "treatment" refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a patient is successfully "treated" for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.

The term "effective amount" means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.

The term "patient" refers to any animal (e.g., a mammal), including, but not limited to humans, nonhuman primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the term "patient" refers to a human subject.

In embodiments, there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, gastric cancer, lung cancer, hepatocellular cancer, gastrointestinal stromal tumour (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, melanoma and mesothelioma (such as malignant pleural mesothelioma).

In embodiments, there is provided a method of treating hippo mutation-positive cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), ( 11 A), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof. In further embodiments, the hippo mutation-positive cancer is hippo mutation-positive mesothelioma. In embodiments, there is provided a method of treating lung cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( 11 IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a method of treating non-small cell lung cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), ( 11 A), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of Formula (I), (IA), (II), ( I IA), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof is for use in combination with conventional surgery, radiotherapy, chemotherapy and/or immunotherapy. Such chemotherapy could be administered concurrently, simultaneously, sequentially or separately to treatment with the TEAD inhibitor of the present disclosure.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (I IA), (III), (II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and an additional anti-tumour substance for the conjoint treatment of cancer.

In embodiments, there is provided a combination for use in the treatment of cancer comprising a compound of the Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and an additional anti-tumour agent.

In embodiments, there is provided a compound of the Formula (I), (IA), (II), (HA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, in combination with an additional anti-tumour agent.

In embodiments, the additional anti-tumour argent is a selected from an EGFR inhibitor, KRAS inhibitor, BRAF inhibitor, CDK4/6 inhibitor, MEK inhibitor, MET inhibitor, PI3K inhibitor, AKT inhibitor or ALK inhibitor.

The additional anti-tumour agent may be a third generation EGFR TKL

Third-generation EGFR TKIs are inhibitors of EGFR bearing activating mutations that also significantly inhibit EGFR bearing the T790M mutation and do not significantly inhibit wild-type EGFR. Examples of third-generation TKIs include compounds of Formula (I), osimertinib, AZD3759, lazertinib, nazartinib, CO1686 (rociletinib), HM61713, ASP8273, EGF816, PF-06747775 (mavelertinib), avitinib (abivertinib), alflutinib (AST2818) and CXCK-101 (RX-518), HS-10296 and BPI-7711. Further examples include oritinib (SH-1028), Befotertinib (D-0316), ASK-120067, ZN-e4, YZJ-0318, TL007 XZP (kenaitinib), YK-029A, SLC005-I, TY-9591, XZP-5809-TT1, ZSP0391, and TQB3456. In any embodiment where "third generation EGFR TKI" is mentioned in a general sense, the third- generation EGFR TKI is selected from osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, abivertinib or a pharmaceutically acceptable salt thereof, alf I utinib or a pharmaceutically acceptable salt thereof, CXCK-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof and BPI-7711 or a pharmaceutically acceptable salt thereof. In embodiments, the third generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

Osimertinib: The free base of osimertinib is known by the chemical name: /V-(2-{2-dimethylamino ethyl-methylamino}-4-methoxy-5-{[4-(l-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl) prop-2- enamide. Osimertinib is described in WO 2013/014448, the contents of which is incorporated by reference. Osimertinib is also known as AZD9291. Osimertinib may be found in the form of the mesylate salt: /V-(2-{2-dimethylamino ethyl-methylamino}-4-methoxy-5-{[4-(l-methylindol-3- yl)pyrimidin-2-yl]amino}phenyl) prop-2-enamide mesylate salt. Osimertinib mesylate is also known as TAGRISSO™.

Osimertinib mesylate is currently approved as an oral once daily tablet formulation, at a dose of 80 mg (expressed as free base, equivalent to 95.4 mg osimertinib mesylate), for the treatment of metastatic EGFR T790M mutation positive NSCLC patients. A 40 mg oral once daily tablet formulation (expressed as free base, equivalent to 47.7 mg osimertinib mesylate) is available should dose modification be required. The tablet core comprises pharmaceutical diluents (such as mannitol and microcrystalline cellulose), disintegrants (such as low-substituted hydroxypropyl cellulose) and lubricants (such as sodium stearyl fumarate). The tablet formulation is described in WO 2015/101791, the contents of which is incorporated by reference.

In an aspect, the composition is in the form of a tablet, wherein the tablet core comprises: (a) about 19 parts of osimertinib mesylate; (b) about 59 parts of mannitol; (c) about 15 parts of microcrystalline cellulose; (d) about 5 parts of low-substituted hydroxypropyl cellulose; and (e) about 2 parts of sodium stearyl fumarate; and wherein all parts are by weight and the sum of the parts (a)+(b)+(c)+(d)+(e)=100.

AZD3759: The free base of AZD3759 is known by the chemical name: 4-[(3-chloro-2- fluorophenyl)amino]-7-methoxy-6-quinazolinyl (2R)-2,4-dimethyl-l-piperazinecarboxylate. AZD3759 is described in WO 2014/135876, the contents of which is incorporated by reference. Lazertinib: The free base of lazertinib is known by the chemical name /V-{5-[(4-{4- [(dimethylamino)methyl]-3-phenyl-lH-pyrazol-l-yl}-2-pyrimidinyl)amino]-4-methoxy-2-(4- morpholinyl)phenyl}acrylamide. Lazertinib is described in WO 2016/060443, the contents of which is incorporated by reference. Lazertinib is also known by the names YH25448 and GNS-1480.

Nazartinib: The free base of Nazartinib is known by the chemical name: N-(7-chloro-l-(l-(4- (dimethylamino)but-2-enoyl)azepan-3-yl)-lH- benzordlimidazol-2-yl)-2-methylisonicotinamide. Nazartinib is disclosed in WO 2013/184757, the contents of which is incorporated by reference.

Avitinib (abivertinib): The free base of avitinib is known by the chemical name: N-(3-((2-((3-fluoro-4- (4-methylpiperazin-l-yl)phenyl)amino)-7H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)phenyl)prop-2-enamide. Avitinib is disclosed in US2014038940, the contents of which is incorporated by reference. Avitinib is also known as abivertinib.

Alf I utinib (furmonertinib): The free base of alf I utinib is known by the chemical name: N -{2-{[2- (dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(l-methyl-lH -indol-3- yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide. Alfl utinib is disclosed in WO 2016/15453, the contents of which is incorporated by reference. Alflutinib is also known as AST2818.

Afatinib: The free base of afatinib is known by the chemical name: /V-[4-(3-chloro-4-fluoroanilino)-7- [(3S)-oxolan-3-yl] oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide. Afatinib is disclosed in WO 02/50043, the contents of which is incorporated by reference. Afatinib is also known as Gilotrif.

CK-101: The free base of CK-101 is known by the chemical name: /V-(3-(2-((2,3-difluoro-4-(4-(2- hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide. CK-101 is disclosed in WO 2015/027222, the contents of which is incorporated by reference. CK-101 is also known as RX- 518.

HS-10296 (aumolertinib): The free base of HS-10296 is known by the chemical name: /V-[5-[[4-(l- cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy- phenyl]prop-2-enamide. HS-10296 is disclosed in WO 2016/054987, the contents of which is incorporated by reference.

BPI-7711: The free base of BPI-7711 is known by the chemical name: /V-[2-[2- (dimethylamino)ethoxy]-4-methoxy-5-[[4-(l-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2- enamide. BPI-7711 is disclosed in WO 2016/94821, the contents of which is incorporated by reference. Dacomitinib: The free form of dacomitinib is known by the chemical name: (2Ej-/V-{4-[(3-chloro-4- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-l-yl)but-2-enamide. Dacomitinib is described in WO 2005/107758, the contents of which is incorporated by reference. Dacomitinib is also known by the name PF-00299804.

In embodiments, there is provided a compound of Formula (I), (I A), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and a third generation EGFR TKI for the conjoint treatment of cancer, such as non-small cell lung cancer.

In embodiments, there is provided a combination for use in the treatment of cancer, such as non- small cell lung cancer, comprising a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and a third generation EGFR TKI.

In embodiments, there is provided a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, in combination with a third generation EGFR TKI.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and osimertinib, or a pharmaceutically acceptable salt thereof, for the conjoint treatment of cancer, such as non-small cell lung cancer.

In embodiments, there is provided a combination for use in the treatment of cancer, such as non- small cell lung cancer, comprising a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and osimertinib, or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, in combination with osimertinib, or a pharmaceutically acceptable salt thereof.

Herein, where the term "conjoint treatment" is used in reference to a combination treatment, it is to be understood that this may refer to simultaneous, separate or sequential administration. In one aspect, "conjoint treatment" refers to simultaneous administration. In another aspect, "conjoint treatment" refers to separate administration. In a further aspect, "conjoint treatment" refers to sequential administration.

In embodiments, there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said patient, where the amounts of the compound of Formula (I), (IA), (II), (HA), (III), (I I IA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.

In embodiments, there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering a third generation EGFR TKI to said patient, where the amounts of the compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, and the third generation EGFR TKI are jointly effective in producing an anti-cancer effect.

In embodiments, there is provided a method of treating cancer, such as non-small cell lung cancer, in a patient comprising administering to the patient an effective amount of a compound of Formula (I),

(IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering osimertinib, or a pharmaceutically acceptable salt thereof, to said patient, where the amounts of the compound of Formula (I), (IA), (II), ( 11 A), (III), ( II IA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, and the osimertinib, or a pharmaceutically acceptable salt thereof substance are jointly effective in producing an anti-cancer effect.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (I IA), (III), (II IA), (IV), (IVA) or

(IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, such as non- small cell lung cancer, wherein the cancer is resistant to treatment with an EGFR TKI.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (I IA), (III), (II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, such as non- small cell lung cancer, wherein the cancer is resistant to treatment with a third generation EGFR TKI. In further embodiments, the third-generation EGFR TKI is selected from osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, abivertinib or a pharmaceutically acceptable salt thereof, alf I utinib or a pharmaceutically acceptable salt thereof, CXCK-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof and BPI-7711 or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a compound of Formula (I), (IA), (II), (I IA), (III), (II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of non-small cell lung cancer, wherein the non-small cell lung cancer is resistant to treatment with osimertinib or a pharmaceutically acceptable salt thereof.

In embodiments, there is provided a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, wherein the cancer is resistant to treatment with an EGFR TKI.

Although the compounds of the Formula (I) are primarily of value as therapeutic agents for use in patients, they are also useful whenever it is required to inhibit TEAD. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

Certain compounds of Formula (I) may be prepared through the reaction of a suitable aromatic electrophile (for example a compound of Formula (Al), (All) or (AHI) as defined below) and a suitable nucleophile, optionally in the presence of a catalyst. A non-limiting example of such a reaction is the reaction of Intermediate 1 and tert-butyl (S)-3-aminopyrrolidine-l-carboxylate as part of the synthesis of Example 1.

Intermediate 1

In one aspect, there is provided a compound of Formula (Al),

wherein

X¹ and X² are independently selected from CH and N; either X³ is CH and X⁴ is selected from CR⁵ and N, or X³ is N and X⁴ is CR⁵;

L is a covalent bond, O or CH2;

R¹ is Ci-4 alkyl or C3-4 cycloalkyl;

R³, R⁴ and R⁵ are independently selected from H, C1-4 fluoroalkyl, C1-4 alkoxy, -S(Ci.₄ alkyl), -O(Ci.₄ fluoroalkyl), -S(Ci.₄ fluoroalkyl), F, Cl, C3-4 fluorocycloalkyl, R^j and R^k, wherein R^j is C3-4 cycloalkyl optionally substituted with -CN, C1-4 alkoxy or C_w fluoroalkyl and R^k is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy; and

X^A is selected from F, Cl, Br, I, OSO2CF3, OSC Ph and O(4-toluenesulfonyl), or a salt thereof.

In embodiments, the compound of Formula (Al) is a compound of Formula (All),

wherein L, R¹, R², R³, R⁴, X³, X⁴ and X^A are as defined for a compound of Formula (Al), or a salt thereof.

In embodiments, the compound of Formula (Al) is a compound of Formula (Alli),

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein L is a covalent bond. In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein L is O.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein L is CHj.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein R¹ is C1-4 alkyl, such as CH3.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein R² is H or CH3, such as H.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein R³ and R⁵ are independently selected from H, Cl, F and C1-4 alkyl, and optionally R⁴ is C1-4 fluoroalkyl, -O(Ci.₄ fluoroalkyl) or -S(Ci.₄ fluoroalkyl).

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein R³ and R⁵ are, and optionally R⁴ is CF?H, CF3, OCF3, OCF2H or SCF3.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein R³ and R⁵ are H and R⁴ is CF3.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein X³ is CH and X⁴ is CR⁵.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein X³ is CH and X⁴ is N.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein X³ is N and X⁴ is CR⁵.

In embodiments, there is provided a compound of Formula (Al), (All) or (Alli), or a salt thereof, wherein X^A is F or Cl.

Examples

The specification will now be illustrated by the following non-limiting Examples in which, generally:

(i) operations were carried out at ambient temperature, i.e. in the range 17 to 25°C and under an atmosphere of an inert gas such as nitrogen unless otherwise stated;

(ii) evaporations were carried out by rotary evaporation or utilising GENEVAC equipment or BIOTAGE vlO evaporator or ROTA VAPOR BUCHI and FREEZEMOBILE 35EL from SP SCIENTIFIC in vacuo and workup procedures were carried out after removal of residual solids by filtration and quenching with appropriate solvent;

(iii) flash chromatography purifications were performed on an automated BIOTAGE ISOLERA ONE or BIOTAGE SELEKT or TELEDYNE ISCO COMBIFLASH Rf using prepacked BIOTAGE SFAR SILICA HC (20 pm) and BUCHI SILICA ECOFLEX (50 pm);

(iv) preparative chromatography was performed on a AGILENT MDAP 1290 Prep system, fractions were collected when both detectors (UV and MS) detect a peak, or via supercritical fluid chromatography performed on a WATERS Prep 100 SFC-MS instrument with MS- and UV- triggered collection or a SEPIATEC PREP SFC 100 instrument with UV collection;

(v) yields, where present, are not necessarily the maximum attainable;

(vi) in general, the structures of compounds of Formula (I) were confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values were measured on the delta scale (proton magnetic resonance spectra were acquired using a BRUKER NEO 500 (500 MHz) or BRUKER nano AVIIIHD 400 (400 MHz) instrument); measurements were taken at 27 °C (300 K) unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; br, broad signal;

(vii) in general, compounds of Formula (I) were also characterised by mass spectroscopy following liquid chromatography (UPLC); UPLC was carried out using a UPLC-MS was carried out using a WATERS ACQUITY UPLC and WATERS SQD mass spectrometer (column temp 30°C, UV detection = 210-400 nm, mass spec = ESI with positive/negative switching) at a flow rate of 1 mL/min using a solvent gradient of 2 to 98% B over 1.5 mins (total runtime with equilibration back to starting conditions 2 min), where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile (for acid work) or A = 0.1% ammonium hydroxide in water and B =acetonitrile (for base work). For acid analysis the column used was WATERS ACQUITY HSS T3, 1.8 mm, 2.1 x 30 mm; for base analysis the column used was WATERS ACQUITY BEH C18, 1.7 mm, 2.1 x 30mm;

(viii) intermediate purity was assessed by thin layer chromatographic, mass spectral, HPLC (high performance liquid chromatography) and/or NMR analysis;

(ix) Where reactions were conducted in a microwave reactor, this was done using a BIOTAGE INITIATOR and BIOTAGE Microwave Vials; (x) The skilled person will be aware that the chemical name of a given compound may vary depending on the software package used to name it. For this specification, PERKIN ELMER E- NOTEBOOK was used to name compounds.

(xi) the following abbreviations have been used:

Aq aqueous

Boc tert-butyloxycarbonyl

Cbz benzyloxycarbonyl

CDCI3 deuterochloroform

DCM dichloromethane

DIPEA /V,/V-diisopropylethylamine

DMF /V'/V-dimethylformamide

DMSO dimethyl sulfoxide dppf l,l'-bis(diphenylphosphino)ferrocene

EtOAc ethyl acetate

HPLC high performance liquid chromatography

MeCN acetonitrile

MeOH methanol

Ms methanesulfonyl rt room temperature

SFC Supercritical fluid chromatography

TFA trifluoroacetic acid

THF tetrahydrofuran

Intermediate 1: 5-chloro-3-methyl-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one

Intermediate 1

8-bromo-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one lodomethane (1.65 mL, 26.5 mmol) was added to a mixture of 8-bromopyrido[4,3-d]pyrimidin-4(3H)- one (5.0 g, 22 mmol) and K2CO3 (6.1 g, 44 mmol) in DMF (50 mL) and the reaction mixture was stirred at rt for 2 hrs. The mixture was then diluted with DCM (150 mL) and water (150 mL). The phases were separated and the aqueous layer was extracted with DCM (3 x 150 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness. The crude material was dried under vacuum to afford 8-bromo-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (4.6 g, 86% yield) as an orange solid which was used without further purification. ¹H NMR (500 MHz, DMSO-d6) 6 3.52 (3H, s), 8.69 (1H, s), 9.05 (1H, s), 9.23 (1H, s); m/z: (ES⁺) [M+H]⁺ = 240.

8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine 6-oxide

3-Chlorobenzoperoxoic acid (70% purity, 9.4 g, 38 mmol) was added to a mixture of 8-bromo-3- methylpyrido[4,3-d]pyrimidin-4(3H)-one (4.6 g, 19 mmol) in DCM (150 mL) and the reaction mixture was stirred at rt for 16 hrs. The reaction mixture was then diluted with a solution of 7:1 CHCU/isopropanol (250 mL) and water (50 mL). The phases were separated and the organic layer was washed with saturated aq. NajSzOs (70 mL), saturated aq. K2CO3 and water (2 x 100 mL). The combined aqueous phases were then extracted with 7:1 CHCU/isopropanol (9 x 150 mL). The combined organics were dried over Na2SO₄, filtered and concentrated to dryness. The crude material was dried under vacuum to afford 8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine 6- oxide (3.0 g, 62% yield) as a beige color solid which was used without further purification. ¹H NMR (500 MHz, DMSO-d6) 63.51 (3H, s), 8.56 (1H, s), 8.62 (1H, d), 8.94 (1H, d); m/z (ES⁺) [M+H]⁺ = 256.

8-bromo-5-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one POCU (3.0 mL, 32 mmol) was added to a mixture of 8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3- d]pyrimidine 6-oxide (1.66 g, 6.48 mmol) in MeCN (30 mL) and the mixture was stirred at 80 °C for 5 hrs. After cooling down to rt, the mixture was evaporated under vacuum to remove most of the solvent and POCI3. The crude material was then diluted with DCM (400 mL) and washed with saturated aq. K2CO3 (50 mL) and water (2 x 50 mL). The organic phase was dried over NajSC , filtered and concentrated to dryness. The material was dried under vacuum to afford 8-bromo-5-chloro-3- methylpyrido[4,3-d]pyrimidin-4(3H)-one (1.3 g, 75% yield) as a beige color solid which was used without further purification. ^TH NMR (500 MHz, DMSO-d₆) 6 3.49 (3H, s), 8.73 (1H, s), 8.85 (1H, s); m/z: (ES⁺) [M+H]⁺ = 274.

Intermediate 3: 5-chloro-3-methyl-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one

8-Bromo-5-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (1.94 g, 7.05 mmol), (4- (trifluoromethyl)phenyl)boronic acid (1.61 g, 8.46 mmol), Pd2(dba)s (0.32 g, 0.35 mmol), tris(o- tolyl)phosphine (0.43 g, 1.4 mmol) and CS2CO3 (6.89 g, 21.2 mmol) were diluted with dioxane (70 mL) and H2O (7 mL) under an atmosphere of N2. The reaction mixture was heated to 40 °C and stirred for 4 hrs. The reaction mixture was cooled to rt and diluted with DCM (300 mL). The organic layer was washed with saturated aq. NH₄CI (2 x 40 mL) and water (40 mL), dried over Na2SO₄, filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 20% EtOAc in hexanes) to afford 5-chloro-3-methyl-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin- 4(3H)-one (Intermediate 3, 1.2 g, 51% yield) as a beige color solid. ¹H NMR (500 MHz, DMSO-d6) 6 3.50 (3H, s), 7.85 (4H, q), 8.61 (1H, s), 8.67 (1H, s); m/z: (ES⁺) [M+H]⁺ = 340.

Example 1: (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(4- (trifluoromethyl)phenyl)pyrido[4,3-c/]pyrimidin-4(3H)-one

Intermediate 1 Example 1 tert-butyl (S)-3-((3-methyl-4-oxo-8-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-

5-yl)amino)pyrrolidine-l-carboxylate DIPEA (0.31 mL, 1.8 mmol) was added to a mixture of 5-chloro-3-methyl-8-(4- (trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 1, 0.10 g, 0.30 mmol) and tert-butyl (S)-3-aminopyrrolidine-l-carboxylate (0.11 g, 0.60 mmol) in DMSO (0.8 mL). The reaction mixture was heated to 90 °C and stirred for 16 hrs. After cooling down to rt, the reaction mixture was diluted with DCM (50 mL) and water (30 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 50% EtOAc in hexanes) to afford tert-butyl (S)-3-((3-methyl-4-oxo-8-(4-(trifluoromethyl)phenyl)-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate (135 mg, 92% yield) as a white solid. NMR (500 MHz, DMSO-d6) 6 1.42 (9H, br d), 1.96 (1H, br dd), 2.20 - 2.32 (1H, m), 3.23 (1H, br d), 3.38 - 3.45 (2H, m), 3.48 (3H, s), 3.67 (1H, br d), 4.61 - 4.71 (1H, m), 7.78 (4H, s), 8.38 (1H, s), 8.48 (1H, s), 9.16 (1H, br s); m/z: (ES⁺) [M+H]⁺ = 490.

(S)-3-methyl-5-(pyrrolidin-3-ylamino)-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)- one hydrochloride

HCI (4 M in dioxane, 2.0 mL, 8.0 mmol) was added to a mixture of tert-butyl (S)-3-((3-methyl-4-oxo- 8-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l- carboxylate (0.13 g, 0.27 mmol) in MeOH (2 mL) at rt and the reaction mixture was stirred for 1.5 hrs. The reaction mixture was concentrated to dryness and the crude material was dried under vacuum to afford (S)-3-methyl-5-(pyrrolidin-3-ylamino)-8-(4-(trifluoromethyl)phenyl)pyrido[4,3- d]pyrimidin-4(3H)-one hydrochloride (112 mg, 99% yield) as a white solid which was used directly without purification. ^TH NMR (500 MHz, DMSO-d6) 6 1.98 - 2.07 (1H, m), 2.41 (1H, dq), 3.15 - 3.31 (2H, m), 3.37 (1H, br d), 3.54 - 3.62 (3H, m), 3.66 - 3.73 (1H, m), 4.79 - 4.86 (1H, m), 7.78 (4H, s), 8.36 (1H, s), 8.57 (1H, s), 9.25 - 9.37 (1H, m), 9.37 - 9.48 (1H, m), 9.50 - 9.61 (1H, m); m/z: (ES⁺) [M-HCI+H]⁺ = 390.

(S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(4-(trifluoromethyl)phenyl)pyrido[4,3- d]pyrimidin-4(3H)-one

A solution of acryloyl chloride (25 pL, 0.30 mmol) in DCM (2 mL) was added to a mixture of (S)-3- methyl-5-(pyrrolidin-3-ylamino)-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (0.11 g, 0.25 mmol) in DCM (4 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 hrs. After warming up to rt, the reaction mixture was diluted with DCM (25 mL) and water (25 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 25 mL). The combined organics were dried over NajSCU, filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 70% EtOAc in DCM) to afford (S)-5-((l- acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)- one (Example 1, 68 mg, 61% yield) as a white solid. ^TH NMR (500 MHz, DMSO-d6) 6 1.95 - 2.16 (1H, m), 2.23 - 2.40 (1H, m), 3.42 - 3.61 (5H, m), 3.70 - 4.02 (2H, m), 4.64 - 4.83 (1H, m), 5.69 (1H, ddd), 6.16 (1H, ddd), 6.55 - 6.67 (1H, m), 7.74 - 7.81 (4H, m), 8.39 (1H, d), 8.49 (1H, s), 9.18 (1H, dd); m/z:

(ES⁺) [M+H]⁺ = 444.

Example 2: (S)-4-((l-acryloylpyrrolidin-3-yl)amino)-6-methyl-l-(4-

(trifluoromethyl)phenyl)pyrido[3,4-c/]pyridazin-5(6H)-one

2-oxo-l,2-dihydropyridine-3,4-dicarboxylic acid

Sodium hydroxide (3.7 g, 93 mmol) was added to a mixture of diethyl 2-chloropyridine-3,4- dicarboxylate (1.2 g, 4.7 mmol) in dioxane (10 mL) and water (3 mL). The reaction mixture was heated to 100 °C and stirred for 66 hrs. The reaction mixture was cooled to rt, diluted with water (50 mL), and quenched with concentrated aq. HCI (10 mL). The mixture was then extracted with EtOAc (10 x 100 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness.

The crude material was dried under vacuum to afford 2-oxo-l,2-dihydropyridine-3,4-dicarboxylic acid (0.63 g, 74% yield) as a white solid which was used without further purification. ¹H NMR (500 MHz, methanol-d4) 66.62 (1H, d), 7.83 (1H, d). dimethyl 2-oxo-l,2-dihydropyridine-3,4-dicarboxylate

Concentrated H2SO4 (0.21 mL, 3.8 mmol) was added to a mixture of 2-oxo-l,2-dihydropyridine-3,4- dicarboxylic acid (0.70 g, 3.8 mmol) in MeOH (16 mL) and the reaction mixture was heated to 60 °C and stirred for 89 hrs. The reaction mixture was cooled to rt and then concentrated under vacuum to remove most of the MeOH. The resulting residue was diluted with water (20 mL) and extracted with EtOAc (5 x 100 mL). The combined organics were dried over Na2SO₄, filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 90% EtOAc in hexanes) to afford dimethyl 2-oxo-l,2-dihydropyridine-3,4-dicarboxylate (0.48 g, 60% yield) as a white solid. ^XH NMR (500 MHz, methanol-d4) 63.88 (3H, s), 3.91 (3H, s), 6.71 (1H, d), 7.61 (1H, d); m/z: (ES⁺) [M+H]⁺ = 212. dimethyl l-methyl-2-oxo-l,2-dihydropyridine-3,4-dicarboxylate lodomethane (0.24 mL, 3.8 mmol) was added to a mixture of dimethyl 2-oxo-l,2-dihydropyridine-

3.4-dicarboxylate (0.54 g, 2.6 mmol) and K2CO3 (0.71 g, 5.1 mmol) in DMF (10 mL). The reaction mixture was stirred at rt for 2 hrs and then heated to 80 °C with stirring for an additional 1 hr. The reaction mixture was cooled to rt and diluted with DCM (300 mL). The organic layer was washed with water (5 x 40 mL), dried over Na2SO₄, filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 80% EtOAc in hexanes) to afford dimethyl 1-methyl- 2-oxo-l,2-dihydropyridine-3,4-dicarboxylate (0.4 g, 70% yield) as a white solid. ^XH NMR (500 MHz, methanol-d4) 63.62 (3H, s), 3.89 (3H, s), 3.91 (3H, s), 6.72 (1H, d), 7.86 (1H, d); m/z: (ES⁺) [M+H]⁺ = 226.

6-methyl-2,3-dihydropyrido[3,4-d]pyridazine-l,4,5(6H)-trione

Hydrazine monohydrate (0.23 mL, 4.7 mmol) was added to a mixture of dimethyl l-methyl-2-oxo- l,2-dihydropyridine-3,4-dicarboxylate (0.21 g, 0.93 mmol) in EtOH (4mL) and the reaction mixture was heated to 78 °C and stirred for 15 hrs. The reaction mixture was cooled to rt, and the suspension was collected by filtration and washed with cold ethanol (2 x 10 mL). The solid was dried under vacuum to afford 6-methyl-2,3-dihydropyrido[3,4-d]pyridazine-l,4,5(6H)-trione (0.18 g, 100% yield) as a yellow solid which was used without further purification. ^XH NMR (500 MHz, DMSO-d6) 6 3.63 (3H, s), 6.93 (1H, d), 8.15 (1H, d); m/z: (ES⁺) [M+H]⁺ = 194.

1.4-dichloro-6-methylpyrido[3,4-d]pyridazin-5(6H)-one POCU (0.93 mL, 10 mmol) was added to a mixture of 6-methyl-2,3-dihydropyrido[3,4-d]pyridazine- l,4,5(6H)-trione (97 mg, 0.50 mmol) and DIPEA (0.35 mL, 2.0 mmol) in MeCN (10 mL) and the reaction mixture was heated to 80 °C and stirred for 16 hrs. The reaction mixture was cooled to rt and evaporated under vacuum to remove most of the solvent and POCI3. The resulting residue was diluted with DCM (80 mL) and saturated aq. K2CO3 (80 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 x 80 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness. The crude material was dried under vacuum to afford 1,4- dichloro-6-methylpyrido[3,4-d]pyridazin-5(6H)-one (84 mg, 73% yield) as a dark orange solid which was used without further purification. ¹H NMR (500 MHz, CDCI3) 6 3.71 (3H, s), 6.80 (1H, d), 7.74 (1H, d); m/z: (ES⁺) [M+H]⁺ = 230. tert-butyl (S)-3-((l-chloro-6-methyl-5-oxo-5,6-dihydropyrido[3,4-d]pyridazin-4- yl)amino)pyrrolidine-l-carboxylate

DIPEA (0.44 mL, 2.5 mmol) was added to a mixture of l,4-dichloro-6-methylpyrido[3,4-d]pyridazin- 5(6H)-one (0.12 g, 0.50 mmol) and tert-butyl (S)-3-aminopyrrolidine-l-carboxylate (0.14 g, 0.75 mmol) in DMSO (3 mL). The reaction mixture was heated to 95 °C and stirred for 21 hrs. After cooling down to rt, the reaction mixture was diluted with DCM (200 mL) and washed with water (3 x 40 mL). The organic layer was dried over NajSC , filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 50% EtOAc in DCM) to afford tert-butyl (S)-

3-((l-chloro-6-methyl-5-oxo-5,6-dihydropyrido[3,4-d]pyridazin-4-yl)amino)pyrrolidine-l-carboxylate (116 mg, 61% yield) as a yellow solid. ^TH NMR (500 MHz, DMSO-d6) 6 1.39 - 1.43 (9H, m), 1.94 - 1.98 (1H, m), 2.20 - 2.32 (1H, m), 3.23 (1H, br t), 3.37 - 3.46 (2H, m), 3.57 (3H, s), 3.62 - 3.73 (1H, m), 4.58 - 4.66 (1H, m), 6.66 (1H, d), 8.13 (1H, d), 9.12 (1H, br s); m/z: (ES⁺) [M+H]⁺ = 380. tert-butyl (S)-3-((6-methyl-5-oxo-l-(4-(trifluoromethyl)phenyl)-5,6-dihydropyrido[3,4-d]pyridazin-

4-yl)amino)pyrrolidine-l-carboxylate tert-Butyl (S)-3-((l-chloro-6-methyl-5-oxo-5,6-dihydropyrido[3,4-d]pyridazin-4-yl)amino)pyrrolidine- 1-carboxylate (0.12 g, 0.31 mmol), (4-(trifluoromethyl)phenyl)boronic acid (87 mg, 0.46 mmol), PdCh dppfXCHzCk) (37 mg, 0.050 mmol) and CS2CO3 (0.30 g, 0.92 mmol) were diluted with dioxane (4 mL) and H2O (1 mL) under an atmosphere of N2. The reaction mixture was heated to 95 °C and stirred for 3 hrs. The reaction mixture was cooled to rt and diluted with DCM (200 mL). The organic phase was washed with saturated aq. NH₄CI (80 mL) and water (80 mL), dried over Na2SO₄, filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 30% EtOAc in DCM) to afford tert-butyl (S)-3-((6-methyl-5-oxo-l-(4-(trifluoromethyl)phenyl)-5,6- dihydropyrido[3,4-d]pyridazin-4-yl)amino)pyrrolidine-l-carboxylate (105 mg, 70% yield) as a light yellow solid. ^TH NMR (500 MHz, DMSO-d6) 6 1.42 (9H, br d), 1.99 - 2.06 (1H, m), 2.30 (1H, br s), 3.23 - 3.30 (1H, m), 3.44 (2H, br d), 3.57 (3H, s), 3.67 - 3.80 (1H, m), 4.75 (1H, br s), 6.43 (1H, d), 7.80 - 7.93 (4H, m), 7.96 (1H, d), 9.32 (1H, br s); m/z: (ES⁺) [M+H]⁺ = 490.

(S)-6-methyl-4-(pyrrolidin-3-ylamino)-l-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridcizin-5(6H)- one hydrochloride

HCI (4 M in dioxane, 2.0 mL, 8 mmol) was added to a mixture of tert-butyl (S)-3-((6-methyl-5-oxo-l- (4-(trifluoromethyl)phenyl)-5,6-dihydropyrido[3,4-d]pyridazin-4-yl)amino)pyrrolidine-l-carboxylate (0.11 g, 0.21 mmol) in MeOH (2 mL). The reaction mixture was stirred at rt for 2.5 hrs. The reaction mixture was concentrated to dryness and the crude material was dried under vacuum to afford (S)- 6-methyl-4-(pyrrolidin-3-ylamino)-l-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-5(6H)-one hydrochloride (90 mg, 99% yield) as a light yellow solid which was used without purification. ¹H NMR (500 MHz, DMSO-d6) 6 2.05 - 2.14 (1H, m), 2.45 - 2.49 (1H, m), 3.37 - 3.52 (2H, m), 3.61 - 3.74 (5H, m), 4.88 - 4.96 (1H, m), 6.54 (1H, d), 7.83 (2H, d), 7.93 - 7.99 (2H, m), 8.17 (1H, br d), 9.35 - 9.58 (2H, m), 9.94 (1H, br s); m/z: (ES⁺) [M-HCI+H]⁺ = 390.

(S)-4-((l-acryloylpyrrolidin-3-yl)amino)-6-methyl-l-(4-(trifluoromethyl)phenyl)pyrido[3,4- d]pyridazin-5(6H)-one

A solution of acryloyl chloride (18 pL, 0.22 mmol) in DCM (2 mL) was added to a mixture of afford (S)-6-methyl-4-(pyrrolidin-3-ylamino)-l-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-5(6H)-one hydrochloride (79 mg, 0.19 mmol) in DCM (4 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hrs. After warming up to rt, the reaction mixture was diluted with DCM (25 mL) and water (25 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 x 25 mL). The combined organics were dried over NajSCU, filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 90% EtOAc in DCM) to afford (S)-4-((l- acryloylpyrrolidin-3-yl)amino)-6-methyl-l-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-5(6H)- one (Example 2, 48 mg, 58% yield) as a white solid. ^XH NMR (500 MHz, DMSO-d6) 6 1.99 - 2.20 (1H, m), 1. 1 - 2.45 (1H, m), 3.48 - 3.66 (5H, m), 3.76 (1H, br d), 3.81 - 4.08 (1H, m), 4.74 - 4.92 (1H, m), 5.63 - 5.75 (1H, m), 6.16 (1H, ddd), 6.43 (1H, d), 6.55 - 6.70 (1H, m), 7.79 - 7.94 (4H, m), 7.96 (1H, dd), 9.35 (1H, dd); m/z: (ES⁺) [M+H]⁺ = 444.

Example 3: (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2- yl)pyrido[4,3-d]pyrimidin-4(3H)-one

8-bromo-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one lodomethane (1.65 mL, 26.5 mmol) was added to a mixture of 8-bromopyrido[4,3-d]pyrimidin-4(3H)- one (5.0 g, 22 mmol) and K2CO3 (6.1 g, 44 mmol) in DMF (50 mL) and the reaction mixture was stirred at rt for 2 hrs. The mixture was then diluted with DCM (150 mL) and water (150 mL). The phases were separated, and the aqueous layer was extracted with DCM (3 x 150 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness. The crude material was dried under vacuum to afford 8-bromo-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (4.6 g, 86% yield) as an orange solid which was used without further purification. ¹H NMR (500 MHz, DMSO-d6) 6 3.52 (3H, s), 8.69 (1H, s), 9.05 (1H, s), 9.23 (1H, s); m/z: (ES⁺) [M+H]⁺ = 240.

8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine 6-oxide

3-Chlorobenzoperoxoic acid (70% purity, 9.4 g, 38 mmol) was added to a mixture of 8-bromo-3- methylpyrido[4,3-d]pyrimidin-4(3H)-one (4.6 g, 19 mmol) in DCM (150 mL) and the reaction mixture was stirred at rt for 16 hrs. The reaction mixture was then diluted with a solution of 7:1 CHCU/isopropanol (250 mL) and water (50 mL). The phases were separated and the organic layer was washed with saturated aq. NajSzOs (70 mL), saturated aq. K2CO3 (70 mL) and water (2 x 100 mL). The combined aqueous phases were then extracted with 7:1 CHCls/isopropanol (9 x 150 mL). The combined organics were dried over Na2SO₄, filtered, and concentrated to dryness. The crude material was dried under vacuum to afford 8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3- d]pyrimidine 6-oxide (3.0 g, 62% yield) as a beige color solid which was used without further purification. ^TH NMR (500 MHz, DMSO-d6) 6 3.51 (3H, s), 8.56 (1H, s), 8.62 (1H, d), 8.94 (1H, d); m/z: (ES⁺) [M+H]⁺ = 256. 8-bromo-5-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one

POCI3 (3.0 mL, 32 mmol) was added to a mixture of 8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3- d]pyrimidine 6-oxide (1.66 g, 6.48 mmol) in MeCN (30 mL) and the mixture was heated to 80 °C and stirred for 5 hrs. After cooling down to rt, the mixture was evaporated under vacuum to remove most of the solvent and POCI3. The crude material was then diluted with DCM (400 mL) and washed with saturated aq. K2CO3 (50 mL) and water (2 x 50 mL). The organic phase was dried over NajSC , filtered, and concentrated to dryness. The material was dried under vacuum to afford 8-bromo-5- chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (1.3 g, 75% yield) as a beige color solid which was used without further purification. ^TH NMR (500 MHz, DMSO-d₆) 6 3.49 (3H, s), 8.73 (1H, s), 8.85 (1H, s); m/z: (ES⁺) [M+H]⁺ = 274.

Intermediate 2: tert-butyl (S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5- yl)amino)pyrrolidine-l-carboxylate

DIPEA (1.1 mL, 6.2 mmol) was added to a mixture of 8-bromo-5-chloro-3-methylpyrido[4,3- d]pyrimidin-4(3H)-one (0.28 g, 1.0 mmol) and tert-butyl (S)-3-aminopyrrolidine-l-carboxylate (0.38 g, 2.1 mmol) in DMSO (2 mL). The reaction mixture was heated to 90 °C and stirred for 16.5 hrs.

After cooling down to rt, the reaction mixture was diluted with DCM (60 mL) and water (30 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 60 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 40% EtOAc in hexanes) to afford tert-butyl (S)-3-((8- bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate (Intermediate 2, 364 mg, 84% yield) as a beige color solid. ¹H NMR (500 MHz, DMSO-d6) 6 1.40 (9H, br d), 1.92 (1H, br d), 2.21 (1H, br d), 3.18 (1H, br d), 3.38 (2H, br s), 3.47 (3H, s), 3.63 (1H, br d), 4.51 - 4.60 (1H, m), 8.43 (1H, s), 8.58 (1H, s), 8.98 (1H, br s); m/z: (ES⁺) [M+H]⁺ = 424. tert-butyl (S)-3-((3-methyl-4-oxo-8-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[4, 3- d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate tert-Butyl (S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine- 1-carboxylate (0.21 g, 0.50 mmol), 2-(tributylstannyl)-5-(trifluoromethyl)pyridine (0.44 g, 1.0 mmol), and Pd(PPh3)4 (87 mg, 0.080 mmol) were diluted with toluene (10 mL) under an atmosphere of N2. The reaction mixture was heated to 105 °C and stirred for 65 hrs. The reaction mixture was cooled to rt and diluted with DCM (60 mL) and saturated aq. NH₄CI (30 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were dried over Na2SO₄, filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 40% EtOAc in DCM) to afford tert-butyl (S)-3-((3-methyl-4-oxo-8-(5- (trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[4,3-c/]pyrimidin-5-yl)amino)pyrrolidine-l- carboxylate (210 mg, 86% yield) as a light yellow solid. ¹H NMR (500 MHz, CDCL) 6 1.49 (9H, br s), 1.97 - 2.06 (1H, m), 2.30 - 2.39 (1H, m), 3.26 - 3.46 (1H, m), 3.59 (5H, s), 3.85 (1H, dd), 4.86 (1H, br s),

7.96 (1H, br d), 8.14 (2H, s), 8.87 - 8.94 (1H, m), 8.96 (1H, s), 9.27 (1H, br s); m/z: (ES⁺) [M+H]⁺ = 340.

(S)-3-methyl-5-(pyrrolidin-3-ylamino)-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3-d]pyrimidin- 4(3H)-one hydrochloride

HCI (4 M in dioxane, 4.0 mL, 16 mmol) was added to a mixture of tert-butyl (S)-3-((3-methyl-4-oxo-8- (5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l- carboxylate (0.21 g, 0.43 mmol) in MeOH (4 mL) and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated to dryness and the crude material was dried under vacuum to afford (S)-3-methyl-5-(pyrrolidin-3-ylamino)-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one hydrochloride (112 mg, 100% yield) as a beige color solid which was used without purification. ^TH NMR (500 MHz, DMSO-d6) 6 2.02 (1H, br d), 2.41 (1H, br dd), 3.16 - 3.30 (2H, m), 3.37 - 3.42 (1H, m), 3.57 (3H, s), 3.66 - 3.74 (1H, m), 4.85 (1H, br d), 8.22 - 8.28 (1H, m), 8.36 (1H, d), 8.62 (1H, s), 8.84 (1H, s), 9.02 (1H, s), 9.18 - 9.34 (2H, m), 9.34 - 9.41 (1H, m); m/z: (ES⁺) [M- HCI+H]⁺ = 391.

(S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one

A solution of acryloyl chloride (29 pL, 0.36 mmol) in DCM (3 mL) was added to a mixture of (S)-3- methyl-5-(pyrrolidin-3-ylamino)-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (0.13 g, 0.30 mmol) and EtaN (0.17 mL, 1.2 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 hrs. The reaction mixture was warmed to rt and diluted with DCM (25 mL) and water (25 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 25 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness. The crude material was purified by flash silica chromatography (0 to 80% EtOAc in DCM) to afford (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one (Example 3, 59 mg, 44% yield) as a white solid. ^XH NMR (500 MHz, CDCL) 6 2.06 - 2.23 (1H, m), 2.35 - 2.51 (1H, m), 3.59 (3H, d), 3.64 - 3.89 (3H, m), 3.99 - 4.14 (1H, m), 4.87 - 4.94 (1H, m), 5.71 (1H, ddd), 6.38 - 6.54 (2H, m), 7.94 - 7.99 (1H, m), 8.12 - 8.19 (2H, m), 8.91 (1H, d),

8.97 (1H, s), 9.27 (1H, br dd); m/z: (ES⁺) [M+H]⁺ = 445. Example 4: (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethoxy)pyridin-2- yl)pyrido[4,3-d]pyrimidin-4(3H)-one

Example 4 tert-butyl (S)-3-((3-methyl-4-oxo-8-(5-(trifluoromethoxy)pyridin-2-yl)-3,4-dihydropyrido[4, 3- d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate

Pd(0Ac)2 (69.8 mg, 0.311 mmol), tert-butyl (S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3- d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate (Intermediate 2, 0.660 g, 1.56 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.975 g, 7.777 mmol), di((ls,3S)- adamantan-l-yl)(butyl)phosphane (112 mg, 0.312 mmol), and potassium acetate (153 mg, 1.56 mmol) were diluted in 1,4-dioxane (15 mL) under an atmosphere of N2. The resulting mixture was heated to 80 °C and stirred for 18 hrs. Potassium phosphate, tribasic (991 mg, 4.67 mmol), Pd(0Ac)2 (34.9 mg, 0.155 mmol), and 2-bromo-5-(trifluoromethoxy)pyridine (941 mg, 3.89 mmol) were added to the reaction mixture, followed by water (1.5 mL). The resulting mixture was heated to 80 °C and stirred for 16 hrs. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The crude material was purified by reverse phase chromatography (C18: 30 to 80% MeCN in water w/ 0.1% HCO2H) to afford tert-butyl (S)-3-((3-methyl-4-oxo-8-(5-(trifluoromethoxy)pyridin- 2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate (200 mg, 25% yield) as a yellow solid. ^TH NMR (400 MHz, DMSO-d6) 6 1.41 (s, 9H), 1.89 - 2.02 (m, 1H), 2.20 - 2.30 (m, 1H), 3.21 (d, 1H), 3.38 - 3.43 (m, 2H), 3.49 (s, 3H), 3.63 - 3.70 (m, 1H), 4.64 - 4.73 (m, 1H), 7.92 - 7.97 (m, 1H), 8.20 (d, 1H), 8.54 (s, 1H), 8.71 (d, 1H), 8.74 (s, 1H), 9.27 (s, 1H); m/z: (ES⁺) [M+H]⁺ = 507.

(S)-3-methyl-5-(pyrrolidin-3-ylamino)-8-(5-(trifluoromethoxy)pyridin-2-yl)pyrido[4,3-d]pyrimidin- 4(3H)-one hydrochloride tert-Butyl (S)-3-((3-methyl-4-oxo-8-(5-(trifluoromethoxy)pyridin-2-yl)-3,4-dihydropyrido[4,3- d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate (194 mg, 0.383 mmol) was dissolved in HCI (4 M in dioxane, 5 mL, 20 mmol) and the reaction mixture stirred at rt for 1 h. The solvent was removed under reduced pressure to afford (S)-3-methyl-5-(pyrrolidin-3-ylamino)-8-(5- (trifluoromethoxy)pyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (120 mg, 71% yield) as a yellow solid which was used without purification. ¹H NMR (400 MHz, DMSO-d6) 6 1.97 - 2.08 (m, 1H), 2.37 - 2.46 (m, 1H), 3.16 - 3.30 (m, 1H), 3.34 - 3.40 (m, 1H), 3.51 - 3.54 (m, 2H), 3.57 (s, 3H), 4.81

- 4.90 (m, 1H), 7.97 - 8.02 (m, 1H), 8.24 (d, 1H), 8.65 (s, 1H), 8.72 (s, 1H), 8.75 (d, 1H), 9.38 (s, 1H), 9.45 (d, 1H); m/z: (ES⁺) [M+H]⁺ = 407.

(S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethoxy)pyndin-2-yl)pyndo[4,3- d]pyrimidin-4(3H)-one

Triethylamine (0.11 mL, 0.81 mmol) was added to a solution of (S)-3-methyl-5-(pyrrolidin-3- ylamino)-8-(5-(trifluoromethoxy)pyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (120 mg, 0.27 mmol) and acryloyl chloride (32.9 pL, 0.407 mmol) in DCM (0.6 mL) at 0 °C over a period of 2 min. The resulting mixture was stirred at 0 °C for 1 hr. The solvent was removed under reduced pressure and the crude material was purified by preparative HPLC (Column = Sunfire prep C18, 30 x 150 mm, 5pm; Mobile Phase = 32 to 45% MeCN in water w/ 0.1% HCO2H over 9 min; Flow rate = 60 mL/min; UV detection @ 254/220 nm) to afford (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8- (5-(trifluoromethoxy)pyridin-2-yl)pyrido[4,3-d7pyrimidin-4(3H)-one (Example 4, 70 mg, 56% yield) as a white solid. ^TH NMR (400 MHz, DMSO-d6) 6 1.95 - 2.13 (m, 1H), 2.23 - 2.39 (m, 1H), 3.40 - 3.49 (m, 3H), 3.56 (s, 2H), 3.70 - 4.00 (m, 2H), 4.67 - 4.84 (m, 1H), 5.64 - 5.72 (m, 1H), 6.12 - 6.19 (m, 1H), 6.51

- 6.69 (m, 1H), 7.92 - 7.97 (m, 1H), 8.21 (d, 1H), 8.54 (s, 1H), 8.72 (d, 1H), 8.76 (s, 1H), 9.18 - 9.38 (m, 1H); m/z (ES⁺) [M+H]⁺ = 461.

Example 5: 5-(((3/?,4S)-l-acryloyl-4-fluoropyrrolidin-3-yl)amino)-3-methyl-8-(5- (trifluoromethyl)pyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one

Example 5

2-fluoro-4-iodo-N-methylnicotinamide

Oxalyl chloride (8.20 mL, 93.6 mmol) and DMF (58 pL, 0.75 mmol) were added to a suspension of 2- fluoro-4-iodonicotinic acid (20.0 g, 74.9 mmol) in DCM (150 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, then rt for 1 hr. The reaction mixture was concentrated to dryness to afford 2-fluoro-4-iodonicotinoyl chloride as an orange solid, which was dissolved in THF (150 mL) and cooled to 0 °C. MeNHj (2 M in THF, 44.9 mL, 89.9 mmol) and triethylamine (13.57 mL, 97.38 mmol) were added, and the resulting mixture was warmed to rt and stirred for 36 hrs. The reaction mixture was diluted with EtOAc (200 mL) and was washed with water (80 mL) and brine (50 mL). The organics were dried over NajSO^ filtered, and concentrated to dryness. The obtained solid was rinsed with hexanes to afford 2-fluoro-4-iodo-/V-methylnicotinamide (19.67 g, 94% yield) as an off- white solid which was used without further purification. ¹H NMR (500 MHz, DMSO-d6) 6 2.79 (3H, d), 7.88 (1H, d), 7.96 (1H, d), 8.57 - 8.69 (1H, m); m/z: (ES⁺) [M+H]⁺ = 281.

4-amino-2-fluoro-N-methylnicotinamide

Ammonium hydroxide (7.23 mL, 186 mmol) was added to a mixture of 2-fluoro-4-iodo-/V- methylnicotinamide (5.20 g, 18.6 mmol), copper(l) iodide (0.707 g, 3.71 mmol), (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid (0.974 g, 7.43 mmol), and potassium carbonate (7.70 g, 55.7 mmol) in DMSO (40 mL). The resulting mixture was heated to 50 °C and stirred for 4 hrs. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (3 x 15 mL), dried over NajSC , filtered, and concentrated to dryness to afford 4-amino-2-fluoro-/V-methylnicotinamide (2.63 g, 84% yield) as an off-white solid which was used directly without further purification. ¹H NMR (500 MHz, DMSO-d6) 6 2.75 (3H, d), 6.55 (1H, d), 7.08 (2H, br s), 7.63 (1H, d), 8.11 (1H, br s); m/z: (ES⁺) [M+H]⁺ = 170.

4-amino-5-bromo-2-fluoro-N-methylnicotinamide

Bromine (3.33 mL, 64.7 mmol) was added to a solution of 4-amino-2-fluoro-/V-methylnicotinamide (10.84 g, 64.08 mmol) in AcOH (90 mL) and water (90 mL). The resulting mixture was stirred at rt for 2 hrs. The reaction mixture was quenched with dropwise addition of saturated aq. NajSjOs until the orange color disappeared. The reaction mixture was concentrated to dryness, and the crude residue was carefully diluted with saturated aq. NaHCOs (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were washed with brine (100 mL), dried over NajSC , filtered, and concentrated to dryness to afford 4-amino-5-bromo-2-fluoro-/V-methylnicotinamide (12.4 g, 78% yield) as a faint yellow/off-white solid which was used directly without further purification. ¹H NMR (500 MHz, DMSO-d6) 6 2.76 (3H, d), 7.08 (2H, br s), 8.02 (1H, s), 8.39 (1H, br s); m/z: (ES⁺) [M+H]⁺ = 248.

8-bromo-5-fluoro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one

A mixture of 4-amino-5-bromo-2-fluoro-/V-methylnicotinamide (1.02 g, 4.11 mmol), triethoxymethane (18.00 mL, 108.2 mmol), and 4-methylbenzenesulfonic acid hydrate (0.782 g, 4.11 mmol) in NMP (4.0 mL) was heated to 75 °C and stirred for 22 hrs. The reaction mixture was cooled to rt and the formed precipitate was filtered and washed with water and EtOAc. The filtrate phases were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over NajSC , filtered, and concentrated to dryness. The crude material was diluted with MeOH (20 mL) and water (40 mL) and sonicated for a few minutes. The precipitate was collected by filtration and washed with 50% EtOAc/hexanes, and then dried to afford 8-bromo-5-fluoro-3- methylpyrido[4,3-d]pyrimidin-4(3H)-one (0.899 g, 85% yield) as a white solid which was used directly without further purification. ^XH NMR (500 MHz, DMSO-d6) 63.48 (s, 3H), 8.68 (s, 1H), 8.74 (s, 1H); m/z: (ES⁺) [M+H]⁺ = 258. tert-butyl (3R,4S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)-4- fluoropyrrolidine-l-carboxylate

A mixture of tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-l-carboxylate (475 mg, 2.33 mmol), 8- bromo-5-fluoro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (0.300 g, 1.16 mmol), and DIPEA (1.02 mL, 5.81 mmol) in DMSO (5 mL) was heated to 60 °C and stirred for 16 hrs. The reaction mixture was cooled to rt, diluted with DCM (20 mL), and washed with brine (3 x 10 mL). The organic layer was dried over NajSC , filtered, and concentrated to dryness to afford tert-butyl (3R,4S)-3-((8-bromo-3- methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)-4-fluoropyrrolidine-l-carboxylate (300 mg, 58% yield) as a white solid which was used without purification. ¹H NMR (400 MHz, DMSO-d6) 6 1.42 (9H, d), 3.48 (3H, s), 3.57 (1H, s), 3.64 (1H, t), 3.92 (1H, q), 4.77 - 4.93 (2H, m), 5.30 (1H, dt), 8.45 (1H, s), 8.61 (1H, s), 9.18 (1H, t); m/z: (ES⁺) [M+H]⁺ = 442. tert-butyl (3S,4R)-3-f luoro-4-((3-methyl-4-oxo-8-(5-(trifluoromethyl)pyridin-2-yl)-3, 4- dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate

A mixture of tert-butyl (3R,4S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5- yl)amino)-4-fluoropyrrolidine-l-carboxylate (0.20 g, 0.45 mmol), 2-(tributylstannyl)-5- (trifluoromethyl)pyridine (296 mg, 0.679 mmol), and Pd(dppf)Clz (49.6 mg, 0.0678 mmol) in dioxane (4 mL) was heated to 90 °C and stirred for 16 hrs. The reaction mixture was cooled to rt, diluted with DCM (20 mL), and washed with brine (3 x 10 mL). The organic layer was dried over NajSC , filtered, and concentrated to dryness. The crude material was purified by silica flash chromatography (0 to 100% EtOAc in petroleum ether) to afford tert-butyl (3S,4R)-3-fluoro-4-((3-methyl-4-oxo-8-(5- (trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l- carboxylate (180 mg, 78% yield) as a white solid. ^TH NMR (400 MHz, DMSO-d6) 6 1.43 (9H, d), 3.07 (1H, dt), 3.44 (3H, s), 3.53 - 3.72 (2H, m), 3.72 - 3.94 (1H, m), 3.95 - 4.07 (1H, m), 5.34 (1H, dt), 8.23 (1H, dd), 8.34 (1H, d), 8.58 (1H, s), 8.83 (1H, s), 9.01 (1H, dd), 9.50 (1H, dd); m/z: (ES⁺) [M+H]⁺ = 509.

5-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one hydrochloride tert-Butyl (3S,4R)-3-fluoro-4-((3-methyl-4-oxo-8-(5-(trifluoromethyl)pyridin-2-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate (180 mg, 0.35 mmol) was dissolved in HCI (4 M in dioxane, 1 mL, 4 mmol) and the reaction mixture was stirred at rt for 30 min. The solvent was removed under reduced pressure to afford 5-(((3R,4S)-4-fluoropyrrolidin-3- yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (140 mg, 89% yield) as a white solid which was used without purification. ^XH NMR (400 MHz, DMSO-d6) 6 3.07 (1H, d), 3.52 (3H, s), 3.66 (2H, d), 3.75 - 3.86 (1H, m), 5.04 - 5.22 (1H, m), 5.37 - 5.57 (1H, m), 8.27 (1H, dd), 8.35 (1H, d), 8.64 (1H, s), 8.85(1H, s), 9.03 (1H, d), 9.53 (1H, d), 9.92 (2H, d); m/z: (ES⁺) [M+H]⁺ = 409.

5-(((3R,4S)-l-acryloyl-4-fluoropyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2- yl)pyrido[4,3-d]pyrimidin-4(3H)-one

5-(((3R,4S)-4-Fluoropyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one hydrochloride (0.070 mg, 0.17 mmol) was added to a mixture of 3- chloropropanoyl chloride (43.5 mg, 0.343 mmol) and NaHCOs (144 mg, 1.71 mmol) in THF (3.5 mL) and water (1 mL) at rt. The resulting mixture was stirred at rt for 3 hrs. Triethylamine (0.239 mL, 1.71 mmol) in MeCN (3.5 mL) was added to the reaction, and the resulting mixture was heated to 80 °C and stirred for 16 hrs. The reaction mixture was cooled to rt, diluted with MeCN (10 mL), and washed with saturated aq. NH₄CI (3 x 5 mL). The organic layer was dried over NajSC , filtered, and concentrated to dryness. The crude material was purified by preparative HPLC (Column = Sunfire Prep C18 OBD column, 30 x 150 mm, 5 pm; Mobile Phase = 20% MeCN in water w/ 0.1% HCO2H for 1 min, then 36 to 56% MeCN in water w/ 0.1% HCO2H over 8 min; Flow rate = 60 mL/min; UV detection @ 254/220 nm) to afford 5-(((3R,4S)-l-acryloyl-4-fluoropyrrolidin-3-yl)amino)-3-methyl-8- (5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 5, 15 mg, 19% yield) as a white solid. ^TH NMR (400 MHz, DMSO-d6) 6 3.11 - 3.62 (1H, m), 3.51 - 3.59 (3H, s) , 3.69 - 3.86 (1H, m), 3.92 - 4.09 (1H, m), 4.16 - 4.33 (1H, m), 4.93 - 5.21 (1H, m), 5.31 - 5.54 (1H, m), 5.69 - 5.77 (1H, m), 6.16 - 6.24 (1H, m), 6.56 - 6.68 (1H, m), 8.25 (1H, dd), 8.36 (1H, dd), 8.61 (1H, d), 8.85 (1H, d), 9.01 - 9.05 (1H, m), 9.51 - 9.60 (1H, m); m/z: (ES⁺) [M+H]⁺ = 463.

Example 6: (S)-8-((l-acryloylpyrrolidin-3-yl)amino)-2-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-

2,7-naphthyridin-l(2H)-one

5-bromo-2-methyl-2,7-naphthyridin-l(2H)-one lodomethane (0.26 mL, 4.2 mmol) was added to a mixture of 5-bromo-2,7-naphthyridin-l(2H)-one (0.78 g, 3.5 mmol) and K2CO3 (0.96 g, 6.9 mmol) in DMF (20 mL) and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was diluted with DCM (300 mL) and washed with water (5 x 40 mL). The organic layer was dried over Na2SO₄, filtered, and concentrated to dryness. The crude material was purified by silica flash chromatography (0 to 50% EtOAc in hexanes) to afford 5-bromo- 2-methyl-2,7-naphthyridin-l(2H)-one (0.63 g, 76% yield) as a beige solid. ¹H NMR (500 MHz, CDCU) 6 3.65 (3H, s), 6.74 (1H, d), 7.40 (1H, d), 8.88 (1H, s), 9.53 (1H, s); m/z: (ES⁺) [M+H]⁺ = 239.

4-bromo-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridine 2-oxide

A mixture of 5-bromo-2-methyl-2,7-naphthyridin-l(2H)-one (2.69 g, 11.3 mmol) and m-CPBA (5.55 g, 22.5 mmol) in DCM (50 mL) was stirred at rt for 17 hrs. The reaction mixture was diluted with DCM (100 mL) and washed with saturated aq. NajSjOs (30 mL), saturated aq. NaHCOs (30 mL), and water (30 mL). The organic layer was dried over NajSC , filtered, and concentrated to dryness to afford 4- bromo-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridine 2-oxide (1.388 g, 48% yield) as a brown solid, which was carried forward without purification, m/z: (ES⁺) [M+H]⁺ = 255.

5-bromo-8-chloro-2-methyl-2,7-naphthyridin-l(2H)-one

A mixture of 4-bromo-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridine 2-oxide (1.388 g, 5.442 mmol) and POCI3 (3.04 mL, 32.7 mmol) in MeCN (40 mL) was heated to 80 °C and stirred for 2.5 hrs. The reaction mixture was cooled to rt and concentrated to dryness. The crude residue was diluted with DCM (150 mL) and washed with water (30 mL). The organic layer was dried over NajSC , filtered, and concentrated to dryness to afford 5-bromo-8-chloro-2-methyl-2,7-naphthyridin-l(2H)-one (1.076 g, 72% yield) as a brown solid, which was carried forward without purification. ¹H NMR (500 MHz, DMSO-d6) 6 3.52 (3H, s), 6.68 (1H, d), 8.01 (1H, d), 8.70 (1H, s); m/z: (ES⁺) [M+H]⁺ = 273. tert-butyl (S)-3-((4-bromo-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-l-yl)amino)pyrrolidine-l- carboxylate

DIPEA (0.351 mL, 2.01 mmol) was added to a mixture of 5-bromo-8-chloro-2-methyl-2,7- naphthyridin-l(2H)-one (110 mg, 0.40 mmol) and tert-butyl (S)-3-aminopyrrolidine-l-carboxylate (112 mg, 0.601 mmol) in DMSO (1.5 mL) and the reaction mixture was heated to 60 °C and stirred for 16 hrs. The reaction mixture was cooled to rt, diluted with MeOH (5 mL), and directly subjected to reverse phase chromatography (C18: 5 to 100% MeCN in water w/ 0.1% NH4HCO3) to afford tert- butyl (S)-3-((4-bromo-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-l-yl)amino)pyrrolidine-l- carboxylate (160 mg, 94% yield) as a white solid. ^XH NMR (300 MHz, DMSO-d6) 6 1.40 (9H, s), 1.84 - 1.99 (1H, m), 2.13 - 2.27 (1H, m), 3.12 - 3.21 (1H, m), 3.38 (2H, t), 3.49 (3H, s), 3.58 - 3.68 (1H, m), 4.44 - 4.60 (1H, m), 6.54 (1H, d), 7.83 (1H, d), 8.27 (1H, s), 9.69 (1H, t); m/z: (ES⁺) [M+H]⁺ = 425. tert-butyl (S)-3-((7-methyl-8-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)-7,8-dihydro-2,7-naphthyridin-l- yl)amino)pyrrolidine-l-carboxylate Pd(dppf)Cl2 (25.9 mg, 0.0354 mmol), tert-butyl (S)-3-((4-bromo-7-methyl-8-oxo-7,8-dihydro-2,7- naphthyridin-l-yl)amino)pyrrolidine-l-carboxylate (150 mg, 0.35 mmol) and 2-(tributylstannyl)-5- (trifluoromethyl)pyridine (232 mg, 0.532 mmol) were diluted in 1,4-dioxane (2 mL) under an atmosphere of Nj. The reaction mixture was heated to 80 °C and stirred for 6 hrs. The reaction mixture was cooled to rt, diluted with DCM (10 mL), and washed with saturated KF (2 mL) and brine (2 mL). The organic layer was dried over NajSC , filtered, and concentrated to dryness. The crude material was dissolved in MeOH (3 mL) and subjected to reverse phase chromatography (C18: 5 to 100% MeCN in water w/ 0.1% TFA) to afford tert-butyl (S)-3-((7-methyl-8-oxo-4-(5- (trifluoromethyl)pyridin-2-yl)-7,8-dihydro-2,7-naphthyridin-l-yl)amino)pyrrolidine-l-carboxylate (150 mg, 86% yield) as a brown solid. ^TH NMR (300 MHz, DMSO-d6) 6 1.40 - 1.43 (9H, m), 1.92 - 2.01 (1H, m), 2.21 - 2.28 (1H, m), 3.18 - 3.26 (1H, m), 3.39 - 3.44 (2H, m), 3.51 (3H, s), 3.63 - 3.71 (1H, m), 4.57 - 4.71 (1H, m), 6.97 (1H, d), 7.71 (1H, d), 7.86 (1H, d), 8.24 -8.32 (1H, m), 8.40 (1H, s), 9.06 (1H, d), 10.03 - 10.12 (1H, m); m/z: (ES⁺) [M+H]⁺ = 490.

(S)-8-((l-acryloylpyrrolidin-3-yl)amino)-2-methyl-5-(5-(tnfluoromethyl)pyndin-2-yl)-2,7- naphthyridin-l(2H)-one tert-Butyl (S)-3-((7-methyl-8-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)-7,8-dihydro-2,7-naphthyridin-l- yl)amino)pyrrolidine-l-carboxylate (0.10 g, 0.20 mmol) was dissolved in HCI (4 M in dioxane, 0.5 mL, 2 mmol) and the reaction mixture was stirred at rt for 1.5 hrs. The reaction mixture was concentrated to dryness to afford crude (S)-2-methyl-8-(pyrrolidin-3-ylamino)-5-(5- (trifluoromethyl)pyridin-2-yl)-2,7-naphthyridin-l(2H)-one hydrochloride. The obtained material was diluted in DCM (2 mL). Triethylamine (0.085 mL, 0.61 mmol) and acryloyl chloride (16.5 pL, 0.204 mmol) were added and the reaction mixture was stirred at rt for 10 min. The reaction mixture was directly subjected to preparative HPLC (Column = Xselect CSH C18 OBD 30 x 150 mm 5 pm; Mobile Phase = 23 to 45% MeCN in water w/ 0.1% HCO2H over 7 min; Flow rate = 60 mL/min; UV detection @ 254/220 nm) to afford (S)-8-((l-acryloylpyrrolidin-3-yl)amino)-2-methyl-5-(5- (trifluoromethyl)pyridin-2-yl)-2,7-naphthyridin-l(2H)-one (Example 6, 25 mg, 28% yield) as a white solid. NMR (400 MHz, DMSO-d6) 6 1.93 - 2.14 (m, 1H), 2.23 - 2.39 (m, 1H), 3.41 - 3.47 (m, 1H), 3.51 (s, 3H), 3.54 - 3.60 (m, 1H), 3.70 - 4.02 (m, 2H), 4.64 - 4.83 (m, 1H), 5.64 - 5.74 (m, 1H), 6.12 - 6.21 (m, 1H), 6.54 - 6.70 (m, 1H), 6.97 (dd, 1H), 7.69 - 7.74 (m, 1H), 7.84 - 7.89 (m, 1H), 8.27 - 8.32 (m, 1H), 8.41 (d, 1H), 9.07 (s, 1H), 10.07 - 10.14 (m, 1H); m/z: (ES⁺) [M+H]⁺ = 444.

Biological Data The data in Table 1 were generated using the Examples of the present specification and the assays described below.

(i) TEAD4 FRET

Compounds were dosed with a final DMSO concentration of 1% (v/v). Compound IC₅o values were assessed following a 10-point, half-logio dilution schema starting at 100 pM compound concentration. Specifically, human TEAD protein from TEAD4(217-434) was cloned into an overexpression vector, expressed as an /V-terminal HIS-TEV-Avi-tagged fusion protein in E coli, and subsequently purified, then protein was chemically depalmitoylated & biotinylated. The assay was performed in 384-well LV plates (384-well black, medium binding, PS, HIBASE, GREINER #784076) and run in the presence and absence of the compound of interest. Each well of 5 pL assay mixture contained 10 mM Tris-HCI (pH 7.5), 100 mM NaCI, 0.05 mM EDTA, 1 mM TECP, 1% DMSO, 0.03% Pluronic acid F127, 20 nM dePai Avi TEAD4 (217-434) -depalmitoylated & biotinylated protein, 0.8 nM Streptavidin Terbium cryptate (CisBio#610SATLB), 625 nM FAM labelled Probe A. Reactions were incubated at 25°C for 120 min before reading on a PHERASTAR FSX Plate Reader (337 520 490 HTRF module required) (Supplier BMP).

The data file from the PHERAstar FSX contains both the acceptor (520 nm) and donor channels (490 nm) ("Channel A" = acceptor channel (520 nm), "Channel B" = donor channel (490 nm)). The ratio of the donor and acceptor (Channel A / Channel B) is calculated within Genedata Assay Analyzer. Subsequently, the dose-response of the ratio to testing compound concentration was fitted to a select fit model that will provide the best fit quality using automatic parameter (SMARTFIT) to derive IC₅o values for each testing compound.

Probe A is 3',6'-dihydroxy-3-oxo-N-{8-[2-(5-{2-[4-(trifluoromethyl)anilino]phenyl}-2H-tetrazol-2- yl)acetamido]octyl}-3H-spiro[[2]benzofuran-l,9'-xanthene]-5-carboxamide;

(ii) TEAD Reporter Assay

MCF7-Tead cell line was obtained from BPS BIOSCIENCE (catalog number 60618) and was maintained in DMEM containing 10% fetal calf serum, 2mM glutamine, and 400pg/ml G418. Cells were grown in a humidified incubator at 37 °C with 5% CO2. Cells were distributed to flat bottom white polystyrene TC treated 384 well plates at a density of 3,500 cells/well in 30pL. Cells were incubated for 24 hours at 37 °C with 5% CO2. Cells were acoustically dosed using an Echo 555, with compounds serially diluted in 100% DMSO. Plates were incubated for an additional 24 hours. Cells were examined for luciferase activity through the addition of 30pL Bright-Glo luciferase (Promega catalog number E2620). Plates were incubated for 10 minutes at room temperature and luminescence was read using Tecan plate reader. The data obtained with each compound was exported to GENEDATA software to perform curve fitting analysis. IC50 value was calculated based on the concentration of compound that is required to give a 50% effect compared to DMSO control.

(iii) Control reporter (MCF7-Luciferase)

MCF7-Luciferase cell line was obtained from GENTARGET (catalog number SC050-L) and was maintained in DMEM containing 10% fetal calf serum, 2mM glutamine. Cells were grown in a humidified incubator at 37°C with 5% CO2. Cells were distributed to flat bottom white polystyrene TC treated 384 well plates at a density of 3,500 cells/well in 30pL. Cells were incubated for 24 hours at 37 °C with 5% CO2. Cells were acoustically dosed using an Echo 555, with compounds serially diluted in 100% DMSO. Plates were incubated for an additional 24 hours. Cells were examined for luciferase activity through the addition of 30uL Bright-Glo luciferase (Promega catalog number E2620). Plates were incubated for 10 minutes at room temperature and luminescence was read using Tecan plate reader. The data obtained with each compound was exported to GENEDATA software to perform curve fitting analysis. IC50 value was calculated based on the concentration of compound that is required to give a 50% effect compared to DMSO control.

Table 1

Synthesis of Probe A

tert-butyl (8-(2-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2- yl)acetamido)octyl)carbamate l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 110 mg, 0.29 mmol) and DIPEA (84 pL, 0.48 mmol) were added to a solution of 2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetic acid (70 mg, 0.19 mmol, disclosed in WO2018204532, the contents of which are incorporated by reference) and tert-butyl (8- aminooctyl)carbamate (71 mg, 0.29 mmol) in DMF (1.8 mL) at 0 °C, and the reaction mixture was stirred for 3 hrs while slowly warming to rt. The crude reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aq. NaHCOs (2 x 20 mL), saturated aq. NH₄CI (2 x 20 mL) and brine (20 mL). The organic layer was dried over NajSC , filtered and concentrated to dryness. The crude material was purified by flash silica chromatography (0-50% EtOAc in Hex) to afford tert-butyl (8-(2- (5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamido)octyl)carbamate (53.7 mg, 47% yield) as a white solid. ^TH NMR (500 MHz, DMSO-d6) 6 1.22 (9H, br s), 1.29 - 1.38 (9H, m), 1.41 (3H, br d), 2.87 (2H, q), 3.09 (2H, q), 5.49 (2H, s), 6.72 (1H, br t), 7.13 - 7.19 (1H, m), 7.24 (2H, br d), 7.45 - 7.50 (1H, m), 7.52 - 7.59 (3H, m), 8.03 (1H, dd), 8.40 (1H, br t), 8.77 (1H, s); m/z: (ES⁺) [M+H]⁺ = 590.

N-(8-aminooctyl)-2-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamide

TFA (0.50 mL, 6.5 mmol) was added to a solution of tert-butyl (8-(2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamido)octyl)carbamate (50 mg, 0.08 mmol) in DCM (1 mL) at 0 °C and the reaction mixture was stirred for 45 min. The reaction mixture was concentrated to dryness to afford /V-(8-aminooctyl)-2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamide TFA as a pale blue oil. 3',6'-dihydroxy-3-oxo-N-(8-(2-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2- yl)acetamido)octyl)-3H-spiro[isobenzofuran-l,9'-xanthene]-5-carboxamide (Probe A)

HATU (61 mg, 0.16 mmol) and DIPEA (86 pL, 0.49 mmol) were added to a solution of 5- carboxyfluorescein (60 mg, 0.16 mmol) and /V-(8-aminooctyl)-2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamide (60 mg, 0.12 mmol) in DMF (1.1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hrs before warming to rt with stirring for an additional 1 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aq. NH₄ (2 x 30 mL) and brine (30 mL). The organic layer was dried over NajSC , filtered and concentrated to dryness. The resulting residue was purified by preparative HPLC (Column = Xbridge C18, 4.6 mm x 50 mm, 5 pm; Gradient = 13 to 95% MeCN in H2O w/ 0.2% NH₄OH over 4 min; Flow rate = 0.6 mL/min; UV detection @ 254) to afford 3',6'-dihydroxy-3-oxo-/V-(8-(2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamido)octyl)-3H-spiro[isobenzofuran- l,9'-xanthene]-5-carboxamide (82 mg, 79 %) as a bright red solid. ¹H NMR (500 MHz, DMSO-d6) 6 1.29 (9H, br d), 1.39 - 1.48 (2H, m), 1.49 - 1.59 (2H, m), 2.53 (2H, br s), 3.10 (2H, q), 5.50 (2H, s), 6.45 (2H, br d), 6.54 (2H, br s), 6.58 (2H, s), 7.12 - 7.19 (1H, m), 7.24 (2H, d), 7.28 (1H, d), 7.43 - 7.50 (1H, m), 7.54 (3H, t), 8.03 (1H, dd), 8.11 (1H, br d), 8.43 (1H, s), 8.50 (1H, br t), 8.72 (1H, br t), 8.78 (1H, s); m/z: (ES⁺) [M+H]⁺ = 848.

The above description of illustrative embodiments is intended only to acquaint others skilled in the art with the Applicant's specification, its principles, and its practical application so that others skilled in the art may readily adapt and apply the specification in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples, while indicating embodiments of this specification, are intended for purposes of illustration only. This specification, therefore, is not limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the specification that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the specification that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

Claims

1. A compound of Formula (I):

wherein: X¹ and X² are independently selected from CH and N;

L is a covalent bond, O or CH₂; either X³ is CH and X⁴ is selected from CR⁵ and N, or X³ is N and X⁴ is CR⁵;

R¹ is Ci-4 alkyl or C3-4 cycloalkyl;

R² is selected from H and R¹, wherein R¹ is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy; R³, R⁴ ,R⁵ are independently selected from H, C1.4 fluoroalkyl, C1.4 alkoxy, -S(Ci_₄ alkyl), -O(Ci_₄ fluoroalkyl), -S(Ci_₄ fluoroalkyl), F, Cl, C3-4 fluorocycloalkyl, R^j and R^k, wherein R^j is C3-4 cycloalkyl optionally substituted with -CN, C1-4 alkoxy or C1-4 fluoroalkyl and R^k is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy;

G is selected from

R⁶ is H, OH, F, -CN, C(=O)NH₂, N(CI-₄ al kyl )₂, C1.4 alkoxy, C1-4 fluoroalkyl, R¹⁰ or R¹¹;

R⁷ is H, C1-4 alkoxy, R¹⁰ or R¹¹; either R⁸ and R⁹ are independently selected from H, R¹⁰ and R¹¹; or R⁸ and R⁹, together with the carbon atom to which they are attached, form a cyclopropane or cyclobutane ring; each R¹⁰ is independently Ci-₄ alkyl optionally substituted with Ci.₄ alkoxy, N(Ci.₄alkyl)2 or OH; each R¹¹ is independently C_3.4 cycloalkyl optionally substituted with Ci-₄ alkoxy or OH;

J is selected from

R¹² is H or F;

R¹³ is H, CH₂F or CH₃; wherein a Ci-₄ fluoroalkyl is a saturated linear or branched hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom; and wherein a C_3.4 fluorocycloalkyl is a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom; or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim

1, wherein X¹ is CH.

3. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim

1, wherein X¹ is N.

4. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein X² is CH.

5. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein X² is N.

6. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein X³ is CH or N and X⁴ is CR⁵.

7. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein L is a covalent bond.

8. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, wherein R⁴ is Ci-₄ fluoroalkyl, -O(Ci.₄ fluoroalkyl) or -S(Ci.₄ fluoroalkyl).

9. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, wherein R⁴ is CFjH, CF2CH3, CF3, OCF3, OCF2H or SCF3.

10. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, wherein R³ and R⁵ are independently selected from H, Cl, F and Ci-₄ alkyl.

11. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, wherein R³ and R⁵ are both H.

12. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, wherein R¹ is CH3.

13. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 12, wherein R² is H.

14. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13, wherein G is selected from

15. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, wherein R⁶ is H, OH, F, CH2OH or CH2OCH3.

16. A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 15, and a pharmaceutically acceptable excipient.

17. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 16, for use in therapy.

18. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 16, for use in the treatment of cancer.

19. A method of treating cancer in a patient comprising administering to the patient a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 16.