WO2021224818A1

WO2021224818A1 - Isoindolone compounds as hpk1 inhibitors

Info

Publication number: WO2021224818A1
Application number: PCT/IB2021/053791
Authority: WO
Inventors: Omar Ahmad; Matthew L. DEL BEL; Klaus Ruprecht Dress; Rebecca Anne Gallego; Mingying He; Mehran Jalaie; Ted William Johnson; Robert Steven Kania; Michele Ann Mctigue; Sajiv Krishnan Nair; Jamison Bryce Tuttle; Dahui Zhou; Ru Zhou
Original assignee: Pfizer Inc.
Priority date: 2020-05-08
Filing date: 2021-05-05
Publication date: 2021-11-11

Abstract

This invention relates to compounds of general Formula I and pharmaceutically acceptable salts thereof, in which R¹, R², R^2a, R³, R⁴, (R⁵)_a and X are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.

Description

Isoindolone Compounds as HPK1 Inhibitors

This application claims the benefit of U. S. Provisional Application No. 63/021 ,844 filed on May 8, 2020, the contents of which is hereby incorporated by reference in its entirety.

Field of the Invention

The present invention relates to compounds of Formula I, and their pharmaceutically acceptable salts, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds, salts and compositions of the present invention are HPK1 inhibitors and as such may be used to enhance the activation of the immune system in the treatment or amelioration of abnormal cell proliferative disorders, such as cancer and amelioration of vaccine therapies.

Background

Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen activated protein kinase kinase kinase kinase 1 (MAP4K1), is a member of the mammalian Ste20-like family of serine/threonine kinases that operates via the JNK and ERK signalling pathways. HPK1 is mainly expressed in hematopoietic organs and cells (e.g., T-cells, B-cells, and dendritic cells), suggesting potential involvement of HPK1 in the regulation of signaling in hematopoietic lineages, including lymphocytes. (Shui, et al, “Hematoppietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cel-mediated immune responses”, Nature Immunology 8, 84-91 (2006)).

For example, stimulation of the T-Cell Receptor (TCR) induces HPK1 tyrosine 379 phosphorylation and relocation to the plasma membrane. Enzymatic activation of HPK1 is accompanied by phosphorylation of regulatory sites in the HPK1 kinase activation loop. Full activation of HPK1 is dependent on autophosphorylation of threonine 165 and phosphorylation by protein kinase D (PKD) of serine 171 (Arnold et al., “Activation of Hematopoietic Progenitor Kinase 1 Involves Relocation, Autophosphorylation, and Transphosphorylation by Protein Kinase D 1. ” , Mol Cell Biol 25 (6), 2364-83 (2005)). HPK1 mediated phosphorylation of adaptor protein SLP76 ultimately leads to the destabilization of the TCR signaling complex which impedes and attenuates downstream mitogen-activated protein (MAP) kinase signaling events necessary for T-cell activation and proliferation. (Hernandez, et al., “The kinase activity of hematopoietic progenitor kinase 1 is esential for the regulation of T cell function”, Cell Reports 25, (1), 80-94, (2018)). HPK1 kinase has also been shown to negatively regulate T-cell signaling by the PGE2 receptor in a PKA-dependent manner. Furthermore, HPK1 kinase has been reported to play roles in: i) activation-induced cell death (AICD) and JNK activation; ii) regulation of leukocyte function-associated antigen-1 (LFA-1) integrin activation on T-cells by direct competition with adhesion and degranulation promoting adaptor protein (ADAP) for binding of the SLP76 SH2- domain; and iii) regulation of activation via nuclear factor KB (NF- KB) signaling by interacting with IKK-a and -b. Studies have also shown HPK1 negatively regulates MAP kinase pathway signaling and AP-1 transcription in T-cells. (reviewed in Hernandez, et al. 2018).

The research conducted to date on HPK1 kinases suggests that HPK1 inhibition plays a role in enhancing dendritic and T-cell responses and thereby heightening anti-tumor immunity, virus clearance and response to vaccine therapy.

Summary

The present invention provides, in part, compounds of Formula I, and pharmaceutically acceptable salts thereof. Such compounds can inhibit the activity of HPK1 kinase, thereby effecting biological functions. Also provided are pharmaceutical compositions and medicaments, comprising the compounds or salts of the invention, alone or in combination with additional anticancer therapeutic agents or palliative agents.

The present invention also provides, in part, methods for preparing the compounds, pharmaceutically acceptable salts and compositions of the invention, and methods of using the foregoing.

In one embodiment, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, halogen, (Ci-Ce)alkyl, halo(Cr C₆)alkyl, (CrC₆)alkoxy, halo(Ci-C₆)alkoxy, -N(R⁶)(R⁷), -SO2CH₃, (C₃-C₆)cycloalkyl, (C₃- C₆)cycloalkoxy, (4- to 6-membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, (C₃-Ce)cycloalkyl, (C₃-C₆)cycloalkoxy, (4- to 6- membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (CrCe)alkyl, (CrCe)alkoxy, halo(CrC₆)alkyl, halo(CrC₆)alkoxy, (C₃-C₆)cycloalkyl, and -N(R⁶)(R⁷);

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and (CrCe)alkyl, wherein said (CrCe)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, and hydroxy;

R² is: i) hydrogen; ii) -(CH2)_mN(R⁸)(R⁹), wherein m is an integer selected from 0, 1, 2, or 3, and R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, (Cr Ce)alkyl, -C(0)(C C₃)alkyl and -C(0)NH(C C₃)alkyl, wherein said (C C₆)alkyl, -C(0)(C C₃)alkyl and -C(0)NH(CrC₃)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, oxo, hydroxy, and (4- to 6-membered)heterocycloalkyl; iii) (Ci-C₆)alkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, and hydroxy; iv) a (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkoxy, and halo(Ci- C₆)alkoxy, wherein said (Ci-Ce)alkyl and halo(Ci-Ce)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, and (Ci-C₆)alkoxy; or v) -SO2-NH2;

R^2a is selected from the group consisting of hydrogen, halogen, (Ci-Ce)alkyl, halo(Ci- C₆)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, -N(R⁶)(R⁷), (4- to 6-membered)heterocycloalkyl, wherein said (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, and (4- to 6- membered)heterocycloalkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, and (C₃-Ce)cycloalkyl;

R³ is selected from the group consisting of hydrogen, hydroxy, (Ci-Ce)alkyl, halo(Ci- C₆)alkyl, (Ci-Ce)alkoxy, and halo(Ci-Ce)alkoxy;

X is carbon or nitrogen;

R⁴ is a (Ci-Ce)alkyl, (Ci-C₆)alkoxy, -C(O)N(R¹⁰)(R¹¹), aryl, O-aryl, (C₃-C₆)cycloalkyl, O- (C₃-C₆)cycloalkyl, NH-(C₃-C₆)cycloalkyl, a (4- to 6-membered)heterocycloalkyl or a (5- to 10- membered)heteroaryl, wherein said (Ci-Ce)alkyl, (Ci-Ce)alkoxy, aryl, O-aryl, (C₃-Ce)cycloalkyl, 0-(C₃-C₆)cycloalkyl, NH-(C₃-C₆)cycloalkyl, a (4- to 6-membered)heterocycloalkyl, and (5- to 10- membered)heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Cr C₆)alkoxy, halo(Ci-C₆)alkoxy, -(C₃-C₆)cycloalkyl, and (4- to 6-membered)heterocycloalkyl, wherein said (Ci-Ce)alkyl, halo(Ci-C₆)alkyl, (Ci-Ce)alkoxy, and halo(Ci-Ce)alkoxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, and (C₃-Ce)cycloalkyl, wherein the (Ci-Ce)alkoxy, and (C₃-Ce)cycloalkyl are optionally substituted with 1 to 2 halogen; and wherein R¹⁰ and R¹¹ are each independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, and (C₃-Ce)cycloalkyl, wherein said (CrC₆)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, and (C3-Ce)cycloalkyl;

R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, (Ci-Ce)alkyl, halo(CrC₆)alkyl, (CrCe)alkoxy, and halo(CrCe)alkoxy; and a is an integer selected from 0 or 1 , provided that when X is nitrogen a is 0; and provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides therapeutic methods and uses comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a method for the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Compounds of the invention may be administered as single agents, or may be administered in combination with other anti-cancer therapeutic agents, in particular standard of care agents appropriate for the particular cancer.

In a further embodiment, the invention provides a method for the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional anti-cancer therapeutic agent, which amounts are together effective in treating said abnormal cell growth.

In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular a medicament for treatment of cancer.

In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth, in particular cancer, in a subject.

In a further embodiment, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth, in particular cancer, in a subject.

In another embodiment, the invention relates to a pharmaceutical composition for use in the treatment of abnormal cell growth in a subject in need thereof, which composition comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In another embodiment, the invention provides the use of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of abnormal cell or pathogen growth in a subject.

In frequent embodiments of the foregoing compounds, methods and uses, the abnormal cell growth is cancer.

In some embodiments, the methods and uses provided result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; (5) inhibiting angiogenesis; (6) enhancing T-cell responses; or (7) enhancing dendritic and B cell responses; (8) heightening of anti-tumor activity; (9) enhancing vaccine therapies; and (10) enhancing immune-system mediated removal of pathogens such as viruses, bacteria, or parasite (e.g., intestinal worms).

In another embodiment, the invention provides a method for the treatment of HPK1- dependent disorders and enhancing an immune response in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder or enhancing said immune response.

In some embodiments, the methods and uses described herein further comprise administering to the subject an amount of an additional anticancer therapeutic agent, vaccine or a palliative agent, which amounts are together effective in treating said abnormal cell growth or pathogen. Each of the embodiments of the compounds of the present invention described below can be combined with one or more other embodiments of the compounds of the present invention described herein not inconsistent with the embodiment(s) with which it is combined.

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

In addition, each of the embodiments below describing the invention envisions within its scope the pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase “or a pharmaceutically acceptable salt thereof” is implicit in the description of all compounds described herein.

Detailed Description

Definitions and Exemplifications

The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art. As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

The term “about” refers to a relative term denoting an approximation of plus or minus 10% of the nominal value it refers, in one embodiment, to plus or minus 5%, in another embodiment, to plus or minus 2%. For the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a tighter range.

As used herein, the term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl ring.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention includes each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-e alkyl” is specifically intended to include Ci alkyl (methyl), C₂ alkyl (ethyl), C₃ alkyl, C₄ alkyl, C₅ alkyl, and Ob alkyl. For another example, the term “a 5- to 6-membered heteroaryl group” is specifically intended to include any 5-, 6-membered heteroaryl group.

As used herein, a "HPK1 antagonist" or a "HPK1 inhibitor" is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of HPK1 (e.g., serine/threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with a protein binding partner, such as SLP76). Antagonism using the HPK1 antagonist does not necessarily indicate a total elimination of the HPK1 activity. Instead, the activity could decrease by a statistically significant amount. For example, a compound of the present invention may decrease HPK1 activity by at least about 2.5% to about 100%, from about 10% to about 90%, from about 20% to about 70%, from about 30% to about 60%, from about 40% to about 50% compared to an appropriate control. In some embodiments, the HPK1 antagonist reduces, inhibits, or otherwise diminishes the serine/threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist reduces, inhibits, or otherwise diminishes the HPK1- mediated phosphorylation of SLP76 and/or Gads. The presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity.

The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced with either of the other two terms.

The term “(Ci-C₆)alkyl”, as used herein, refers to a saturated, branched- or straight-chain alkyl group containing from 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n- pentyl, isopentyl, neopentyl, and n-hexyl. The term “(Ci-C₆)alkyl” includes “(Ci-C3)alkyl” that is intended to include Ci alkyl (methyl), C2 alkyl (ethyl), and C3 alkyl (propyl, including n-propyl and isopropyl). The term “halo(CrC₆)alkyl” as used herein, refers to a (Ci-Ce)alkyl group as defined above wherein the alkyl group is substituted with one or more halogen atoms. For example, a halo(Cr Ce)alkyl may be selected from fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl.

The term “(CrCe)alkoxy” as used herein, refers to a (CrCe)alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Representative examples of a (CrC₆)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy, and hexyloxy.

The term “halo(CrC₆)alkoxy” as used herein, refers to a (CrCe)alkoxy group as defined above wherein the alkoxy group is substituted with one or more halogen atoms. For example, a halo(CrC₆)alkoxy may be selected from fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy.

As used herein, the term “(C3-C6)cycloalkyl” refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule having from 3 to 6 carbon atoms. A “cycloalkyl’ may be a monocyclic ring, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

A “heterocycloalkyl,” as used herein, refers to a cycloalkyl as defined above, wherein at least one of the ring carbon atoms is replaced with a heteroatom selected from nitrogen, oxygen or sulfur. The term “(4- to 6-membered)heterocycloalkyl” means the heterocycloalkyl substituent contains a total of 4 to 6 ring atoms, at least one of which is a heteroatom. The term “(4- to 8- membered)heterocycloalkyl” means the heterocycloalkyl substituent contains a total of 4 to 8 ring atoms, at least one of which is a heteroatom. A “(6-membered)heterocycloalkyl” means the heterocycloalkyl substituent contains a total of 6 ring atoms, at least one of which is a heteroatom. A “(5-membered)heterocycloalkyl” means the heterocycloalkyl substituent contains a total of 5 ring atoms at least one of which is a heteroatom. The heterocycloalkyl substituent may be attached via a nitrogen atom having the appropriate valence, or via any ring carbon atom. The heterocycloalkyl moiety may be optionally substituted with one or more substituents at a nitrogen atom having the appropriate valence, or at any available carbon atom.

Examples of heterocycloalkyl rings include, but are not limited to, azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydro-triazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydro-oxazolyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl. Further examples of heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1 ,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1 ,3-thiazinan-3-yl, 1,2- tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, 2-oxo-piperidinyl (e.g., 2-oxo- piperidin-1-yl), azabicyclo[2.2.1]heptyl and the like.

A “(C₆-Cio)aryl” refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system containing from 6 to 10 carbon atoms, such as phenyl or naphthyl. The term “-0(C₆-Cio)aryl” refers to an aryl as described above connectd to an oxy substituent.

As used herein, the term “heteroaryl” refers to an aromatic carbocyclic system containing one, two, three or four heteroatoms selected independently from oxygen, nitrogen and sulfur and having one, two or three rings wherein such rings may be fused, wherein fused is defined above. A “(5- to 10-membered) heteroaryl” ring refers to a heteroaryl ring having from 5 to 10 ring atoms in which at least one of the ring atoms is nitrogen, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, sulfur, and nitrogen. A “(5- to 6-membered) heteroaryl” ring refers to a heteroaryl ring having from 5 to 6 ring atoms in which at least one of the ring atoms is nitrogen, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, sulfur, and nitrogen. Examples of heteroaryls include, but are not limited to, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl (e.g., 1 ,2,3-triazol or 1,2,4-triazol), pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, dihydropyrrolotriazolyl, and oxadiazolyl.

It is to be understood that the heteroaryl may be optionally fused to a cycloalkyl group, or to a heterocycloalkyl group, as defined herein.

The heteroaryl substituent may be attached via a nitrogen atom having the appropriate valence, or via any carbon atom. The heteroaryl moiety may be optionally substituted with one or more substituents at a nitrogen atom having the appropriate valence, or at any available carbon atom. The substituent can be attached to the heteroaryl moiety at any available carbon atom or to a heteroatom when the heteroatom is nitrogen having the appropriate valence.

“halo” or “halogen”, as used herein, refers to a chlorine, fluorine, bromine, or iodine atom “hydroxy” or “hydroxyl”, as used herein, means an -OH group.

“cyano”, as used herein, means a -CN group, which also may be depicted:

“Optionally substituted”, as used herein, means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group (up to and including that every hydrogen atom on the designated atom or moiety is replaced with a selection from the indicated substituent group), provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., -CH₃) is optionally substituted, then up to 3 hydrogen atoms on the carbon atom can be replaced with substituent groups. “Patient” or “subject” refers to warm-blooded animals such as, for example, pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.

“Pharmaceutically acceptable” indicates that the substance or composition must be compatible, chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

The term "therapeutically effective amount" as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of an HPK1 kinase-mediated disorder (e.g., cancer), a therapeutically effective amount refers to that amount which has the effect of relieving to some extent (or, for example, eliminating) one or more symptoms associated with the HPK1 kinase-mediated disorder. For example, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer.

The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined herein. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.

“Isomer” means “stereoisomer” and “geometric isomer” as defined below.

“Stereoisomer” refers to compounds that possess one or more chiral centers, which may each exist in the R or S configuration. Stereoisomers include all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.

“Geometric isomer” refers to compounds that may exist in cis, trans, anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof.

As used herein, unless specified, the point of attachment of a substituent can be from any suitable position of the substituent. For example, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

When a substituted or optionally substituted moiety is described without indicating the atom via which such moiety is bonded to a substituent, then the substituent may be bonded via any appropriate atom in such moiety. For example in an optionally substituted (5- to 10- membered)heteroaryl, a substituent on the heteroaryl can be bonded to any carbon atom on the heteroaryl part or on the heteroatom of the heteroaryl, valency permitting. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. This specification uses the terms “substituent,” “radical,” and “group” interchangeably.

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

Compounds

The compounds of Formula I, as described herein, contain a 2,3-dihydro-1 H-isoindol-1- one core wherein the isoindole ring is attached via its nitrogen atom to a 6-membered heteroaryl (pyridine or pyrimidine) that is substituted with R⁴ and an optional R⁵ substituent.

In one embodiment, in Formula I, R¹ is selected from the group consisting of (CrCe)alkyl, (CrCe)alkoxy, halo(CrC₆)alkoxy, -N(R⁶)(R⁷), -S0₂CH₃, (C3-C₆)cycloalkoxy, (4- to 6- membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (Ci-Ce)alkyl, (Cr C₆)alkoxy, (4- to 6-membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl are optionally substituted with 1 substituent selected from the group consisting of hydroxy, cyano, (C₃- C₆)cycloalkyl, and -N(R⁶)(R⁷).

In another embodiment, in Formula I, R¹ is hydrogen.

In another embodiment, in Formula I, R¹ is -SC>2CH₃.

In another embodiment, in Formula I, R¹ is halogen, wherein the halogen is selected from chlorine and fluorine. In certain embodiments the halogen is chlorine.

In another embodiment, in Formula I, R¹ is -N(R⁶)(R⁷), and R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and (Ci-Ce)alkyl, wherein said (Cr C₆)alkyl is optionally substituted with 1 to 3 halogen.

In another embodiment, R¹ is -N(R⁶)(R⁷), and R⁶ and R⁷ are each methyl.

In another embodiment, R¹ is -N(R⁶)(R⁷), and R⁶ and R⁷ are each ethyl.

In another embodiment, R¹ is -N(R⁶)(R⁷), and one of R⁶ and R⁷ is hydrogen and the other is methyl.

In another embodiment, R¹ is -N(R⁶)(R⁷), and one of R⁶ and R⁷ is methyl and the other is ethyl.

In another embodiment, R¹ is a (Ci-Ce)alkyl that is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, wherein the alkyl is optionally substituted with 1 substituent selected from the group consisting of hydroxy, cyano, -N(R⁶)(R⁷), and (Ci-Ce)alkoxy. In certain embodiments, R¹ is propyl that is propan-2-yl. When R¹ is (Ci-Ce)alkyl, the alkyl can be optionally substituted with 1 substituent selected from the group consisting of hydroxy, cyano, -N(R⁶)(R⁷), and (Ci-Ce)alkoxy.

In another embodiment, R¹ is a (Ci-Ce)alkoxy that is methoxy, ethoxy, propanyloxy, or butyloxy, wherein the alkoxy is optionally substituted with 1 substituent selected from the group consisting of hydroxy, and -N(R⁶)(R⁷). In certain embodiments, the alkoxy is propan-2-yloxy. When R¹ is a (Ci-Ce)alkoxy, the alkoxy can be substituted with 1 substituent selected from the group consisting of hydroxy, --N(R⁶)(R⁷), (Ci-Ce)alkyl, and (C₃-Ce)cycloalkyl. In other certain embodiments, R¹ is (Ci-Ce)alkoxy that is optionally substituted to be 2-hydroxyethoxy, or (dimethylamino)ethoxy.

In another embodiment, R¹ is a halo(CrCe)alkoxy selected from the group consisting of fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, and trifluoroethoxy. In certain embodiments, the haloalkoxy is difluoromethoxy. When R¹ is a halo(Cr Ce)alkoxy, the haloalkoxy can be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, cyano, -N(R⁶)(R⁷), (Ci-Ce)alkyl, and (C3-C6)cycloalkyl.

In another embodiment, R¹ is (C3-C6)cycloalkoxy that is cyclopropyloxy.

In certain embodiments, R¹ is a (4- to 6-membered)heterocycloalkyl. When R¹ is a heterocycloalkyl, the heterocycloalkyl may be selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl. In other certain embodiments, R¹ is a heterocycloalkyl that is pyrrolidinyl, morpholinyl, or tetrahydrofuranyl, optionally substitituted as provided herein.

In certain embodiments, R¹ is morpholinyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Cr Ce)alkoxy, and halo(Ci-Ce)alkoxy.

In certain other embodiments, R¹ is pyrrolidinyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkyl, halo(Cr Ce)alkyl, (Ci-Ce)alkoxy, and halo(Ci-Ce)alkoxy.

In certain other embodiments, R¹ is tetrahydrofuranyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkyl, halo(Cr Ce)alkyl, (Ci-Ce)alkoxy, and halo(Ci-Ce)alkoxy.

In certain embodiments, in Formula I, R¹ is a (5- to 6-membered)heteroaryl. When R¹ is a heteroaryl, the heteroaryl may be selected form the group consisting of imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, pyrazinyl, oxazolyl, and thiadiazolyl, each being optionally substituted with 1 to 3 substitutents selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkoxy, and halo(Ci-Ce)alkoxy.

In certain embodiments, R¹ is imidazolyl.

In certain other embodiments, R¹ is a (C3-Ce)cycloalkoxy, wherein said (C3-Ce)cycloalkoxy is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, (Ci-Ce)alkyl, and (Ci-Ce)alkoxy. In other certain embodiments, R¹ is a (C3- C₆)cycloalkyl that is cyclopropyl.

It is to be understood that any of the above-mentioned subgenuses (embodiments) of R¹ can be combined together with any of the subgenuses for R², R^2a, R³, R⁴, R⁵, a, and X as described herein, provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment of Formula I, R² is (4- to 6-membered)heterocycloalkyl), wherein said heterocycloalkyl is azetidinyl or pyrrolidinyl. In another embodiment of Formula I, R^2a is (4- to 6-membered)heterocycloalkyl), wherein said heterocycloalkyl is azetidinyl.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is (CrC3)alkyl, wherein the alkyl is optionally substituted with one hydroxy.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is methyl.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is methyl, wherein the methyl is substituted with hydroxy.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is methyl, wherein the methyl is substituted with tetrahydrofuranyl.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is ethyl.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is ethyl, wherein the ethyl is substituted with methoxy.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is -C(0)NH(CrC₃)alkyl, wherein the -C(0)NH(CrC₃)alkyl is ethylurea.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is -C(0)(Ci-C₃)alkyl, wherein the -C(0)(Ci-C₃)alkyl is acetaldehyde.

In another embodiment, in Formula I, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and one of R⁸ and R⁹ is hydrogen and the other is propyl .wherein the propyl is optionally substituted with hydroxy.

In another embodiment, R² is -(CH₂)_mN(R⁸)(R⁹), wherein m is 1 and R⁸ and R⁹ are both hydrogen.

In another embodiment, R² is S0₂NH₂.

In certain other embodiments, R² is a (4- to 6-membered)heterocycloalkyl and the heterocycloalkyl is azetidine-2-yl or pyrrolidine-2-yl.

It is to be understood that any of the above-mentioned subgenuses (embodiments) of R² can be combined together with any of the subgenuses for R¹, R^2a, R³, R⁴, R⁵, a, and X as described herein, provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment, in Formula I, R^2a is hydrogen.

In another embodiment, R^2a is a (Ci-Ce)alkoxy and the alkoxy is methoxy.

In another embodiment, in Formula I, R^2a is a (4- to 6-membered)heterocycloalkyl and the heterocycloalkyl is azetidinyl. It is to be understood that any of the above-mentioned subgenuses (embodiments) of R^2a can be combined together with any of the subgenuses for R¹ , R², R³, R⁴, R⁵, a, and X as described here, provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment, in Formula I, R³ is hydrogen. It is to be understood that when R³ is hydrogen, said embodiment can be combined together with any of the subgenuses for R¹, R², R⁴, R⁵, a, and X as described here, provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment, in Formula I, R⁴ is a (5- to 6-membered)heteroaryl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halogen, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C3-Ce)cycloalkyl, and (4- to 6- membered)heterocycloalkyl. When R⁴ is a (5- to 6-membered)heteroaryl, the heteroaryl is 1, 2, 3-triazolyl, 1 , 2, 4-triazolyl, imidazolyl, oxazolyl or pyrazolyl. In certain embodiments, the heteroaryl is 1 , 2, 4-triazol-3-yl, optionally substituted at the 4 position with 1 substituent selected from methyl, trifluoromethyl, ethyl, 1-cyclopropylethyl, 1-cyclopropyl-2-hydroxyethyl, 1- cyclopropyl-2,2-difluoroethyl, 2,2-difluorocyclopropylethyl, propyl, butanyl, hydroxybutanyl, 4,4,4- triflourobutan-2-yl, pentanyl, 1 , 1 , 1-trifluoropentan-3-yl, cyclopentyl, or tetrahydrofuran-3-yl.

In certain embodiments, when R⁴ is a (5- to 6-membered)heteroaryl, the heteroaryl is selected from the group consisting of triazolyl, oxazolyl, pyrazolyl, and imidazolyl.

In certain embodiments, R⁴ is triazolyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, hydroxy, (Ci-Ce)alkyl, halo(CrC₆)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, and (C3-C6)cycloalkyl.

In certain embodiments of Formula I, R⁴ is 1,2,4-triazol-3-yl, wherein the triazol-3-yl is substituted at the 4 position with a substituent selected from the group consisting of (Ci-Ce)alkyl, halo(CrC₆)alkyl, -(C3-Ce)cycloalkyl, and (4- to 6-membered)heterocycloalkyl, wherein said (Cr C₆)alkyl and halo(Ci-Ce)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, and (4- to 6-membered)heterocycloalkyl, wherein the (Ci-Ce)alkoxy, and (C3-C6)cycloalkyl are optionally substituted with 1 to 2 halogen.

In another embodiment in Formula I, R⁴ is 1 ,2,4-triazol-3-yl, wherein the triazol-3-yl is substituted at the 4 position with (Ci-Ce)alkyl selected from the group consisting of methyl, ethyl, propyl, propyl, isopropyl, butyl, and tert-butyl.

In another embodiment in Formula I, R⁴ is 1 ,2,4-triazol-3-yl, wherein the triazol-3-yl is substituted at the 4 position with halo(Ci-Ce)alkyl selected from the group consisting of fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, triflourobutanyl, and trifluoropentanyl.

In another embodiment in Formula I, R⁴ is 1 ,2,4-triazol-3-yl, wherein the triazol-3-yl is substituted at the 4 position with -(C3-Ce)cycloalkyl, wherein the (C3-Ce)cycloalkyl is cyclopropyl. In certain embodiments, R⁴ is triazolyl optionally optionally substituted with (Ci-Ce)alkyl, wherein the alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and pentyl.

In another embodiment, R⁴ is a (4- to 6-membered)heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (Ci-Ce)alkyl, halo(CrCe)alkyl, (CrCe)alkoxy, halo(CrCe)alkoxy, and (C3-C6)cycloalkyl. When R⁴ is a (4- to 6-membered)heterocycloalkyl, the heterocycloalkyl may be oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (Ci-Ce)alkyl, halo(CrC₆)alkyl, (CrCe)alkoxy, halo(CrCe)alkoxy, and (C3-Ce)cycloalkyl. In certain embodiments, R⁴ is 2-oxo-1 ,3-oxazolidin-3-yl, optionally substituted at the 4 position with 1 substituent selected from the group consisting of methyl, ethyl, trifluormethyl, and cyclopropyl.

In another embodiment, R⁴ is a phenyl or phenoxy, wherein the phenyl or phenoxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (CrCe)alkoxy, halo(Ci-Ce)alkoxy, and (C3-C6)cycloalkyl.

In certain embodiments R⁴ is phenyl.

In another embodiment, R⁴ is a (C3-Ce)cycloalkyl, a NH-(C3-Ce)cycloalkyl, or a (C3- C₆)cycloalkoxy, wherein the cycloalkyl, NH-cycloalkyl and cycloalkyloxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (CrCe)alkoxy, halo(Ci-Ce)alkoxy, and (C3-Ce)cycloalkyl.

In certain embodiments, R⁴ is a (C3-Ce)cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In certain embodiments, R⁴ is a NH-(C3-C6)cycloalkyl, such as cyclopentylamino.

In certain embodiments, R⁴ is a (C3-Ce)cycloalkoxy, such as cyclopentoxy.

It is to be understood that any of the above-mentioned subgenuses (embodiments) of R⁴ can be combined together with any of the subgenuses for R¹, R², R^2a, R³, R⁵, a, and X as described here, provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment, in Formula I as described herein, X is nitrogen.

In another embodiment, X is carbon, a is 1 , and R⁵ is hydrogen.

It is to be understood that any of the above-mentioned subgenuses (embodiments) of X can be combined together with any of the subgenuses for a, R¹, R², R^2a, R³, R⁴, and R⁵ as described herein, provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-C₆)alkoxy, -N(R⁶)(R⁷), -S0₂CH₃, (C₃-C₆)cycloalkoxy, (4- to 6- membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (Ci-Ce)alkyl, (Cr Ce)alkoxy, halo(Ci-Ce)alkyl, (C₃-Ce)cycloalkyl, (4- to 6-membered)heterocycloalkyl, (5- to 6- membered)heteroaryl, and (C₃-Ce)cycloalkoxy are optionally substituted with 1 substituent selected from the group consisting of hydroxy, cyano, (C₃-Ce)cycloalkyl, and -N(R⁶)(R⁷);

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and (CrC₆)alkyl;

R² is: i) hydrogen; ii) -(CH₂)_mN(R⁸)(R⁹), wherein m is an integer selected from 0, 1, 2, or 3, and R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, (Cr C₆)alkyl, -C(0)(C C₃)alkyl and -C(0)NH(C C₃)alkyl, wherein said (C C₆)alkyl, - C(0)(CrC₃)alkyl and -C(0)NH(CrC₃)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkoxy, cyano, oxo, hydroxy, and (4- to 6-membered)heterocycloalkyl; iii) (Ci-Ce)alkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, and hydroxy; vi) a (4- to 6-membered)heterocycloalkyl; or vii) -SO2NH2;

R^2a is selected from the group consisting of hydrogen, (CrC₃)alkoxy, (4- to 6- membered)heterocycloalkyl;

R³ is hydrogen;

X is carbon;

R⁴ is a (Ci-Ce)alkoxy, -C(O)N(R¹⁰)(R¹¹), aryl, O-aryl, 0-(C₃-C₆)cycloalkyl, a (5- to 6- membered)heterocycloalkyl or a (5-10-membered)heteroaryl, wherein aryl is phenyl, wherein said 0-(C₃-C₆)cycloalkyl, a (5- to 6-membered)heterocycloalkyl, and (5-membered)heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of oxo, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, -(C₃-C₆)cycloalkyl, and (4- to 6- membered)heterocycloalkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy, and (C3-Ce)cycloalkyl; and wherein R¹⁰ and R¹¹ are each independently selected from the group consisting of hydrogen, and (CrCe)alkyl, wherein said (CrCe)alkyl is optionally substituted with (C3-Ce)cycloalkyl, and wherein the 5-memberedheteroaryl is selected from triazolyl, imidazolyl, and oxazolyl;

R⁵ is hydrogen; and a is 1 , provided that at least one of R¹, R², and R^2a is other than hydrogen.

In another embodiment, the present invention is directed to compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, halogen, (Ci-Ce)alkyl, halo(Ci-C₆)alkyl, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, -N(R⁶)(R⁷), -S0₂CH₃, (C₃-

C₆)cycloalkyl, (4- to 6-membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, and (C3-C6)cycloalkoxy, wherein said (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, (C3- C₆)cycloalkyl, (4- to 6-membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, and (C3-C6)cycloalkoxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, (Cr Ce)alkoxy, halo(Ci-Ce)alkyl, halo(Ci-Ce)alkoxy, (C₃-Ce) cycloalkyl, -N(R⁶)(R⁷);

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and (Ci-C₆)alkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkoxy, cyano, and hydroxy;

R^2a is hydrogen;

R² is: i) hydrogen; ii) -(CH2)mN(R⁸)(R⁹), wherein m is an integer selected from 0, 1, 2, or 3, and R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, (Ci- Ce)alkyl, — C(0)(Ci-C₃)alkyi and -C(0)NH(Ci-C₃)alkyl, wherein said (Ci-C₆)alkyl, - C(0)(Ci-C₃)alkyl and -C(0)NH(Ci-C₃)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkoxy, cyano, oxo, hydroxy, and (4- to 6-membered)heterocycloalkyl; iii) (Ci-Ce)alkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkoxy, cyano, and hydroxy; iv) a (4- to 6-membered)heterocycloalkyl; or v) -SO2NH2;

R⁵ is hydrogen; R⁴ is 1,2,4-triazol-3-yl, wherein the triazol-3-yl is substituted at the 4 position with a substituent selected from the group consisting of (Ci-Ce)alkyl, halo(CrCe)alkyl, -(C3- Ce)cycloalkyl, and (4- to 6-membered)heterocycloalkyl, wherein said (CrCe)alkyl and halo(CrC₆)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, cyano, (CrCe)alkoxy, and (C3-Ce)cycloalkyl, wherein the (Cr Ce)alkoxy, and (C3-Ce)cycloalkyl are optionally substituted with 1 to 2 halogen; a is 1; and X is carbon.

In some embodiments, when R⁴ is 1,2,4-triazol-3-yl, the compound of Formula I has the absolute stereochemistry as shown in Formula l-A or l-B:

Formula l-A Formula l-B

or a pharmaceutically acceptable salt thereof, where R¹, R², and R⁵ are defined in any embodiment for Formula I, and

R⁴ is 1,2,4-triazol-3-yl, wherein the triazol-3-yl is substituted at the 4 position with a substituent selected from the group consisting of (Ci-Ce)alkyl, and halo(CrCe)alkyl, wherein said (CrCe)alkyl and halo(CrCe)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, and (4- to 6-membered)heterocycloalkyl, wherein the (Ci-Ce)alkoxy, and (C3-C6)cycloalkyl are optionally substituted with 1 to 2 halogen.

Each of the embodiments described herein with respect to Formula I is also applicable to compounds of Formula l-A and l-B.

R¹ is selected from the group consisting of hydrogen, halogen, (Ci-Ce)alkyl, halo(Ci- C₆)alkyl, (CrC₆)alkoxy, halo(Ci-C₆)alkoxy, -N(R⁶)(R⁷), (C₃-C₆)cycloalkyl, (4- to 6- membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, and (C3-Ce)cycloalkoxy, wherein said (Ci-Ce)alkyl, (CrCe)alkoxy, halo(CrCe)alkyl, (C3-Ce)cycloalkyl, (4- to 6- membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, and (C3-C6)cycloalkoxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, cyano, (C3-Ce)cycloalkyl, -N(R⁶)(R⁷); R⁶ and R⁷ are each independently selected from the group consisting of hydrogen and (Ci-Ce)alkyl, wherein said (CrCe)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, and hydroxy; R^2a is hydrogen;

R² is: i) hydrogen; ii) -(CH2)_mN(R⁸)(R⁹), wherein m is an integer selected from 0, 1, 2, or 3, and R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, (Cr C₆)alkyl, -C(0)(C C₃)alkyl and -C(0)NH(C C₃)alkyl, wherein said (C C₆)alkyl, - C(0)(CrC₃)alkyl and -C(0)NH(CrC₃)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkoxy, cyano, oxo, hydroxy, and (4- to 6-membered)heterocycloalkyl; iii) (Ci-Ce)alkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkoxy, cyano, and hydroxy; iv) a (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkoxy, and halo(CrC₆)alkoxy, wherein said (Ci-Ce)alkyl and halo(Ci-Ce)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, and (Ci-Ce)alkoxy; or v) -SO2NH2;

R⁵ is hydrogen;

R⁴ is 2-oxo-1 ,3-oxazolidin-3-yl, optionally substituted at carbon 4 by one substituent selected from the group consisting of halogen, cyano, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Cr Ce)alkoxy, halo(Ci-Ce)alkoxy, -(C₃-Ce)cycloalkyl, and (4- to 6-membered)heterocycloalkyl, wherein said (Ci-Ce)alkyl and halo(Ci-Ce)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkoxy, and (C₃-C₆)cycloalkyl, wherein the (Ci-Ce)alkoxy, and (C₃-Ce)cycloalkyl are optionally substituted with 1 to two halogen; a is 0; and X is carbon.

In another embodiment in Formula I, wherein R⁴ is 2-oxo-1 ,3-oxazolidin-3-yl, optionally substituted at carbon 4 by (Ci-Ce)alkyl, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, propyl, isopropyl, butyl, and tert-butyl.

In another embodiment in Formula I, wherein R⁴ is 2-oxo-1 ,3-oxazolidin-3-yl, optionally substituted at carbon 4 by halo(Ci-Ce)alkyl, said halo(Ci-Ce)alkyl selected from the group consisting of fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, triflourobutanyl, and trifluoropentanyl.

In another embodiment in Formula I, wherein R⁴ is 2-oxo-1,3-oxazolidin-3-yl, optionally substituted at carbon 4 by -(C3-Ce)cycloalkyl, wherein the (C3-Ce)cycloalkyl is cyclopropyl.

In some embodiments, the compound of Formula I, wherein R⁴ is 2-oxo-1,3-oxazolidin-3- yl, has the absolute stereochemistry as shown in Formula l-C or l-D:

Formula l-C Formula l-D

or a pharmaceutically acceptable salt thereof, where R¹, R², and R⁵, are defined as for any embodiment of Formula I, and the substituent off of R⁴, represented in the diagram as R¹² for simplicity, is any substituent allowed in any embodiment for such optional substitution of R⁴.

Each of the embodiments described herein with respect to Formula I is also applicable to compounds of Formula l-C and l-D.

In another aspect, the invention provides a compound selected from the group consisting of the compounds exemplifiedherein, or a pharmaceutically acceptable salt thereof.

The compounds of the invention are selective against HPK1 kinase.

A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients. In other embodiments, the pharmaceutical composition further comprises at least one additional anticancer therapeutic agent.

In another embodiment the invention provides a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.

In some embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent or a palliative agent. In some such embodiments, the at least one additional agent is an anti-cancer therapeutic agent as described below. In some such embodiments, the combination provides an additive, greater than additive, or synergistic anti-cancer effect. In one embodiment, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent (e.g., an anticancer therapeutic agent), which amounts are together effective in treating said abnormal cell growth.

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. Compounds of the invention may be administered as single agents, or may be administered in combination with other anti-cancer therapeutic agents, in particular standard of care agents appropriate for the particular cancer.

In some embodiments, the methods provided result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; (5) inhibiting angiogenesis; (6) enhancing T-cell responses; (7) enhancing dendritic and B cell responses; (8) heightening of anti tumor activity; (9) enhancing vaccine therapies; and (10) enhancing immune-system mediated removal of pathogens such as viruses, bacteria, worms.

In another aspect, the invention provides a method for the treatment of a disorder mediated by HPK1 kinase activity, in a subject, such as certain cancers, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder.

Unless indicated otherwise, all references herein to the inventive compounds include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.

Compounds of the invention may exist in the form of pharmaceutically acceptable salts such as, e.g., acid addition salts and base addition salts of the compounds of Formula I provided herein. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the parent compound. The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of Formula I disclosed herein.

For example, the compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,

1 , 1 ’-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, g-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode and valerate salts.

Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium.

The compounds of the invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

Those compounds of the invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds herein. These salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

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

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention are known to one of skill in the art.

Salts of the present invention can be prepared according to methods known to those of skill in the art. A pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

It will be understood by those of skill in the art that the compounds of the invention in free base form having a basic functionality may be converted to the acid addition salts by treating with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the invention may be reconverted to the corresponding free base by treating with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a temperature of between about 0° C and 100° C. The free base form may be isolated by conventional means, such as extraction with an organic solvent. In addition, acid addition salts of the compounds of the invention may be interchanged by taking advantage of differential solubilities of the salts, volatilities or acidities of the acids, or by treating with the appropriately loaded ion exchange resin. For example, the interchange may be affected by the reaction of a salt of the compounds of the invention with a slight stoichiometric excess of an acid of a lower pK than the acid component of the starting salt. This conversion is typically carried out at a temperature between about 0°C and the boiling point of the solvent being used as the medium for the procedure. Similar exchanges are possible with base addition salts, typically via the intermediacy of the free base form.

The compounds of the invention may exist in both unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when the solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d₆-acetone, d₆-DMSO.

Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety.

The invention also relates to prodrugs of the compounds of Formula I provided herein. Thus, certain derivatives of compounds of the invention which may have little or no pharmacological activity themselves can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and ‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

Some non-limiting examples of prodrugs in accordance with the invention include:

(i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (CrCs)alkyl;

(ii) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (Ci-C₆)alkanoyloxymethyl, or with a phosphate ether group; and

(iii) where the compound contains a primary or secondary amino functionality (-NH₂ or -NHR where R ¹ H), an amide thereof, for example, replacement of one or both hydrogens with a suitably metabolically labile group, such as an amide, carbamate, urea, phosphonate, sulfonate, etc.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Finally, certain inventive compounds may themselves act as prodrugs of other of the inventive compounds.

Also included within the scope of the invention are metabolites of compounds of Formula I as described herein, i.e. , compounds formed in vivo upon administration of the drug.

The compounds of Formula I provided herein may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line ( - ), a solid wedge (“^^ ), or a dotted wedge ( . ^IMI). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included and the attached stereocenter. For example, unless stated otherwise, it is intended that the compounds of the invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

Compounds of the invention that have chiral centers may exist as stereoisomers, such as racemates, enantiomers, or diastereomers.

Stereoisomers of the compounds of Formula I herein can include cis and trans isomers, optical isomers such as (R) and (S) enantiomers, diastereomers, geometric isomers, rotational isomers, atropisomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).

Also included are acid addition or base addition salts wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

The compounds of the invention may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of the invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula I provided.

In addition, some of the compounds of the invention may form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are unsymmetrical. The interconversion of atropisomers is slow enough to allow separation and isolation under predetermined conditions. The energy barrier to thermal racemization may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or superfluid critical chromatography (SFC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

The enantiomeric purity of compounds described herein may be described in terms of enantiomeric excess (ee), which indicates the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%. Similarly, diastereomeric purity may be described in terms of diasteriomeric excess (de).

The present invention also includes isotopically-labeled compounds, which are identical to those recited in one of Formula I provided, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹ P, ³²P, ³⁵S, ¹⁸F, and ³⁶CI. Certain isotopically-labeled compounds of the invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. , ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-labeled compounds of the invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

Therapeutic Methods and Uses The invention further provides therapeutic methods and uses comprising administering the compounds of the invention, or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutic agents or palliative agents.

In one embodiment, the invention provides a method for the treatment of abnormal cell growth in a subject comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In frequent embodiments, the abnormal cell growth is cancer.

In another embodiment, the invention provides a method for the treatment of cancer in a subject comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional anticancer therapeutic agent, which amounts are together effective in treating said cancer.

Compounds of the invention include compounds of Formula I as described herein, or a pharmaceutically acceptable salt thereof.

In still another embodiment, the invention provides a method of inhibiting cancer cell proliferation in a subject, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a method of inhibiting cancer cell invasiveness in a subject, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a method of causing cell death in cancer cells in a subject, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In still another embodiment, the invention provides a method of enhancing vaccine therapies in a mammal, comprising administering to the mammal a therapeutically effective amount of a vaccine, and further comprising administering to the mammal a therapeutically effective amount of a compound of any of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

In still another embodiment, the invention provides a method of improving the immune system’s ability to clear a viral infection, bacterial infection, or pathogen (including parasitic worms) in a subject, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention provides a method for enhancing immune-system mediated removal of pathogens, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The method includes administering the compound of the invention as monotherapy or in combination with other agents to treat the infection or pathogen.

The presently disclosed compounds find use in inhibiting the activity of the HPK1 kinase. HPK1 , also referred to as mitogen activated protein kinase kinase kinase kinase 1 or MAP4K1 , is a member of the germinal center kinase subfamily of Ste20-related serine/threnonine kinases. HPK1 kinase functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKKI, MLK3 and TAK1 , leading to the activation of the MAPK Jnk.

HPK1 polynucleotides and polypeptides are known in the art (Hu et al. (1996) Genes Dev. 10: 2251-2264, which is herein incorporated by reference in its entirety). HPK1 polypeptides comprise a variety of conserved structural motifs. HPK1 polypeptides comprise an amino-terminal Ste20-like kinase domain that spans amino acid residues 17-293, which includes the ATP - binding site from amino acid residues 23-46. The kinase domain is followed by four pro line-rich (PR) motifs that serve as binding sites for SH3 -containing proteins, such as CrkL, Grb2, HIP-55, Gads, Nek, and Crk. The four PR motifs span amino acid residues 308-407, 394-402, 432-443, and 468-477, respectively. HPK1 becomes phosphorylated and activated in response to TCR or BCR stimulation. TCR- and BCR- induced phosphorylation of the tyrosine at position 381 , located between PR1 and PR2, mediates binding to SLP-76 in T cells or BLNK in B cells via a SLP-76 or BLNK SH2 domain, and is required for activation of the kinase. A citron homology domain found in the C-terminus of HPK1, approximately spanning residues 495-800, may act as a regulatory domain and may be involved in macromolecular interactions.

The presently disclosed compounds bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the presently disclosed compounds reduce, inhibit, or otherwise diminish the HPK1-mediated phosphorylation of SLP76 and/or Gads. The presently disclosed compounds may or may not be a specific HPK1 inhibitor. A specific HPK1 inhibitor reduces the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the inhibitor on any other protein (e.g., other serine/threonine kinases). In certain embodiments, the presently disclosed compounds specifically inhibit the serine/threonine kinase activity of HPK1.

The presently disclosed compounds can be used in a method for inhibiting HPK1. Such methods comprise contacting HPK1 with an effective amount of a presently disclosed compound. The term "contacting" means bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit the activity of HPK1. The compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject.

Any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1 , such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads- 14-3-3 complex from LAT-containing microclusters, or T or B cell activation.

The presently disclosed compounds can be used to treat a HPK1 -dependent disorder. As used herein, a "HPK1-dependent disorder" is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition. The presently disclosed compounds also find use in enhancing an immune response in a subject in need thereof. Such methods comprise administering an effective amount of a presently disclosed compound (i.e., any of the compounds of Formula I, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof). The term "enhancing an immune response" refers to an improvement in any immunogenic response to an antigen. Non-limiting examples of improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells), enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2- or adenosine induced immune suppression, and enhanced priming and/or cytolytic activity of CD8 T cells. In some embodiments, the CD8 T cells in the subject have enhanced priming, activation, proliferation and/or cytolytic activity relative to prior to the administration of the compound of Formula I, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the CD8 T cell priming is characterized by elevated CD44 expression and/or enhanced cytolytic activity in CD8 T cells. In some embodiments, the CD8 T cell activation is characterized by an elevated frequency of IFNy⁺ CD8 T cells. In some embodiments, the CD8 T cell is an antigen-specific T-cell.

In some embodiments, the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of the compound of Formula I, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the antigen presenting cells are dendritic cells. In some embodiments, the maturation of the antigen presenting cells is characterized by an increased frequency of CD83⁺ dendritic cells. In some embodiments, the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.

Engagement of the TCR leads to HPK1 activation, which functions as a negative regulator of TCR-induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signalling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, which leads to the recruitment of 14-3-3 proteins that bind to the phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, which leads to T cell dysfunction, including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol 195(5): 839-853). The term "dysfunction" in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and/or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth. The term "dysfunctional", as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, gamma-IFN) and/or target cell killing.

The term "anergy" refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor {e.g. increase in intracellular Ca in the absence of ras-activation). T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation. The unresponsive state can often be overriden by the presence of lnterleukin-2. Anergic T-cells do not undergo clonal expansion and/or acquire effector functions.

The term "exhaustion" refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signalling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signalling, but from sustained signalling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1 , B7-H3, B7-H4, etc.).

"Enhancing T cell function" means to induce, cause or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells. Examples of enhancing T cell function include: increased secretion of cytokines (e.g., gamma- interferon, IL-2, IL-12, and TNFa), increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B.

Accordingly, the presently disclosed compounds of Formula I, or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof are useful in treating T cell dysfunctional disorders. A "T cell dysfunctional disorder" is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation. In a particular embodiment, a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1. In another embodiment, a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. In a specific aspect, the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell dysfunctional disorders characterized by T- cell dysfunction include unresolved acute infection, chronic infection and tumor immunity.

Thus, the presently disclosed compounds can be used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer. "Immunogenecity" refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response.

"Tumor immunity" refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.

In one aspect, provided herein is a method for treating of cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the subject has melanoma. The melanoma may be at early stage or at late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be at early stage or at late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be at early stage or at late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer may be at early stage or late state. In some embodiments, the subject has a hematological malignancy. The hematological malignancy may be at early stage or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be at early stage or at late stage. In some embodiments, the subject has breast cancer. The breast cancer may be at early stage or at late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be at early stage or at late stage. In some embodiments, the cancer has elevated levels of T-cell infiltration.

In some embodiments, the treatment results in a sustained response in the subject after cessation of the treatment. "Sustained response" refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain the same or smaller as compared to the size at the beginning of the administration phase.

The treatment methods disclosed herein may result in a partial or complete response. As used herein, "complete response" or "CR" refers to disappearance of all target lesions; "partial response" or "PR" refers to at least a 30 percent decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD; and "stable disease" or"SD" refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started. As used herein, "overall response rate" (ORR) refers to the sum of complete response (CR) rate and partial response (PR) rate.

The treatment methods disclosed herein can lead to an increase in progression free survival and overall survival of the subject administered the HPKI antagonist. As used herein, "progression free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease. As used herein, "overall survival" refers to the percentage of subjects in a group who are likely to be alive after a particular duration of time.

In some embodiments of the methods provided herein, the abnormal cell growth is cancer, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer and thyroid cancer. In further embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer.

In some embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer.

In some embodiments, the cancer is ovarian cancer

In other embodiments, the cancer is breast cancer, including, e.g., ER-positive/HR-positive breast cancer, HER2-negative breast cancer; ER-positive/HR-positive breast cancer, HER2- positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

In some embodiments, the compound of the invention is administered as first line therapy. In other embodiments, the compound of the invention is administered as second (or later) line therapy. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with a CDK4/CDK6 inhibitor. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with one or more chemotherapy regimens, e.g., including taxanes or platinum agents. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with HER2 targeted agents, e.g., trastuzumab.

The terms “abnormal cell growth” and “hyperproliferative disorder” are used interchangeably in this application.

“Abnormal cell growth”, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous). Abnormal cell growth includes the abnormal growth of tumors that are resistant to endocrine therapy, HER2 antagonists or CDK4/6 inhibition.

The term “additional anticancer therapeutic agent” as used herein means any one or more therapeutic agent, other than a compound of the invention, that is or can be used in the treatment of cancer, such as agents derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, and immuno- oncology agents (immuno-oncology agents include monoclonal antibodies, bispecific antibodies, cytokines, CAR-t cells).

As used herein “cancer” refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemia, lymphoma and myeloma. Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one.

In some embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer.

Dosage Forms and Regimens

Administration of the compounds of the invention may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

The amount of the compound of the invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.1 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

Formulations and Routes of Administration

As used herein, a "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

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

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.

For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties.

Parenteral Administration

The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres. The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. The disclosures of these references are incorporated herein by reference in their entireties.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1 ,1 ,2-tetrafluoroethane or 1,1,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 mI_ to 100mI_. A typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing a desired mount of the compound of the invention. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

Other Technologies

Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties.

Dosage

The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7000 mg/day, preferably about 0.1 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

Kit-of-Parts

Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus, the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid.

Combination Therapy

As used herein, the term “combination therapy” refers to the administration of a compound of the invention together with an at least one additional pharmaceutical or medicinal agent (e.g., an anti-cancer agent, vaccine, antibacterial agent, antiviral agent, or antiparasitic agent), either sequentially or simultaneously.

As noted above, the compounds of the invention may be used in combination with one or more additional agents, such as anti-cancer agents. The efficacy of the compounds of the invention in certain tumors may be enhanced by combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents, such as PD-1 antagonists and the like.

When a combination therapy is used, the one or more additional agents may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, the additional agent is administered to a mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional agent is administered to the mammal (e.g., a human) after administration of the compound of the invention. In another embodiment, the additional agent is administered to the mammal (e.g., a human) simultaneously with the administration of the compound of the invention.

The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of the invention, as defined above (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (preferably 1 to 3) anti-cancer therapeutic agents.

In particular embodiments, a compound of the invention may be administered in combination with one or more: targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, Kras, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src/Abl, RTK/Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK2, CDK4, CDK4/CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1 , EZH2 or Hsp90, or immunomodulatory agents, such as PD-1 antagonists, PD-L1 antagonists, CTLA-4 antagonists, 0X40 agonists, 4-1 BB agonists, or CD80 agonists.

In other embodiments, a compound of the invention may be administered in combination with a standard of care agent, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole or trastuzumab.

Synthetic Methods

The compounds of Formula I, may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and transformations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art [such as those methods disclosed in standard reference books such as the Compendium of Organic Synthetic Methods, Vol. I-XIII (published by Wiley-lnterscience)]. Preferred methods include, but are not limited to, those described below. During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 ; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wley & Sons, 1999, which are hereby incorporated by reference.

Compounds of Formula I, or their pharmaceutically acceptable salts, can be prepared according to the reaction Schemes discussed herein below. Unless otherwise indicated, the substituents in the Schemes are defined as above.

Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the various symbols, superscripts, and subscripts used in the schemes, methods, and examples are used for convenience of representation and/or to reflect the order in which they are introduced in the schemes, and are not intended to necessarily correspond to the symbols, superscripts, or subscripts in the appended claims. Additionally, one skilled in the art will recognize that in many cases, these compounds will be mixtures and enantiomers that may be separated at various stages of the synthetic schemes using conventional techniques, such as, but not limited to, crystallization, normal-phase chromatography, reversed-phase chromatography, and chiral chromatography, to afford single enantiomers. The schemes are representative of methods useful in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.

Compounds of the invention are prepared according to the exemplary procedures provided herein and modifications thereof known to those of skill in the art.

The following abbreviations are used throughout the Examples: “Ac” means acetyl, “AcO” or “OAc” means acetoxy, “ACN” means acetonitrile, “aq” means aqueous, “atm” means atmosphere(s), “BOC”, “Boc” or “boc” means N-terf-butoxycarbonyl, “Bn” means benzyl, “Bu” means butyl, “nBu” means normal-butyl, “tBu” means tert- butyl, “DBU” means 1,8- diazabicyclo[5.4.0]undec-7-ene, “Cbz” means benzyloxycarbonyl, “DCM” (CH2CI2) means methylene chloride, “de” means diastereomeric excess, “DEA” means diethylamine, “DIPEA” means diisopropyl ethyl amine, “DMA” means A/,/\/-dimethylacetamide, “DME” means 1,2- dimethoxyethane, "DMF" means A/,/\/-dimethyl formamide, “DMSO" means dimethylsulfoxide, “EDTA” means ethylenediaminetetraacetic acid, “ee” means enantiomeric excess, “Et” means ethyl, “EtOAc” means ethyl acetate, “EtOH” means ethanol, “HOAc” or “AcOH” means acetic acid, “i-Pr” _or “ⁱpr” means isopropyl, “I PA” means isopropyl alcohol, “LAH” means lithium aluminum hydride, “LHMDS” means lithium hexamethyldisilazide (lithium bis(trimethylsilyl)amide), “mCPBA” means meta-chloroperoxy-benzoic acid, “Me” means methyl, “MeOH” means methanol, “MS” means mass spectrometry, "MTBE" means methyl tert- butyl ether, “NCS” means N-chlorosuccinimide, “Ph” means phenyl, “TBHP” means tert- butyl hydroperoxide, “TFA” means trifluoroacetic acid, “THF” means tetrahydrofuran, “SFC” means supercritical fluid chromatography, “TLC” means thin layer chromatography, “Rf” means retention factor, means approximately, “rt” means retention time, “h” means hours, “min” means minutes, “equiv” means equivalents, “sat.” means saturated.

A flask was charged with A/'-[(6-bromopyridin-2-yl)carbonyl]-/\/,/\/- dimethylhydrazonoformamide (8.9 g, 32.8 mmol), (S)-butan-2-amine (2.52 g, 34.5 mmol), acetic acid (52 mL) and acetonitrile (200 mL, c = 0.13 M). The solution was heated to 90 °C and stirred at this temperature for 16 h. TLC analysis (EtOAc/MeOH = 10:1 , UV) showed consumption of the starting material with formation of a new product. The reaction mixture was concentrated to dryness. To the residue was added EtOAc (5 mL) and saturated aqueous Na₂C0₃. The layers were separated. The combined organics were washed with brine (2x30 mL), dried over Na₂S0₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (Biotage, S1O2, 0-5% MeOH/EtOAc) to provide Intermediate 1 (5.1 g, 55% yield) as a pale yellow oil. ¹H NMR (400 MHz, CDCh) d 8.33 (s, 1 H), 8.30 (dd, J = 0.75, 7.78 Hz, 1 H), 7.70 (t, J = 7.78 Hz, 1 H), 7.53 (dd, J = 0.75, 8.03 Hz, 1 H), 5.43 (sxt, J = 6.93 Hz, 1 H), 1.77 - 1.97 (m, 2H), 1.56 (d, J = 7.03 Hz, 3H), 0.94 (t, J = 7.40 Hz, 3H). m/z (ESI) for (CnHi₃BrN₄), 282.7 (M+H)⁺

Intermediate 2: 2-bromo-6-{4-[(1 S)-1-cyclopropylethyl]-4/-/-1 ,2,4-triazol-3-yl}pyridine

A flask was charged with A/'-[(6-bromopyridin-2-yl)carbonyl]-/\/,/\/- dimethylhydrazonoformamide (12 g, 44 mmol), (1S)-1-cyclopropylethan-1-amine (4.15 g, 48.7 mmol), acetic acid (30 ml_) and acetonitrile (120 ml_, c = 0.3 M). The solution was heated to 95 °C and stirred at this temperature for 1 h. TLC analysis (EtOAc, UV) showed consumption of the starting material with formation of a new product. The reaction mixture was concentrated to dryness. To the residue was added EtOAc (150 mL) and H2O (150 mL). To the mixture was added solid K₂CO₃ to adjust to pH~8. The layers were separated. The aqueous layer was extracted with EtOAc (3x200 mL). The combined organics were washed with brine, dried over Na₂SC>4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (Biotage, Si0₂, EtOAc) to provide Intermediate 2 (8 g, 62% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-de) d 9.04 (s, 1 H), 8.16 (d, J = 7.7 Hz, 1 H), 7.95 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1 H), 4.61 (dd, J = 6.8, 9.2 Hz, 1 H), 1.54 (d, J = 6.8 Hz, 3H), 1.49 - 1.38 (m, 1 H), 0.73 - 0.60 (m, 1 H), 0.47 - 0.30 (m, 3H). m/z (ESI) for (Ci₂Hi₃BrN₄), 294.9 (M+H)⁺

Intermediate 3: 2-bromo-6-[4-(1-cyclopropylethyl)-4/-/-1 ,2,4-triazol-3-yl]pyridine

A flask was charged with A/'-[(6-bromopyridin-2-yl)carbonyl]-/\/,/\/- dimethylhydrazonoformamide (1 g, 4 mmol), 1-cyclopropylethan-1-amine (345 g, 4.1 mmol), acetic acid (2 mL) and acetonitrile (12 mL, c = 0.3 M). The solution was heated to 95 °C and stirred at this temperature for 18 h. TLC analysis (EtOAc, UV) showed consumption of the starting material with formation of a new product. The reaction mixture was concentrated to dryness. To the residue was added EtOAc (10 mL) and H₂0 (10 mL). To the mixture was added solid Na₂C0₃ to adjust to pH~8. The layers were separated. The aqueous layer was extracted with EtOAc (3x200 mL). The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (Biotage, Si0₂, EtOAc) to provide Intermediate 3 (690 g, 60% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO- cfe) 69.04 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.95 (t, J = 7.9 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1H), 4.61 (dd, J = 6.8, 9.2 Hz, 1 H), 1.54 (d, J = 6.8 Hz, 3H), 1.49 -1.38 (m, 1 H), 0.73 - 0.60 (m, 1 H), 0.47 - 0.30 (m, 3H). m/z (ESI) for (Ci₂Hi₃BrN₄), 294.9 (M+H)⁺

Intermediate 4: 2-bromo-6-[4-(4,4,4-trifluorobutan-2-yl)-4/-/-1 ,2,4-triazol-3-yl]pyridine

A flask was charged with A/'-[(6-bromopyridin-2-yl)carbonyl]-/\/,/\/- dimethylhydrazonoformamide (15 g, 55 mmol), 4,4,4-trifluorobutan-2-amine (9.4 g, 57.5 mmol), acetic acid (40 mL) and acetonitrile (160 mL, c = 0.28 M). The solution was heated to 95 °C and stirred at this temperature for 16 h. TLC analysis (EtOAc, UV) showed consumption of the starting material with formation of a new product. The reaction mixture was concentrated to dryness. To the mixture was added solid K2CO3 to adjust to pH~8. The layers were separated. The aqueous layer was extracted with EtOAc (3x200 ml_). The combined organics were washed with brine, dried over Na₂SC>4, filtered and concentrated to dryness. The residue was purified by preparative HPLC (Phenomenex Synergi Max-RP, 150 x 50 mm, 10 pm particle size, 15-45% gradient of acetonitrile and water (0.1% TFA), 120 mL/min) to provide Intermediate 4 (11 g, 56% yield) as a yellow solid. ¹H NMR (400MHz, CDCh) d 8.37 (s, 1 H), 8.33 (dd, J = 0.8, 7.8 Hz, 1 H), 7.73 (t, J = 7.9 Hz, 1 H), 7.57 (dd, J = 0.8, 7.8 Hz, 1 H), 5.87 (sxt, J = 6.9 Hz, 1 H), 3.01 - 2.83 (m, 1 H), 2.72 - 2.54 (m, 1H), 1.74 (d, J = 7.0 Hz, 3H). m/z (ESI) for (CiiHioBrF₃N₄), 336.8 (M+H)⁺.

Intermediate 5: 2-bromo-6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridine

2-bromo-6-[4-(4,4,4-trifluorobutan-2-yl)-4/-/-1 ,2,4-triazol-3-yl]pyridine was purified by chiral SFC on a Diacel Chiralpak IC column (250 m x 50 mm, 3 pm particle size), which was eluted with 35% EtOH (0.1% NhUOH) in CO2. The first-eluting peak obtained at a flow rate of 200 mL/min gave Intermediate 5 (5.3 g, 28% yield, >99% ee). ¹H NMR (400 MHz, CDCh) d 8.39 (s, 1 H), 8.35 (dd, J = 0.9, 7.8 Hz, 1 H), 7.75 (t, J = 7.9 Hz, 1 H), 7.59 (dd, J = 0.9, 7.9 Hz, 1 H), 5.89 (sxt, J = 6.9 Hz, 1 H), 2.95 (dqd, J = 6.4, 10.6, 15.0 Hz, 1H), 2.66 (dqd, J = 7.2, 10.2, 15.1 Hz, 1 H), 2.06 (s, 1 H), 1.85 - 1.69 (m, 3H). m/z (ESI) for (CiiHioBrF₃N₄), 335.1 (M+H)⁺. [a]²⁰ _D = -33.62 (c = 0.5 g/100 ml_, MeOH).

Intermediate 6: 2-bromo-6-(4-propyl-4/-/-1 ,2,4-triazol-3-yl)pyridine

A flask was charged with A/'-[(6-bromopyridin-2-yl)carbonyl]-/\/,/\/- dimethylhydrazonoformamide (100 mg, 0.37 mmol), propylamine (24 mg, 0.41 mmol), acetic acid (0.3 mL) and acetonitrile (1.2 mL, c = 0.2 M). The solution was heated to 95 °C and stirred at this temperature for 16 h. LCMS analysis showed consumption of the starting material with formation of the product. The reaction mixture was concentrated to dryness. To the residue was dissolved in H2O (20 mL) and extracted with EtOAc (3x20 mL). The combined organics were washed with saturated aqueous NaHCOs (15 mL) and brine (30 mL), dried over anhydrous dried over Na₂S0₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (Biotage, S1O2, EtOAc) to provide Intermediate 6 (80 mg, 81% yield) as a yellow solid. ¹H NMR (400 MHz, CDCh) d 8.33 (d, J = 7.8 Hz, 1 H), 8.21 (s, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.53 (d, J = 7.9 Hz, 1 H), 4.49 (dd, J = 8.1, 6.6 Hz, 2H), 1.89 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). m/z (ESI) for (Ci₀HiiBrN₄), 267.0 (M+H)⁺

Intermediate 7: tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl]methylcarbamate

Step 1: 1,3-dibromo-5-methoxy-2-methylbenzene

To a solution of 3,5-dibromo-4-methylphenol (11.95 g, 44.93 mmol) in acetone (180 ml_, c = 0.25 M) was added K₂CO₃ (12.4 g, 89.9 mmol) and Mel (14.0 g, 98.9 mmol) at 30 °C. The mixture was stirred at 75 °C for 4 h. TLC analysis (PE/EtOAc=6:1) showed consumption of the starting material. The reaction mixture was cooled to 10 °C and quenched with water (30 ml_). EtOAc (100 ml_) was added and the mixture was separated. The aqueous layer was extracted with EtOAc (50 ml_). The combined organics were washed with brine (100 ml_), dried over anhydrous Na₂S0₄, filtered, and concentrated. The residue was purified by flash chromatography (Isco, 120 g S1O2, petroleum ether) to provide 1 ,3-dibromo-5-methoxy-2-methylbenzene (12.3 g, 98% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) d 7.15 - 7.07 (m, 2H), 3.85 - 3.73 (m, 3H), 2.55 - 2.46 (m, 3H).

Step 2: dimethyl 5-methoxy-2-methylbenzene-1,3-dicarboxylate

A mixture of 1,3-dibromo-5-methoxy-2-methylbenzene (7a) (12.3 g, 43.9 mmol), PdCI₂(dppf) (2.01 g, 2.75 mmol) and TEA (13.3 g, 132 mmol) in MeOH (350 ml_, c = 0.13 M) was sealed under an atmosphere of CO (0.8 MPa) and stirred at 100 °C for 40 h. TLC analysis (petroleum ether) indicated consumption of the starting material. The reaction mixture was combined with a parallel reaction conducted with 900 mg 1 ,3-dibromo-5-methoxy-2- methylbenzene. The mixture was filtered. The filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated to dryness to provide a red solid. The residue was purified by flash chromatography (Isco, 120 g S1O2, petroleum ether/EtOAc = 6:1) to provide dimethyl 5-methoxy- 2-methylbenzene-1,3-dicarboxylate (10.5 g, 93% yield) as a colorless oil. ¹H NMR (400 MHz, CDC ) d 7.41 (s, 2H), 3.94 - 3.88 (m, 6H), 3.83 (s, 3H), 2.59 (s, 3H).

Step 3: dimethyl 2-(bromomethyl)-5-methoxybenzene-1 ,3-dicarboxylate

To a stirred solution of dimethyl 5-methoxy-2-methylbenzene-1,3-dicarboxylate (7b) (5.5 g, 23.1 mmol) in CH₃CN (120 ml_, 0.19 M) was added NBS (4.93 g, 27.7mmol) and AIBN (75.8 mg, 0.46 mmol) at 30 °C. The reaction mixture was stirred at 80 °C for 3.5 h. TLC analysis (petroleum ether/EtOAc = 6:1) showed consumption of the starting material. The reaction mixture was quenched with 10% aqueous Na₂S₂C>₃ (30 ml_) and extracted with EtOAc (2x50 ml_). The combined organics were washed with brine (50 ml_), dried over Na₂SC>₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (Isco, 80 g Si0₂, petroleum ether/EtOAc = 6:1) to provide dimethyl 2-(bromomethyl)-5-methoxybenzene-1 ,3-dicarboxylate (6.6 g, 77% yield) as a white solid. ¹H NMR (400 MHz, CDCIs) d 7.52 (s, 2H), 5.35 (s, 2H), 3.98 (s, 6H), 3.89 (s, 3H).

Step 4: methyl 6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindole-4-carboxylate

A solution of dimethyl 2-(bromomethyl)-5-methoxybenzene-1,3-dicarboxylate (7c) (10.5 g, 33.1 mmol) in aqueous NH₄OH (40 ml_, c = 0.83) in sealed flask was heated to 50 °C and stirred for 4 h. LCMS analysis showed consumption of the starting material. The reaction mixture was filtered. The filter cake was washed with H₂0 (100 ml_) and CH₂CI₂ (100 ml_). The filter cake was stirred in MeCN (50 ml_) for 20 min. The suspension was filtered and the filter cake was washed with MeCN (2x10 ml_). The solid was dried to provide methyl 6-methoxy-1-oxo-2,3- dihydro-1/-/-isoindole-4-carboxylate (6.88 g, 94% yield) as a white solid, which was taken on without further purification. ¹HNMR (400 MHz, DMSO-de) d 8.77 (s, 1H), 7.61 (d, J = 2.3 Hz, 1 H), 7.44 (d, J = 2.3 Hz, 1H), 4.51 (s, 2H), 3.89 (d, J = 1.5 Hz, 6H). m/z (ESI) for (CnHnNCU), 221.9 (M+H)⁺.

Step 5: 4-(hydroxymethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one

To a solution of methyl 6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindole-4-carboxylate (7d) (5.01 g, 22.65 mmol) in dry DCM (100 ml_) was added DIBAL-H (1 M in toluene, 90.6 ml_, 90.6 mmol) dropwise at 0-5 °C under N2. After addition, the mixture was stirred at 25 °C for 1 h. TLC analysis (petroleum ether/EtOAc = 1 :2) and LCMS analysis showed consumption of the starting material. The reaction was quenched with 25% aqueous Rochelle salt (500 ml_) and the mixture was stirred at 25 °C for 1 h. Some solids precipitated from the mixture. The suspension was filtered and the filter cake was washed with H2O (200 ml_) and DCM (50 ml_). The filter cake was collected and dried to provide 4-(hydroxymethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one (4.0 g, 91%) as a pink solid. ¹H NMR (400M Hz, DMSO-de) d 8.51 (s, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 7.04 (d, J = 2.3 Hz, 1 H), 5.30 (t, J = 5.6 Hz, 1 H), 4.57 (d, J = 5.5 Hz, 2H), 4.29 (s, 2H). m/z (ESI) for (C10H11NO3), 193.8 (M+H)⁺.

Step 6: tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]methylcarbamate

To a solution of 4-(hydroxymethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one (7e) (4.7 g, 24.3 mmol) in dry DCM (220 ml_, c = 0.11 M) under N₂ was added TEA (12.3 g, 17.1 ml_, 122 mmol) and MsCI (9.75 g, 6.59 ml_, 85.1 mmol) dropwise at 0 °C. The resultant mixture was stirred at 0 °C for 1 h. LCMS analysis showed consumption of the starting material. Then MeNH₂ (2 M in THF, 122 mL, 243 mmol) was added dropwise and the mixture was stirred for 18 h at 25 °C. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The volatiles were removed under reduced pressure. The residue was dissolved in DCM (200 mL, c = 0.12 M). TEA (12.3 g, 17.1 mL, 122 mmol) and B0C2O (15.9 g, 73 mmol) were added. The mixture was stirred at 25 °C for 2 h. LCMS analysis showed formation of the desired product. The mixture was quenched with H₂0 (100 mL) and extracted with DCM (2x100 mL). The combined organics were washed with brine (100 mL), dried over Na2SC>4, filtered, and concentrated. The residue was purified by flash chromatography (Isco, 80 g S1O2, EtOAc/MeOH = 20:1) to provide a yellow solid (4.2 g). To the solid was slurried with MTBE (30 mL) for 10 min. The suspension was filtered and the filter cake was washed with MTBE (2x10 mL). The filter cake was collected and dried to provide the title compound as a yellow solid (2.9 g). The filtrate was concentrated in vacuum to give a yellow solid, which was purified by flash chromatography (Isco, 20 g S1O2, EtOAc/MeOH = 20:1) to provide additional product (640 mg) as a yellow solid. The batches were combined to provide Intermediate 7 (3.54 g, 48% yield) as a yellow solid. ¹H NMR (400 MHz, CDCb) d 7.28 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1 H), 6.53 (br. s, 1H), 4.48 (s, 2H), 4.33 (s, 2H), 3.90 - 3.84 (m, 3H), 2.80 (br. s, 3H), 1.49 (br. s, 9H). m/z (ESI) for (C16H22N2O4), 307.2 (M+H)⁺. Examples

General Methods

Unless stated otherwise, the variables in Schemes have the same meanings as defined herein. For ease of reference, R¹² has been used when discussing substituents off of R⁴. The amines mentioned herein may constitute protected amines that are deprotected under standard conditions known in the art.

Method A

Formula I

Referring to Method A, where R^2a and R³ are each hydrogen, in a first step a dibromination of the compound of formula A-1 provides the compound of formula A-2. During this step, the R¹ substituent should be represented by the same moiety as is desired in the final product, Formula I, or a protected variation thereof. In a next step, the compound of formula A-2 undergoes carbonylation to form the compound of formula A-3. The compound of formula A-3 then undergoes radical bromination with /V-bromosuccinimide to provide the bromide of formula A-4. In a next step, reaction of the compound of formula A-4 with ammonia yields the compound of formula A-5. Reduction of the ester of formula A-5 with DIBAL provides the alcohol of formula A- 6. Next, activation of the alcohol functionality of formula A-6, as a mesylate (A-7, Y= OSO₂CH₃) followed by either: i) azidation (A-7, Y= N₃) and reduction of the azide functionality under standard conditions to provide primary amines (formula A-7, Y= NH₂); or ii) direct displacement of the mesylate (formula A-7, Y= OSO₂CH₃) with an amine to yield a compound of formula A-7 (Y= N(R⁸)(R⁹)).

Protection of the amino functionality as the corresponding tert- butyl carbamate, formula A-7 (Y= N(R⁸)Boc) is followed by coupling with the compound of formula A-8 under palladium or copper catalysis to provide protected lactams of Formula I (R²=CH2N(R⁸)Boc). During this step, the R⁴ and R⁵ substituents of formula A-8 should be represented by the same moiety as is desired in the final product, Formula I, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields lactams of Formula I.

Method B

Referring to Method B, where R^2a and R³ are each hydrogen, in a first step an alkylation of the compound of formula B-1 provides the compound of formula B-2. During this step, the R¹³ substituent should be represented by the same moiety as is desired in the final product, Formula B-9. R¹³ is being used for convenience for the R¹ substituents that are attached to the phenyl moiety via oxygen. In a next step, the compound of formula B-2 undergoes carbonylation to form the compound of formula B-3. The compound of formula B-3 then undergoes radical bromination with /V-bromosuccinimide to provide the bromide of formula B-4. In a next step, reaction of the compound of formula B-4 with ammonia yields the compound of formula B-5. Reduction of B-5 with DIBAL provides the alcohol of formula B-6. Next, activation of the alcohol functionality of formula B-6, affords mesylate (B-7, Y= OSO₂CH₃) followed by either: i) azidation (B-7, Y= N₃) and reduction of the azide functionality under standard conditions to provide primary amines (formula B-7, Y= NH₂); or ii) direct displacement of the mesylate (formula B-7, Y= OSO₂CH₃) with an amine to yield a compound of formula B-7 (Y= N(R⁸)(R⁹). Protection of the amino functionality as the corresponding tert- butyl carbamate, formula

B-7 (Y= N(R⁸)Boc), is followed by coupling with the bromopyridine of formula B-8 under palladium or copper catalysis to provide protected lactams of Formula B-9. During this step, the R¹² substituent of formula B-8 should be represented by the same moiety as is desired in the final product, Formula B-9, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields lactams Formula B-9, where R⁴ is triazole.

B-10 B-11 B-12 B-8

Preparation of the compound of formula B-8 can be accomplished by hydrazinolysis of the bromopyridine ester of formula B-10 (J. Med. Chem., 60(2), 722-748; 2017) to form the compound of formula B-11. Next, reaction of the hydrazide of formula B-11 with dimethylformamide dimethyl acetal provides the compound of formula B-12. Condensation of the compound of formula B-12 with an amine (e.g., R¹²-NH₂) gives the triazole of formula B-8. During this step, the R¹² substituent of the amine should be represented by the same moiety as is desired in the final product, Formula B-9, or a protected variation thereof.

Method C

Referring to Method C, where R^2a and R³ are each hydrogen, in a first step palladium- mediated coupling of the compound of formula C-1 (e.g., W = Br) with the compound of formula C-2 provides the compound of the formula C-3. During this step, the R¹² substituent should be represented by the same moiety as is desired in the final product, Formula C-4, or a protected variation thereof. From the compound of formula C-3, coupling with the lactam of formula A-7 (Y=N(R⁸)Boc) under palladium or copper catalysis provides lactams of Formula C-4 (R²=CH₂N(R⁸)BOC). During this step, the R¹ substituent should be represented by the same moiety as is desired in the final product, Formula C-4, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields lactams of the Formula C- 4.

Method D

Referring to Method D, where R^2a and R³ are each hydrogen, in a first step, hydrazinolysis of the compound of formula C-1 (e.g. W = F) yields a compound of formula D-1. In a next step diazotization of the hydrazine of formula D-1 yields the azide of formula D-2. Next, cycloaddition of the azide of formula D-2 with an alkyne provides the 1,2,3-triazole of the formula D-3. During this step, the R¹² substituent of the alkyne should be represented by the same moiety as is desired in the final product, Formula D-4, or a protected variation thereof. In a next step, coupling of the compound of formula D-3 with a lactam of the formula A-7 under palladium or copper catalysis provides a lactam of Formula D-4. In this step, Y=N(R⁸)Boc and the R¹ substituent of formula A- 7 should be represented by the same moiety as is desired in the final product, Formula D-4, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula D-4.

Method E

Referring to Method E, where R^2a and R³ are each hydrogen, in a first step, protection of the compound of formula E-1 (e.g. 4-bromo-5-isopropyl-1/-/-pyrazole) with a tetrahydropyranyl (THP) group yields the pyrazole of formula E-2. During this step, the R¹² substituent of formula E-2 should be represented by the same moiety as is desired in the final product, Formula E-4, or a protected variation thereof. Next the compound of the formula of E-2 is coupled with a compound of formula C-1 (e.g., 2,6-dibrompyridine where W = Br) to give the bromopyridine of formula E-3. In a next step, coupling of the compound of formula E-3 with the lactam of the formula A-7 under palladium or copper catalysis provides the lactam of the Formula E-4. In this step, Y= N(R⁸)Boc and the R¹ substituent of A-7 should be represented by the same moiety as is desired in the final product, Formula E-4, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula E-4.

Method F

Referring to Method F, where R^2a and R³ are each hydrogen, in a first step, reaction of pyridine of formula C-1 (e.g. W = I) and amide of the formula F-1 provides the compound of formula F-2. During this step, the R¹² substituent of formula F-1 should be represented by the same moiety as is desired in the final product, Formula F-4, or a protected variation thereof. Next the compound of the formula of F-2 is cyclized with hydroxylamine hydrochloride to give the bromopyridine of formula F-3. In a next step, coupling of the compound of formula F-3 with the compound of formula A-7 under palladium or copper catalysis provides the lactam of the Formula F-4. In this step, Y= N(R⁸)Boc and the R¹ substituent of A-7 should be represented by the same moiety as is desired in the final product, Formula F-4, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields lactams of Formula F-4.

Method G

Referring to Method G, where R^2a and R³ are each hydrogen, in a first step, reaction of compound of thr bromopyridine of formula C-1 (e.g., where W = Br or F) is reacted with the requisite amine or alcohol to provide the compound of the formula G-1 where the R⁴ substituent is as represented in Formula G-2 or a protected version thereof. In a next step, coupling of the bromopyridine of formula G-1 with the lactam of formula A-7 under palladium or copper catalysis provides the lactam of the Formula G-2. In this step, Y= N(R⁸)Boc and the R¹ substituent of A-7 should be represented by the same moiety as is desired in the final product, Formula G-2, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula G-2.

Method H

Method H provides an alternative route to compounds of Formula G-2. Referring to

Method H, in a first step, coupling of the compound of formula C-1 (e.g. W = Cl) with the compound of formula A-7 under palladium or copper catalysis provides the protected lactams of the formula H-1. In this step, Y= N(R⁸)Boc and the R¹ substituent of formula A-7 should be represented by the same moiety as is desired in the final product, Formula G-2, or a protected variation thereof. Nickel-mediated cross coupling of the compound of the formula H-1 with the required alkyl bromide provides the compound of Formula G-2. Next, cleavage of any protecting group(s) under standard conditions yields lactams of Formula G-2.

I-2 I -3 I -4 Referring to Method I, where R^2a and R³ are each hydrogen, in a first step, coupling of the pyridine of the formula B-9 with the compound of formula A-7 under palladium or copper catalysis provides the lactam of the formula 1-1. In this step, Y= N(R⁸)Boc and the R¹ substituent of A-7 should be represented by the same moiety as is desired in the final product, Formula I-4, or a protected variation thereof. Saponification of the ester of formula 1-1 provides the acid of the formula I-2. Reaction of the acid of formula I-2 with an amine of the formula I-3 furnishes the compound of Formula I-4. During this step, the R¹⁰and R¹¹ substituents of formula I-3 should be represented by the same moiety as is desired in the final product, Formula I-4, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields lactams of Formula I-4. Method J

Referring to Method J, where R^2a and R³ are each hydrogen, in a first step, coupling of the compound of formula C-1 (e.g., W = Br) with the compound of formula A-7 under palladium or copper catalysis provides the lactam of the formula J-1. In this step, Y= N(R⁸)Boc and the R¹ substituent of A-7 should be represented by the same moiety as is desired in the final product, the compound of the Formula J-4, or a protected variation thereof. Palladium-mediated coupling of the compound of the formula J-1 with oxazolidinone of the formula J-2 provides the compound of Formula J-4 where the R¹² substituents should be represented by the same moiety as is desired in the final product, Formula J-4, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields lactams of Formula J-4.

Where not commercially available, the compound of formula J-2 can be prepared via ring closure of amino alcohol J-3 with a reagent such as 1, Y-carbonyldiimidazole.

Method K

Referring to Method K, where R^2a and R³ are each hydrogen, in a first step, acylation of the ketone of the formula K-1 provides the compound of the formula K-2 where the R¹² substituent should be represented by the same moiety as is desired in the final product, Formula K-7, or a protected variation thereof. Cyclization of K-2 with hydrazine yields the compound of formula K- 3 which is followed by bromination with /V-bromosuccinirnde and provides the compound of formula K-4. Protection of the pyrazole of formula K-4, with a tetrahydropyranyl (THP) group yields the pyrazole of formula K-5 (U = Br). The compound of formula K-5 can then be converted to the pinacolatoboronic ester K-5 (U = pinacolatoboron [Bpin]). Next the boronic ester of the formula of K-5 is coupled with a compound of formula C-1 (e.g., W = I) to give the bromopyridine of formula K-6. In a next step, coupling of the formula K-6 with the compound of formula B-7 under palladium or copper catalysis provides the lactam of the Formula K-7. In this step, Y= N(R⁸)Boc and the R¹ substituent of A-7 should be represented by the same moiety as is desired in the final product, Formula K-7, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula K-7.

Method L

Referring to Method L, where R^2a and R³ are each hydrogen, in a first step, iodination of the pyrimidine of formula K-1 ( Org . Lett. 2008, 10(72), 2497) provides the compound of formula L-2. Next the compound of the formula of L-2 is coupled with a compound of formula B-7 to give the bromopyrimidine of formula L-3. In this step, Y= N(R⁸)Boc, and the R¹³ substituent of B-7 should be represented by the same moiety as is desired in the final product, Formula L-4, or a protected variation thereof, for the appropriate R¹ of Formula I. In a next step, coupling of the formula L-3 with the compound of formula K-6 under palladium or copper catalysis to provide the protected lactams of the Formula L-4, where U=pinacolatoboron [Bpin], and the R¹² substituent of K-5 should be represented by the same moiety as is desired in the final product, Formula L- 4, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula L-4. Method M

Referring to Method M, where R^2a and R³ are each hydrogen, in a first step, the compound of the formula of M-1 is protected to provide the carbamate of formula M-2. The compound of formula M-2 undergoes borylation to provide the boronic ester of formula M-3. The compound of formula M-3 can be converted to the corresponding phenol (R¹ = OH) and then alkylated with subsequent cleavage of the carbamate protecting group to provide the compound of the formula M-4 (R¹ = OR¹³, where R¹³ should be represented by the same moiety as is desired in the final product, Formula M-5, or a protected variation thereof for the appropriate R¹ of Formula I). Palladium or copper-mediated coupling of the lactam of formula M-4 to bromopyridine B-8 (R¹² should be represented by the same moiety as is desired in the final product, Formula M-5, or a protected variation thereof) yields the compound of Formula M-5 (R² = Br). Palladium-mediated coupling with K₂S₂O₅ and subsequent conversion of the product to the sulfonamide provides the lactam of Formula M-5 (R² = SO₂NH₂).

Method N

Referring to Method N, where R^2a and R³ are each hydrogen, in a first step, the compound of the formula of N-1 is coupled with the compound of the formula B-8 to provide the compound of formula N-2. In this step, the R¹ substituent of N-1 and the R¹² substituent of B-8 should be represented by the same moiety as is desired in the final product, Formula N-3, or a protected variation thereof. Next, the compound of formula N-2 undergoes either: i. Suzuki cross-coupling with a vinyl boronic ester and subsequent reduction of the resulting alkene to provide Formula N-3 (R² = CH(CH₂)CH₂N(R⁸)Boc). Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula N-3, or ii. Palladium-mediated alpha-arylation of a ketone (e.g. acetone) and subsequent reduction to provide Formula N-3 (R² =CH₂CH(OH)CH₃), or iii. Palladium-mediated alpha-arylation of a ketone (e.g. acetone) and subsequent reductive amination to provide Formula N-3 (R² =CH₂CH(NH2)CH₃), or iv. Suzuki cross-coupling with a vinyl boronic ester to and subsequent iron-mediated reaction with sodium azide to form the corresponding tertiary azide followed by reduction to provide Formula N-3 (R² = C(CH₃)₂NH₂), or v. Palladium-mediated coupling with K₂S₂0s and subsequent conversion of the product to the sulfonamide to provide Formula N-3 (R² = S0₂NH₂).

Method O

Referring to Method O, where R¹ and R³ are each hydrogen, in a first step, the compound of the formula of 0-1 is converted to the corresponding methyl ester of the formula 0-2. Dibromination of the compound of formula 0-2 provides the compound of formula 0-3. Reaction of 0-3 with ammonia yields the compound of formula 0-4. Palladium or copper-mediated coupling of 0-4 to bromopyridine B-8 (R¹² should be represented by the same moiety as is desired in the final product, Formula R-5, or a protected variation thereof) yields the compound of Formula O- 5.

Method P

Referring to Method P, where R^2a and R³ are each hydrogen, in a first step, the compound of the formula of M-1 undergoes carbonylation, reduction to the aldehyde and subsequent reductive amination and protection as the corresponding carbamate to provide the compound of the formula P-1 (Y = N(R⁸)Boc). Iridium-mediated borylation of the compound of formula P-1 provides the compound of formula P-2 (R¹ = pinacolatoboron [Bpin]), which can then be either: i. Converted to the corresponding halogen to provide the compound of formula P-2 where (R¹ is halogen), or ii. Converted to the corresponding amine to provide the of the formula P-2 (R¹ = N(R⁷)R⁸), or iii. Converted to the bromide (R¹ = Br) of the formula P-2, then under copper- mediated conditions transformed to the sulfone of formula P-2 (R¹ is SC>₂Me), or iv. Converted to the bromide (R¹ = Br), then under copper-mediated conditions transformed to the imidazole of formula P-2 (R¹ is imidazole), or v. Converted to the triflate (R¹ = OSO₂CF₃), then under palladium-mediated conditions coupled with a vinyl boronic acid and then reduced to provide formula P-2 (R¹ is CH(CH₃) ), or vi. Converted to the ester (R¹ = CO₂CH₃), then reduced to the corresponding alcohol (R¹ = CH₂OH), converted to the triflate (R¹ = CH₂OSO₂CF₃) and then displaced by cyanide to provide the compound of formula P-2 (R¹ is CH₂CN), or vii. Converted to the ester (R¹ = CO₂CH₃), then reduced to the corresponding alcohol (R¹ = CH₂OH) and alkylated to provide the corresponding ether to provide the compound of formula P-2 (R¹ = CH20-alkyl as allowed in Formula I).

Palladium or copper-mediated coupling of the lactam of the formula P-2 to the bromopyridine of formula B-8 (R¹² should be represented by the same moiety as is desired in the final product, Formula P-3, or a protected variation thereof) yields the compound of Formula P- 3. Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula P-3.

Method Q

P-2 B-8 P-3

Referring to Method Q, where R^2a and R³ are each hydrogen, in a first step, the compound of the formula of P-2 (R¹ = Br) undergoes palladium or copper-mediated coupling to the bromopyridine of formula B-8 (R¹² should be represented by the same moiety as is desired in the final product, Formula P-3, or a protected variation thereof) to yield the compound of Formula P-3 (R¹ = Br). From the compound of Formula P-3, either: i. Stille cross coupling with a tin reagent (e.g. tributyl(l-ethoxyvinyl)tin) and subsequent hydrolysis of the resulting vinyl ether provides the compound of Formula P-3 (R¹ = C(0)CH3). Reduction of ketone of Formula P-3 yields the compound of Formula P-3 (R¹ = CH(OH)CH₃), or ii. Nickel-mediated reductive cross coupling with the requisite alkyl bromide provides the compound of Formula P-3 (R¹ = alkyl or cycloalkyl).

In a final step, cleavage of any protecting group(s) under standard conditions provides the compound of Formula P-3.

Method R

Referring to Method R, where R^2a and R³ are each hydrogen, in a first step silyl protection of the compound of formula B-1 provides the compound of formula B-2 (R¹³ = silyl protecting group, e.g. triisopropylsilyl). In a next step, the compound of formula B-2 undergoes carbonylation to form the compound of formula B-3. The compound of formula B-3 then undergoes radical bromination with /V-bromosuccinimide to provide the bromide of formula B-4. In a next step, reaction of the compound of formula B-4 with ammonia yields the compound of formula B-5. Reduction of B-5 with DIBAL provides the alcohol of formula B-6. Next, activation of the alcohol functionality of formula B-6, as a mesylate (B-7, Y= OSO₂CH₃) followed by either: i) azidation (B-7, Y= N₃) and reduction of the azide functionality under standard conditions to provide primary amines of the formula B-7 (Y= NH2), or ii) direct displacement of the mesylate with primary amines to give the corresponding secondary amines (Y= N(R⁸)(R⁹)) to yield a compound of formula B-7.

Protection of the amino functionality as the corresponding tert- butyl carbamate, formula B-7 (Y= N(R⁸)Boc) is followed by cleavage of the silyl protecting group (R¹³ = H) and subsequent alkylation to provide the compound of formula B-7, where the R¹³ substituent should be represented as defined in the final product R-1 or a protected version thereof. Coupling with the bromo pyridine of formula B-8 under palladium or copper catalysis provides the lactam of Formula R-1 (R²=CH₂N(R⁸)Boc). During this step, the R¹² substituent of formula B-8 should be represented by the same moiety as is desired in the final product, Formula R-1, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions yields the lactam of Formula R-1. Method S

Method S is an alternative route to compounds of Formula P-3. In a first step, the compound of the formula S-1 undergoes coupling with the bromopyridine of formula B-8 under palladium or copper catalysis to provide the lactam of the formula S-2 (Y = OH). During this step, the R¹ substituent of formula S-1 and the R¹² substituent of formula B-8 should be represented by the same moiety as is desired in the final product, Formula P-3, or a protected variation thereof. Activation of the alcohol of the formula S-2 as the mesylate (Y= OSO2CH₃) and displacement by an amine yields the lactam of Formula P-3 (R²=CH2N(R⁸)(R⁹)). Method T

Referring to Method T, where R¹, R^2a, and R³ are each hydrogen, in a first step, the compound of the formula P-1 (Y = OSO2CH₃) undergoes displacement of the mesylate with cyanide followed by reduction and protection of the resulting amine to provide the compound of formula P-1 (Y = CH2NHB0C). The compound of formula P-1 undergoes coupling with the bromopyridine of formula B-8 under palladium or copper catalysis to provide the lactam of Formula T-1. During this step, the R¹² substituent of formula B-8 should be represented by the same moiety as is desired in the final product, Formula T-1, or a protected variation thereof. Next, cleavage of any protecting group(s) under standard conditions and conversion of the resulting amine to the corresponding urea via reaction with an isocyanate to provide the lactam of Formula T-1. Method U

Method U is an alternative route to Formula T-1. In a first step, the compound of the formula of M-1 undergoes palladium-mediated coupling with the bromopyridine of formula B-8 under to palladium or copper catalysis to provide the lactam of the formula U-1. During this step, the R¹² substituent of formula B-8 should be represented by the same moiety as is desired in the final product, Formula T-1, or a protected variation thereof. Palladium-mediated coupling of the compound of formula U-1 with zinc cyanide and subsequent reduction provides the compound of formula U-2. The compound of formula U-2 can be either: i. Protected as the corresponding carbamate and alkylated under basic conditions followed by protecting group cleavage to yield the compound of Formula T-1. ii. Acylated with the requisite acid chloride to provide the compound of Formula T- 1.

Method V

Referring to Method V, where R¹, R^2a, R², and R³ are each hydrogen, in a first step, the compound of the formula of V-1 undergoes palladium-mediated coupling with the bromopyridine of formula B-8 to provide the lactam of the Formula V-2. During this step, the R¹² substituent of formula B-8 should be represented by the same moiety as is desired in the final product, Formula V-2, or a protected variation thereof. Method W

Method W provides an alternative route to compounds of Formula R-1. In a first step, the compound of the formula of B-6 undergoes palladium-mediated coupling with the bromopyridine of formula B-8 to provide the lactam of the Formula R-1. During this step, the R¹³ substituent of formula B-6 and the R¹² substituent of formula B-8 should be represented by the same moiety as is desired in the final product, Formula R-1, or a protected variation thereof.

Representative Examples

Example 1 : 2-(6-{4-[(2S)-butan-2-yl]-4H-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6-methoxy-4- [(methylamino)methyl]-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1 : tert- butyl {[2-(6-{4-[(2S)-butan-2-yl]-4H-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6-methoxy-1-oxo- 2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate

A mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl]methylcarbamate (486 mg, 1.73 mmol), 2-bromo-6-{4-[(2S)-butan-2-yl]-4/-/-1,2,4- triazol-3-yl}pyridine (530 mg, 1.73 mmol), K₃PO₄ (1.10 g, 5.19 mmol), Pd2(dba)3 (158 mg, 0.173 mmol) and Xantphos (200 mg, 0.346 mmol) in dry 1,4-dioxane (20 ml_, c = 0.087 M) was stirred at 85 °C under N2 for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was filtered through Celite^®. The filter cake was washed with 10% MeOH/DCM (5x10 ml_). The combined filtrate was concentrated to provide a yellow gum. The residue was purified by flash chromatography (Isco, 40 g S1O2, EtOAc/MeOH = 20:1) to provide the title compound (700 mg, 80% yield) as a yellow solid. ¹H NMR (400 MHz, CDCIs) d 8.71 (dd, J = 1.0, 8.3 Hz, 1 H), 8.35 (s, 1 H), 8.01 (br. d, J = 7.5 Hz, 1 H), 7.97 - 7.89 (m, 1 H), 7.35 (d, J = 2.3 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 5.42 (br. s, 1 H), 5.08 - 4.89 (m, 2H), 4.64 - 4.37 (m, 2H), 3.90 (s, 3H), 2.87 (br. s, 3H), 2.00 - 1.87 (m, 2H), 1.63 (br. s, 3H), 1.42 (s, 9H), 0.90 (t, J = 7.4 Hz, 3H). m/z (ESI) for (C27H34N6O4), 507.3 (M+H)⁺.

Step 2: 2-(6-{4-[(2S)-butan-2-yl]-4/-/-1,2,4-triazol-3-yl}pyridin-2-yl)-6-methoxy-4- [(methylamino)methyl]-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

To a stirred solution of te/f-butyl {[2-(6-{4-[(2S)-butan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2- yl)-6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (940 mg, 1.86 mmol) in DCM (10 ml_) was added HCI (4.0 M in EtOAc, 20 ml_) at 0 °C. The reaction was stirred at 25 °C for 2 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The suspension was filtered. The filter cake was collected, dissolved in H2O (30 ml_) and lyophilized for 18 h to provide Example 1 (822 mg, 100% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-de) d 9.93 - 9.72 (m, 2H), 9.41 (s, 1 H), 8.69 (d, J = 8.3 Hz, 1 H), 8.15 (t, J = 8.1 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1 H), 5.48 - 5.33 (m, 3H), 4.16 (br. t, J = 5.9 Hz, 2H), 3.91 (s, 3H), 2.60 (t, J = 5.3 Hz, 3H), 2.00 (quin, J = 7.3 Hz, 2H), 1.62 (d, J = 6.6 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H). m/z (ESI) for (C22H26N6O2), 429.2 (M+H)⁺.

Example 2: 6-methoxy-4-[(methylamino)methyl]-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4- triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1 : tert- butyl {[6-methoxy-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3- yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate

A mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl]methylcarbamate (200 mg, 0.653 mmol), 2-bromo-6-[4-(4,4,4-trifluorobutan-2-yl)-4/-/- 1,2,4-triazol-3-yl]pyridine (219 mg, 0.653 mmol), K₃PO₄ (416 mg, 1.96 mmol), Pd₂(dba)₃ (59.8 mg, 0.0653 mmol) and Xantphos (75.5 mg, 0.131 mmol) in dry 1 ,4-dioxane (8 ml_, c = 0.08 M) was degassed with N2. The reaction mixture was heated to 85 °C under N2 and stirred at the same temperature for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction mixture was filtered through Celite^®. The filter cake was washed with 10% MeOH/DCM (3x10 ml_). The combined filtrate was concentrated to provide a yellow gum. The residue was purified by flash chromatography (Isco, 12 g S1O2, petroleum ether/EtOAc = 1 :2) to provide the racemic mixture of the title compound (270 mg, 74% yield) as a yellow solid. The racemic mixture was purified by preparative chiral SFC on a Diacel Chiralcel OD column (250 mm x 50 mm, 5 pm particle size), which was eluted with 30% EtOH (0.1% NH4OH) in CO2. A flow rate of 60 mL/min to provided the title compound (120 mg, 44% yield, >99% ee) as the first eluting peak m/z (ESI) for (C27H31N6O4), 583.2 (M+Na)⁺. [a]²⁰ _D = - 47.29 (c = 0.187 g/100 ml_, MeOH).

Step 2: 6-methoxy-4-[(methylamino)methyl]-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4- triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

To a stirred solution of te/f-butyl {[6-methoxy-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]- 4/-/-1,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (120 mg, 0.214 mmol) in DCM (5 ml_, c = 0.02 M) was added HCI (4.0 M in EtOAc, 5 ml_) at at 0 °C. The reaction was stirred at 25 °C for 3 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction mixture was concentrated to a white solid. The residue was dissolved in H₂0 (30 mL) and lyophilized for 2 d to provide Example 2 (105 mg, 99% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-de) d 9.74 - 9.54 (m, 1H), 9.17 (s, 1 H), 8.66 (d, J = 8.4 Hz, 1 H), 8.13 (t, J = 8.0 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1 H), 7.42 (d, J = 2.2 Hz, 1 H), 6.01 (br. s, 1H), 5.42 - 5.30 (m, 2H), 4.16 (br. s, 2H), 3.91 (s, 3H), 3.32 - 3.03 (m, 2H), 2.62 (br. t, J = 5.1 Hz, 3H), 1.71 (br. d, J = 6.5 Hz, 3H). m/z (ESI) for (C22H23N6O2), 483.3 (M+Na)⁺. [a]²⁰ _D = -9.01 (c = 0.17 g/100 mL, MeOH).

Example 3: 2-(6-{4-[(^)-1-cyclopropylethyl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6-methoxy-4-

[(methylamino)methyl]-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1 : tert- butyl {[2-(6-{4-[(^)-1-cyclopropylethyl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6-methoxy- 1-oxo-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate

A mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl] ethylcarba ate (690 g, 2.35 mmol), 2-bromo-6-[4-(1-cyclopropylethyl)-4/-/-1,2,4- triazol-3-yl]pyridine (721 mg, 2.35 mmol), K3PO4 (1.5 g, 7.06 mmol), Pd₂(dba)₃ (216 mg, 0.235 mmol) and Xantphos (272 mg, 0.471 mmol) in dry 1,4-dioxane (20 ml_, c = 0.12 M) was degassed with N₂. The reaction mixture was heated to 85 °C under N₂ and stirred at the same temperature for 16 h. To the mixture was added H₂0 (50 ml_) and the mixture was extracted with EtOAc (3x30 ml_). The combined organics were washed with brine (50 ml_), dried over Na₂SC>₄, filtered, and concentrated to a yellow solid. The residue was taken up in DCM (2 ml_) and petroleum ether (10 ml_). After stirring a precipitate formed. The mixture was filtered. The filter cake was collected and dried to provide the racemic mixture of the title compound (800 mg, 66% yield) as a yellow solid. The racemic mixture was purified by preparative chiral SFC on a Diacel Chiralpak AS-H column (250 mm x 30 mm, 5 pm particle size), which was eluted with 35% EtOH (0.1% NH4OH) in C0₂. A flow rate of 50 mL/min gave the title compound (300 mg, 38% yield, >99% ee) as the second eluting peak m/z (ESI) for (C^h^NeCU), 540.9 (M+Na)⁺. [a]²⁰ _D = -23.85 (c = 0.170 g/100 ml_, MeOH).

Step 2: 2-(6-{4-[(^)-1-cyclopropylethyl]-4/-/-1,2,4-triazol-3-yl}pyridin-2-yl)-6-methoxy-4-

[(methylamino)methyl]-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

To a stirred solution of tert- butyl {[2-(6-{4-[(1S)-1-cyclopropylethyl]-4/-/-1,2,4-triazol-3- yl}pyridin-2-yl)-6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (300 mg, 0.578 mmol) in DCM (3 ml_, c = 0.06 M) was added HCI (4.0 M in EtOAc, 6 ml_) at at 0 °C. The reaction was stirred at 25 °C for 2 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The suspension was filtered and the filter cake was dried under vacuum to provide Example 3 (261.4 mg, 99% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de + D₂0) d 9.27 (s, 1 H), 8.62 (d, J = 8.3 Hz, 1H), 8.10 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H), 5.13 (s, 2H), 4.75 (br. dd, J = 6.8, 9.0 Hz, 1H), 4.16 (s, 2H), 3.87 (s, 3H), 2.67 (s, 3H), 1.58 (br. d, J = 6.5 Hz, 3H), 1.55 - 1.47 (m, 1H), 0.74 - 0.65, (m, 1H), 0.59 - 0.49 (m, 2H), 0.26 (br. d, J = 5.3 Hz, 1 H). m/z (ESI) for (C₂₂H₂₃N₆0₂), 440.8 (M+Na)⁺. [a]²⁰ _D = -6.406 (c = 0.200 g/100 ml_, MeOH).

Example 4: 6-methoxy-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4/-/-1 ,2,4-triazol-3- yl]pyridin-2-yl}-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1 : tert- butyl [(6-methoxy-1-oxo-2-{6-[4-(propan-2-yl)-4/-/-1 ,2,4-tri azol-3-yl]pyridin-2-yl}-2,3- dihydro-1/-/-isoindol-4-yl)methyl]methylcarbamate

A mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl] ethylcarba ate (70 g, 0.26 mmol), A/'-[(6-bromopyridin-2-yl)carbonyl]-/\/,/\/- dimethylhydrazonoformamide (80.1 mg, 0.262 mmol), K₃PO₄ (167 mg, 0.786 mmol), Pd2(dba)3 (24 mg, 0.0262 mmol) and Xantphos (30.3 mg, 0.0524 mmol) in dry 1 ,4-dioxane (8 ml_, c = 0.06 M) was degassed with N2. The reaction mixture was heated to 85 °C under N₂ and stirred at the same temperature for 16 h. TLC analysis (EtOAc/MeOH = 10:1) showed consumption of the starting material. The reaction was concentrated under vacuum to provide the crude as a brown gum. The residue was purified by flash chromatography (Biotage, S1O2, EtOAc/MeOH = 10:1) to provide the title compound (120 mg, 93% yield) as an off-white solid. ¹H NMR (400 MHz, CDC ) d 8.71 (d, J = 8.4 Hz, 1 H), 8.39 (s, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 7.93 (t, J = 8.0 Hz, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 7.04 (d, J = 2.3 Hz, 1 H), 5.70 - 5.54 (m, 1 H), 4.98 (s, 2H), 4.50 (s, 2H), 3.90 (s, 3H), 2.86 (s, 3H), 1.64 (d, J = 6.8 Hz, 6H), 1.41 (s, 9H). m/z (ESI) for (C26H32N6O4), 493.3 (M+H)⁺.

Step 2: 6-methoxy-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridin-2- yl}-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

To a solution of tert- butyl [(6-methoxy-1-oxo-2-{6-[4-(propan-2-yl)-4/-/-1,2,4-triazol-3- yl]pyridin-2-yl}-2,3-dihydro-1/-/-isoindol-4-yl)methyl]methylcarbamate (120 mg, 0.244 mmol) in EtOAc (5 ml_, c = 0.03 M) was added dropwise HCI (4 N in EtOAc, 2 ml_) at 0 °C. The mixture was stirred at 15 °C for 2 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. H2O (20 ml_) was added to the reaction mixture. The aqueous layer collected and dried by lyophilization to provide Example 4 (86.3 mg, 83%) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 9.86 - 9.70 (m, 2H), 9.46 (s, 1 H), 8.70 (d, J = 8.3 Hz, 1 H), 8.16 (t, J = 8.0 Hz, 1 H), 7.94 (d, J = 7.5 Hz, 1 H), 7.60 (d, J = 2.0 Hz, 1 H), 7.40 (d, J = 2.3 Hz, 1 H), 5.63 - 5.49 (m, 1H), 5.41 (s, 2H), 3.91 (s, 3H), 2.61 (s, 3H), 1.65 (d, J = 6.8 Hz, 6H). m/z (ESI) for (C21H24N6O2), 393.2 (M+H)⁺. Example 5: Synthesis of 2-[6-(4-ethyl-4/-/-1,2,4-triazol-3-yl)pyridin-2-yl]-6-methoxy-4- [(methylamino)methyl]-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1 : tert- butyl ({2-[6-(4-ethyl-4/-/-1 ,2,4-triazol-3-yl)pyridin-2-yl]-6-methoxy-1-oxo-2,3-dihydro- 1/-/-isoindol-4-yl}methyl)methylcarbamate

A mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl]methylcarbamate (75 g, 0.30 mmol), 2-bromo-6-(4-ethyl-4/-/-1 ,2,4-triazol-3-yl)pyridine (90.8 mg, 0.296 mmol), K₃PO₄ (189 mg, 0.889 mmol), Pd₂(dba)₃ (27.1 mg, 0.0296 mmol) and Xantphos (34.3 mg, 0.0593 mmol) in dry 1 ,4-dioxane (5 ml_, c = 0.06 M) was degassed with N₂. The reaction mixture was heated to 85 °C under N₂ and stirred at the same temperature for 16 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The mixture was concentrated to provide a yellow gum. The residue was purified by flash chromatography (Biotage, Si0₂, DCM/MeOH = 15:1) to provide the title compound (120 mg, 85% yield) as a yellow solid. ¹H NMR (400 MHz, CDCh) d 8.72 (d, J = 8.5 Hz, 1H), 8.26 (s, 1H), 8.09 (br. d, J = 7.5 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.40 - 7.33 (m, 1 H), 7.04 (d, J = 2.0 Hz, 1H), 4.99 (br. s, 2H), 4.71 (br. s, 2H), 4.53 (s, 2H), 3.91 (s, 3H), 2.83 (br. s, 3H), 1.56 (br. d, J = 6.8 Hz, 3H), 1.42 (s, 9H). m/z (ESI) for (C^HsoNeCL), 478.9 (M+H)⁺.

Step 2: 2-[6-(4-ethyl-4/-/-1 ,2,4-triazol-3-yl)pyridin-2-yl]-6-methoxy-4-[(methylamino)methyl]-2,3- dihydro-1/-/-isoindol-1-one hydrochloride

A mixture of tert- butyl ({2-[6-(4-ethyl-4/-/-1,2,4-triazol-3-yl)pyridin-2-yl]-6-methoxy-1-oxo- 2,3-dihydro-1/-/-isoindol-4-yl}methyl)methylcarbamate (120 mg, 0.251 mmol) in EtOAc (4 N in EtOAc, 10 ml_) was stirred at 20 °C for 2 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The reaction mixture was filtered. The filter cake was collected and dried by lyopillization to provide Example 5 (75 mg, 72% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 9.74 (br. s, 2H), 9.27 (s, 1H), 8.69 (d, J = 8.3 Hz, 1H), 8.15 (t, J = 8.0 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.62 (d, J = 2.0 Hz, 1 H), 7.41 (d, J = 2.0 Hz, 1 H), 5.38 (s, 2H), 4.71 (q, J = 6.9 Hz, 2H), 4.22 (br. s, 2H), 3.92 (s, 3H), 2.62 (br. t, J = 5.0 Hz, 3H), 1.55 (t, J = 7.2 Hz, 3H). m/z (ESI) for (C₂₀H₂₂N₆O₂), 401.0 (M+Na)⁺. Example 6: 6-methoxy-4-[(methylamino)methyl]-2-[6-(4-propyl-4/-/-1 ,2,4-triazol-3-yl)pyridin-2- yl]-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1 : tert- butyl ({6-methoxy-1-oxo-2-[6-(4-propyl-4/-/-1 ,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro- 1/-/-isoindol-4-yl}methyl)methylcarbamate

A mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl] ethylcarba ate (75 g, 0.28 mmol), 2-bromo-6-(4-propyl-4/-/-1 ,2,4-triazol-3- yl)pyridine (86 mg, 0.281 mmol), K₃P0₄ (179 mg, 0.842 mmol), Pd₂(dba)₃ (25.7 mg, 0.0281 mmol) and Xantphos (32.5 mg, 0.0562 mmol) in dry 1,4-dioxane (5 ml_, c = 0.06 M) was degassed with N₂. The reaction mixture was heated to 85 °C under N₂ and stirred at the same temperature for 16 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The mixture was concentrated to provide a yellow gum. The residue was purified by flash chromatography (Biotage, Si0₂, DCM/MeOH = 15:1) to the title compound (100 mg, 72% yield) as a yellow solid. ¹H NMR (400 MHz, CDCh) d 8.75 (dd, J = 0.8, 8.4 Hz, 1H), 8.25 (s, 1 H), 8.09 (br. d, J = 7.6 Hz, 1 H), 7.98 - 7.92 (m, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.06 (d, J = 2.3 Hz, 1 H), 4.99 (s, 2H), 4.65 (br. s, 2H), 4.55 (s, 2H), 3.93 (s, 3H), 2.85 (br. s, 3H), 1.90 (br. d, J = 7.0 Hz, 2H), 1.44 (s, 9H), 0.98 (t, J = 7.5 Hz, 3H). m/z (ESI) for (C₂₆H₃₂N₆0₄), 492.9 (M+H)⁺.

Step 2: 6-methoxy-4-[(methylamino)methyl]-2-[6-(4-propyl-4/-/-1 ,2,4-triazol-3-yl)pyridin-2-yl]-2,3- dihydro-1/-/-isoindol-1-one hydrochloride

A mixture of te/f-butyl ({6-methoxy-1-oxo-2-[6-(4-propyl-4/-/-1 ,2,4-triazol-3-yl)pyridin-2-yl]- 2,3-dihydro-1/-/-isoindol-4-yl}methyl)methylcarbamate (100 mg, 0.203 mmol) and HCI (4 N in EtOAc, 10 ml_) was stirred at 20 °C for 2 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The reaction mixture was filtered. The filter cake was collected and dried by lyopillization to provide Example 6 (60 mg, 69% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 9.74 (br. s, 2H), 9.23 (s, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.15 (t, J = 8.0 Hz, 1H), 8.00 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1 H), 7.41 (s, 1H), 5.35 (s, 2H), 4.66 (br. t, J = 7.0 Hz, 2H), 4.21 (br. s, 2H), 3.92 (s, 3H), 2.66 - 2.57 (m, 3H), 1.98 - 1.88 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). m/z (ESI) for (C_2iH₂₄N₆0₂), 393.3 (M+H)⁺. Example 7: 4-(aminomethyl)-6-methoxy-2-(6-{4-[(2<¾-4,4,4-trifluorobutan-2-yl]-4/-/-1,2,4-triazol- 3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1: (6-methoxy-1 -oxo-2, 3-dihydro-1/-/-isoindol-4-yl)methyl methanesulfonate

To a solution of 4-(hydroxymethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one (300 mg, 1.55 mmol) in dry DCM (15 ml_, c = 0.1 M) was added TEA (786 mg, 1.09 ml_, 7.76 mmol). MsCI (445 mg, 3.88 mmol) was added dropwise at 0 °C under N2. The mixture was stirred for an additional 2 h at 0 °C. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The reaction mixture was diluted with DCM (10 ml_). The mixture was washed with H2O (3x20 ml_) and brine (30 ml_), dried over Na2SC>4_, filtered, and concentrated to provide the title compound (950 mg, 43% LCMS purity, 97% yield) as a yellow solid, which was taken on without further purification m/z (ESI) for (C11H13NO5S), 271.8 (M+H)⁺. Step 2: 4-(azidomethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one

A solution of (6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl methanesulfonate (950 mg, 43% purity, 1.55 mmol) and Nal (554 mg, 8.52 mmol) in DMF (15 mL, c = 0.1 M) was stirred at 95 °C for 18 h. LCMS analysis showed consumption of the starting material with formation of the desired mass. The reaction was cooled to room temperature and then poured into 1 N NaOH (20 mL). The mixture was extracted with THF (3x20 mL). The combined organics were washed brine (5x20 mL), dried over Na₂SC>₄, filtered to provide the title compound (-1.55 mmol in 60 mL THF), which was taken on without further purification m/z (ESI) for (C₁₀H₁₀N₄O₂), 218.9 (M+H)⁺.

Step 3: 4-(aminomethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one

A mixture of 4-(azidomethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one (-1.55 mmol in 60 ml_ THF) and PPh3 (610 mg, 2.32 mmol) in H2O was stirred at 25 °C for 40 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was concentrated to dryness. To the residue was added EtOAc (30 mL). The combined organics were extracted with 1 N HCI (3x12 mL). The combined aqueous extracts were basified with solid NaHCOs to pH -9 to provide the title compound (-1.55 mmol in 36 mL saturated aq. NaHCOs) which was used directly without further purification.

Step 4: tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]carbamate

A mixture of 4-(aminomethyl)-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one (-1.55 mmol in 36 ml_ saturated aq. NaHCC ) and B0C₂O (677 mg, 3.1 mmol) in THF (10 ml_, c = 0.16 M) was stirred at 20 °C for 16 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. H2O (60 ml_) was added and the mixture was extracted with EtOAc (2x40 ml_). The combined organics were washed with brine (30 ml_), dried over Na2SC>4, filtered, and concentrated to provide a yellow oil. The residue was purified by flash chromatography (Isco, 12 g S1O₂, 0-100% EtOAc/petroleum ether) to provide the title compound (200 mg, 44% yield over 4 steps) as a white solid. ¹H NMR (400 MHz, CDCI₃) d 7.27 (d, J = 2.5 Hz, 1 H), 7.04 (s, 1 H), 6.55 (br. s, 1 H), 4.88 (br. s, 1 H), 4.40 (s, 2H), 4.35 (br. d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 1.46 (s, 9H). m/z (ESI) for (C₁₅H₂₀N₂O₄), 293.1 (M+H)⁺.

Step 5: tert- butyl {[6-methoxy-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3- yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}carbamate

A mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]carbamate (150 mg, 0.513 mmol), 2-bromo-6-[4-(4,4,4-trifluorobutan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridine (172 mg, 0.513 mmol), K₃PO₄ (327 mg, 1.54 mmol), Pd₂(dba)₃ (47 mg, 0.0513 mmol) and Xantphos (59.4 mg, 0.103 mmol) in dry 1,4-dioxane (6 mL, c = 0.09 M) was degassed with N2. The reaction mixture was heated to 85 °C under N2 and stirred at the same temperature for 16 h. LCMS analysis indicated consumption of the starting material with formation of the desired product mass. The reaction mixture was combined with a parallel reaction run on with 50 mg (0.17 mmol) tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]carbamate. The combined reactions were filtered. The filter cake was washed with 10% MeOH/DCM (3x10 ml_). The combined organics were concentrated to provide a yellow solid. The residue was purified by flash chromatography (Isco, 20 g S1O2, petroleum ether/EtOAc = 1 :2) to provide the racemic title compound (230 mg, 62% yield) as a yellow solid. The racemic mixture was purified by preparative chiral SFC on a Diacel Chiralpak IC column (250 mm x 30 mm, 5 pm particle size), which was eluted with 45% EtOH (0.1% NH4OH) in CO2. The first-eluting peak was obtained at a flow rate of 50 mL/min provided the title compound (110 mg, 48% yield) as a white solid m/z (ESI) for (C26H29F3N6O4), 569.0 (M+Na)⁺. [a]²⁰ _D = -43.567 (c = 0.14 g/100 ml_, MeOH).

Step 6: 4-(aminomethyl)-6-methoxy-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1,2,4-triazol-3- yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

To a stirred solution of te/f-butyl {[6-methoxy-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]- 4/-/-1,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}carbamate (105 mg, 0.192 mmol) in DCM (5 ml_, c = 0.02 M) was added HCI (4 N in EtOAc, 5 ml_) at 0 °C. The reaction was stirred at 20 °C for 4 h. LCMS analysis showed consumption of the starting material with formation of the desired mass. The reaction mixture was concentrated to give a white solid. The residue was dissolved in H2O (20 mL) and dried by lyophilization to provide Example 7 (90 mg, 97% yield) was obtained as a light yellow solid. ¹H NMR (400 MHz, DMSO-de) d 9.18 (s, 1 H), 8.74 - 8.63 (m, 3H), 8.13 (dd, J = 7.6, 8.4 Hz, 1 H), 7.92 (dd, J = 0.7, 7.6 Hz, 1 H), 7.51 (d, J = 2.3 Hz, 1 H), 7.39 (d, J = 2.2 Hz, 1 H), 6.07 - 5.92 (m, 1 H), 5.37 - 5.24 (m, 2H), 4.16 - 4.07 (m, 2H), 3.91 (s, 3H), 3.26 (quin, J = 10.5, 15.5 Hz, 1H), 3.13 - 3.00 (m, 1 H), 1.72 (d, J = 6.7 Hz, 3H). m/z (ESI) for (C21H21F3N6O2), 468.9 (M+Na)⁺. [a]²⁰ _D = -15.599 (c = 0.133 g/100 mL, MeOH).

Example 8: 6-methoxy-4-[(methylamino)methyl]-2-{6-[(4S)-4-methyl-2-oxo-1 ,3-oxazolidin-3- yl]pyridin-2-yl}-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1 : (4S)-3-(6-bromopyridin-2-yl)-4-methyl-1 ,3-oxazolidin-2-one

A mixture of 2,6-dibromopyridine (35.0 g, 147.8 mmol), (4S)-4-methyl-1 ,3-oxazolidin-2- one (15 g, 148.4 mmol), and K₃PO₄ (94.1 g, 443 mmol) in 1 ,4-dioxane (300 ml_, c = 0.49 M) was degassed with N₂. Xantphos (9.06 g, 15.7 mmol) and Pd₂(dba)₃ were added. The reaction was evacuated and then backfilled with N₂ three times and then stirred at 63 °C for 5 h. TLC analysis (petroleum ether/EtOAc = 7:1) showed consumption of the starting material with formation of a new product. The mixture was filtered through a pad of Celite^®. The filter cake was washed with EtOAc (200 ml_). The filtrate was concentrated. The crude residue was combined with the crude residue obtained from a parallel reaction run in the same manner with 2 g (4S)-4-methyl-1,3- oxazolidin-2-one (21.1 mmol). The combined crudes were purified by flash chromatography (Biotage, 330 g Si0₂, 0-12% EtOAc/petroleum ether) to provide the title compound (10 g, 23% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-de) d 8.03 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1 H), 4.76 (dqd, J = 4.0, 6.1, 8.2 Hz, 1 H), 4.55 (t, J = 8.3 Hz, 1H), 4.10 (dd, J = 4.0, 8.5 Hz, 1H), 1.38 (d, J = 6.3 Hz, 3H). m/z (ESI) for (C₉H₉BrN₂0₂), 258.8 (M+H)⁺.

Step 2: tert- butyl [(6-methoxy-2-{6-[(4S)-4-methyl-2-oxo-1 ,3-oxazolidin-3-yl]pyridin-2-yl}-1-oxo- 2,3-dihydro-1/-/-isoindol-4-yl)methyl]methylcarbamate

To a mixture of tert- butyl [(6-methoxy-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl] ethylcarba ate (200 g, 0.653 mmol), (4S)-3-(6-bromopyridin-2-yl)-4-methyl-1,3- oxazolidin-2-one (185 mg, 0.718 mmol), and K₃PO₄ (416 mg, 1.96 mmol) in 1,4-dioxane (6 ml_, c = 0.1 M) was added Pd2(dba)3 (59.8 mg, 0.0653 mmol) and Xantphos (75.5 mg, 0.131 mmol) under N₂. The mixture was bubbled through with N₂ for 2 min and then sealed and stirred at 85 °C for 18 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was diluted with DCM (50 ml_), washed with brine (20 ml_), and concentrated to provide a yellow gum. The crude was purified by flash chromatography (Biotage, 20 g Si0₂, 0-50% EtOAc/petroleum ether) to provide the title compound (290 mg, 92% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-de) d 8.22 (d, J = 7.7 Hz, 1 H), 7.92 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 2.2, Hz, 1 H), 7.03 (br. s, 1H), 5.07 - 4.88 (m, 3H), 4.61 - 4.46 (m, 3H), 4.16 (dd, J = 3.7, 8.4 Hz, 1H), 3.86 (s, 3H), 2.85 (br. s, 3H), 1.51 - 1.29 (m, 12H). m/z (ESI) for (C^Hsol UOe), 482.9 (M+H)⁺.

Step 3: 6-methoxy-4-[(methylamino)methyl]-2-{6-[(4S)-4-methyl-2-oxo-1 ,3-oxazolidin-3- yl]pyridin-2-yl}-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

To a solution of tert- butyl [(6-methoxy-2-{6-[(4S)-4-methyl-2-oxo-1 ,3-oxazolidin-3- yl]pyridin-2-yl}-1 -oxo-2, 3-dihydro-1/-/-isoindol-4-yl)methyl]methylcarbamate (290 mg, 0.901 mmol) in DCM (15 mL, c = 0.017 M) was added HCI (4 N in EtOAc, 20 mL) at 0 °C. The mixture was stirred at 28 °C for 2 h. LCMS analysis showed consumption of the starting material. The suspension was filtered. The filter cake was washed with DCM (5 mL). The filter cake was taken up in a mixture of H₂0 (15 mL) and MeCN (5 mL) and then dried by lyophillization to provide Example 8 (235 mg, 93% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 9.65 (br. d, J = 4.5 Hz, 2H), 8.21 (d, J = 8.1 Hz, 1 H), 7.93 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1 H), 5.31 - 5.14 (m, 2H), 5.01 (ddd, J = 3.7, 6.1, 8.0 Hz, 1H), 4.59 (t, J = 8.3 Hz, 1H), 4.23 (br. t, J = 5.6 Hz, 2H), 4.17 (dd, J = 3.6, 8.4 Hz, 1H), 3.90 (s, 3H), 2.62 (t, J = 5.2 Hz, 3H), 1.48 (d, J = 6.1 Hz, 3H). m/z (ESI) for (C₂oH₂₂N₄0₄), 382.8 (M+H)⁺.

Example 9: 6-terf-butyl-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4/-/-1 ,2,4-triazol-3- yl]pyridin-2-yl}-2,3-dihydro-1/-/-isoindol-1-one

Step 1: 1,3-dibromo-5-ferf-butyl-2-methylbenzene

Br₂ (7.04 g, 2.26 mL, 44 mmol) was added dropwise to a mixture of 1-te/f-butyl-4- methylbenzene (3.01 g, 20.3 mmol), iron powder (325 mesh, 35 mg, 0.63 mmol), and CCI₄ (2.5 mL, c = 8.1 M) over 15 min at room temperature. The mixture was stirred at 40° for 5 h. The reaction mixture was poured into H₂0 (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM. The combined organics were dried over Na₂S0₄, filtered, and concentrated. The residue was purified by flash chromatography (Isco, 40 g Si0₂, heptane) to provide the title compound (5.27 g, 85 % yield) as a yellow oil. ¹H NMR (400 MHz, CDCI₃) d 7.50 (s, 2H) 2.54 (s, 3H) 1.29 (s, 9H).

Step 2: dimethyl 5-te/f-butyl-2-methylbenzene-1,3-dicarboxylate

To a solution of 1 ,3-dibromo-5-te/f-butyl-2-methylbenzene (1.21 g, 3.95 mmol) in 50 mL MeOH in a 100 mL Parr bomb was added KOAc (1.58 g, 16.1 mmol), dppp (101 mg, 0.245 mmol), and Pd(OAc)₂ (43.5 mg, 0.194 mmol). The bomb was sealed, purged with N₂ (3x) and CO (4x), and filled with CO (10 bar). The mixture was heated to 100 °C. The internal pressure rose to 190- 200 psi upon heating. The reaction was held at 100 °C overnight. The reaction mixture was allowed to cool down to room temperature, depressurized and then purged with N₂ (2x). Some precipitates were observed. LCMS analysis showed consumption of the starting material with formation of the product mass. The reaction mixture was concentrated to dryness and then purified by flash chromatography (Isco, 40 g Si0₂, 0-20% EtOAc/heptanes) to provide dimethyl the title compound (981 mg, 94% yield) as a clear oil. ¹H NMR (400 MHz, CDCh) d 7.87 (s, 2H) 3.93 (s, 6H) 2.64 (s, 3H) 1.34 (s, 9H). m/z (ESI) for (CI₅H₂₀O₄), 265.2 (M+H)⁺.

Step 3: 6-te/f-butyl-1-oxo-2,3-dihydro-1/-/-isoindole-4-carboxylate

To a solution of dimethyl 5-te/f-butyl-2-methylbenzene-1 ,3-dicarboxylate (981 mg) in CCL (15 ml_, c = 0.25 M) was added NBS (694 mg, 3.9 mmol) and AIBN (60.9 mg, 0.371 mmol). The mixture was stirred at 80 °C for 18 h. LCMS analysis indicated -10% remaining starting material. Additional NBS (89 mg) was added and the mixture was stirred an additional 4 h at 80 °C. LCMS did not indicate further consumption of starting material. The reaction was cooled to room temperature and quenched with saturated aqueous NaHCC>₃. The mixture was extracted with DCM (2x). The combined organics were dried over anhydrous Na₂SC>₄, filtered, and concentrated to provide crude dimethyl 2-(bromomethyl)-5-te/f-butylbenzene-1 ,3-dicarboxylate. The residue was taken up in a solution of NH₃ (7 N in MeOH, 5.3 mL, 37.1 mmol) and stirred at room temperature for 48 h. LCMS analysis indicated that the reaction had gone to completion. The mixture was filtered. The filter cake was washed with EtOAc. The filtrate was concentrated to dryness to provide methyl the title compound (777 mg, 85% yield) as a white solid, which was taken on without further purification. ¹H NMR (400 MHz, DMSO-de) d 8.71 (s, 1 H) 8.16 (d, J = 1.71 Hz, 1 H) 7.92 (d, J = 1.96 Hz, 1 H) 4.56 (s, 2H) 3.84 - 3.93 (m, 3H) 1.33 - 1.39 (m, 9H). m/z (ESI) for (C₁₄H₁₇NO₃), 248.2 (M+H)⁺.

Step 4: 6-te/f-butyl-4-(hydroxymethyl)-2,3-dihydro-1/-/-isoindol-1-one

To a solution of methyl 6-te/f-butyl-1-oxo-2,3-dihydro-1/-/-isoindole-4-carboxylate (131 mg, 0.530 mmol) in THF (5 mL, c = 0.1 M) at 0 °C was added L1BH₄ (46.2 mg, 2.12 mmol). The mixture was warmed to room temperature and stirred for 18 h. LCMS analysis showed -55% remaining starting material. The mixture was cooled to 0 °C and then additional L1BH₄ (50 mg) was added. After 1 h LCMS analysis showed -50% remaining starting material. The reaction mixture was subsequently stirred at 40 °C for 1.5 h. LCMS analysis indicated consumption of the starting material. The mixture was quenched H₂0 and extracted with DCM (2x). The combined organics were dried over Na₂SC>4 and concentrated to provide the title compound (110 mg, 95 % yield) as an off-white solid, which was taken on without further purification m/z (ESI) for (C13H17NO2), 220.2 (M+H)⁺.

Step 5: tert- butyl [(6-te/f-butyl-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]methylcarbamate

Boc

To a solution of 6-te/f-butyl-4-(hydroxymethyl)-2,3-dihydro-1/-/-isoindol-1-one (110 mg, 0.502 mmol) in DCM (10 ml_, c = 0.50 M) was added TEA (245 mg, 0.35 ml_, 2.51 mmol) and MsCI (117 mg, 80.3 mI, 1.0 mmol) at 0 °C. The mixture was stirred a further 30 min at 0 °C. LCMS analysis showed formation of the desired product. A solution of Nh^Me (2 M in THF, 2.51 ml_, 5.02 mmol) was added and the mixture was stirred at room temperature for 8 h. LCMS analysis showed consumption of starting material with formation of the desired product mass. The reaction mixture was concentrated to dryness. The residue was taken up into DCM (10 mL, c = 0.05 M) and B0C2O (113 mg, 0.502 mmol) was added. After 2 h LMCS analysis showed consumption for starting material with formation of the desired product mass. The reaction was quenched with H2O and extracted with DCM (2x). The combined organics were dried over Na2SC>4, filtered, and concentrated. The residue was purified by flash chromatography (Isco, 12 g S1O2, 20-60% EtOAc/heptanes) to provide the title compound (55 mg, 33% yield) as a colorless gum. ¹H NMR (400 MHz, CDCI₃) 67.83 (d, J = 1.59 Hz, 1 H) 7.39 - 7.45 (m, 1H) 4.52 (s, 2H) 4.37 (s, 2H) 2.80 (br. s., 3H) 1.42 - 1.51 (m, 9H) 1.32 - 1.37 (m, 9H). m/z (ESI) for (C19H28N2O3), 233.2 (M-Boc)⁺.

Step 6: 6-te/f-butyl-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridin- 2-yl}-2,3-dihydro-1/-/-isoindol-1-one

A mixture of tert- butyl [(6-te/f-butyl-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl]methylcarbamate (55 mg, 0.17 mmol), 2-bromo-6-[4-(propan-2-yl)-4/-/-1,2,4-triazol-3- yl]pyridine (57.5 mg, 0.215 mmol), K3PO4 (105 mg, 0.496 mmol), Pd₂(dba)₃ (15.3 mg, 0.0165 mmol), and Xantphos (19.1 mg, 0.0331 mmol) in 1 ,4-dioxane (3 mL, c = 0.06 M) was heated to 85 °C and stirred at this temperature for 20 h. LCMS analysis showed -25% remaining starting material. Additional Pd₂(dba)₃ (15 mg) was added and the reaction was stirred at 85 °C for an additional 20 h. LCMS analysis did not show additional conversion. Additional 2-bromo-6-[4- (propan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridine (50 mg), Pd2(dba)3 (12 mg), and Xantphos (15 mg) was added and the mixture was stirred at 50 °C for an additional 20 h. LCMS analysis showed -15% remaining starting material. The reaction was cooled to room temperature and filtered through Celite^®. The filter cake was washed with 10% MeOH/DCM. The filtrate was concentrated. The residue was dissolved in DCM (1 ml_) and HCI (4 N in 1,4-dioxane, 1 ml_) was added. The mixture was stirred at room temperature for 2 h. LCMS analysis showed consumption of the starting material. The reaction was concentrated to dryness. The residue was purified by preparative HPLC on a Phenemonex Gemini NX C18 column (150 x21.2 mm, 5 pm particle size), which was eluted with 30-40% MeCN/H₂0 + 10 mM NhUOAc with a flow rate of 60 mL/min. The resultant product was repurified by preparative SFC on a ZymorSpher HADP column (150 x 21.2mm, 5 pm) column at 35 °C, which was eluted with 10-32% MeOH in CO2 (ramping over 4 min) with a flow rate of 60 mL/min to provide Example 9 (16.2 mg, 23% yield). ¹H NMR (600 MHz, DMSO-de) d 8.94 (s, 1H) 8.63 (d, J = 8.44 Hz, 1 H) 8.04 - 8.10 (m, 1 H) 7.88 - 7.93 (m, 1 H) 7.71 (s, 1H) 7.68 (s, 1H) 5.53 - 5.64 (m, 1 H) 5.18 (s, 2H) 3.82 (br. s., 2H) 2.34 (s, 3H) 1.59 (d, J = 6.60 Hz, 6H) 1.36 (s, 9H). m/z (ESI) for (C₂₄H₃oN0₆), 419.0 (M+H)⁺.

Example 10: 2-(6-{4-[(2S)-butan-2-yl]-4H-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6-(dimethylamino)-4- [(methylamino)methyl]-2,3-dihydro-1/-/-isoindol-1-one

Step 1: tert- butyl methyl[(1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]carbamate

To a suspension of 1-oxo-2,3-dihydro-1/-/-isoindole-4-carbaldehyde (Integral

Biosciences) (878 mg, 5.45 mmol) in MeOH (10 mL, c = 0.3 M) was added MeNH2 (2.0 M in THF,

8.0 mL, 16 mmol) and 2 drops of acetic acid to provide a homogeneous solution, which was stirred for 18 h at room temperature. MP-BH₄ (Biotage) (3.69 g, 10.9 mmol) was added. The mixture was stirred for 2 h at room temperature. The fixture was filtered and the filtrate was concentrated. The residue was taken up into DCM (6.0 mL, c = 0.3 M). TEA (2.76 g, 3.8 mL, 27.2 mmol) and B0C2O (1.19 g, 5.45 mmol) were added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with H₂0 and extracted with DCM (2x). The combined organics were dried over Na₂S04, filtered, and concentrated. The residue was purified by flash chromatography (Isco, 12 g S1O2, 50-100% EtOAc/heptanes) to provide the title compound (571 mg, 38% yield) as a white solid. ¹H NMR (400 MHz, CDCI₃) d 7.84 (d, J = 7.46 Hz, 1 H) 7.46 - 7.53 (m, 1 H) 7.38 - 7.45 (m, 1 H) 6.34 - 6.53 (m, 1H) 4.55 (s, 2H) 4.43 (s, 2H) 2.83 (br. s., 3H) 1.51 (br. s., 9H).

Step 2: tert- butyl methyl{[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1/-/- isoindol-4-yl]methyl}carbamate

A solution of te/f-butyl methyl[(1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]carbamate (725 mg, 2.62 mmol) in THF (15 ml_, c = 0.17 M) in a 40 ml_ vial was sparged with N2 for 10 min. [lr(COD)OMe]₂ (87.0 mg, 0.131 mmol) and 4,4'-di-ferf-butyl-2,2'-dipyridyl (70.4 mg, 0.262 mmol) were added. The reaction was sparged again for 2 min and HBPin (672 mg, 0.761 ml_, 525 mmol) was added. Gas evolution was observed. After gas evolution ceased, the reaction was sealed and stirred at 80 °C for 18 h. LCMS analysis showed remaining starting material. The reaction was sparged with N₂ for 30 min and additional [lr(COD)OMe]₂ (87.0 mg, 0.131 mmol), 4,4'-di -tert- butyl-2,2'-dipyridyl (70.4 mg, 0.262 mmol), and HBPin (672 mg, 0.761 mL, 525 mmol) were added. The mixture was sealed and stirred at 80 °C for 24 h. The reaction was concentrated to dryness. The residue was purified by flash chromatography (Isco, 24 g S1O₂, 50-100% EtOAc/heptanes) to provide the title compound (672 mg, 64% yield) as a brown foam m/z (ESI) for (C₂₁H₃₁BN₂O₅), 403.3 (M+H)⁺.

Step 3: (7-{[(te/f-butoxycarbonyl)(methyl)amino]methyl}-3-oxo-2, 3-dihydro- 1 /-/-isoindol-5- yl)boronic acid

To a solution of tert- butyl methyl{[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,3-dihydro-1/-/-isoindol-4-yl]methyl}carbamate (607 mg, 1.51 mmol) in MeCN (18 m, c = 0.08 M) was added 1 N HCI (2.0 ml_) and polymer-bound boronic acid (200-400 mesh, Aldrich). The mixture was stirred at room temperature for 5 h. LCMS analysis showed consumption of the starting material. The mixture was filtered and the filtrate was concentrated to provide the title compound (449 mg, 93% yield) as a pale yellow solid m/z (ESI) for (C15H21BN2O5), 321.2 (M+H)⁺. Step 4: tert- butyl {[6-(dimethylamino)-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl]methyl}methylcarbamate

A mixture of (7-{[(te/f-butoxycarbonyl)(methyl)amino]methyl}-3-oxo-2,3-dihydro-1/-/- isoindol-5-yl)boronic acid (108 g, 0.337 mmol), Cu(OAc)₂ (91.9 mg, 0.506 mmol), 4 A molecular sieves (337 mg) and DCM (28.7 mg, 0.337 mmol) was stirred at room temperature for 5 min. Then a Me2NH (2 M in THF, 337 mg, 0.675 mmol) and TEA (0.094 ml_, 0.675 mmol) were added. The mixture was stirred under an O2 atmosphere for 20 h. LCMS analysis showed formation of the desired product with some loss of the Boc group. The mixture was filtered and to the filtrate was added B0C2O (75.9 mg, 0.337 mmol) and TEA (0.094 ml_, 0.675 mmol). The mixture was stirred for 2 h. LCMS analysis showed consumption of the des-Boc compound. The reaction was concentrated to dryness. The residue was purified by flash chromatography (Isco, 12 g S1O2, 0- 10% MeOH/DCM) to provide the title compound (68 mg, 63% yield) m/z (ESI) for (C17H25N3O3), 320.2 (M+H)⁺.

Step 5: te/f-butyl {[2-(6-{4-[(2S)-butan-2-yl]-4H-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6-(dimethylamino)- 1-oxo-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate

A mixture of tert- butyl {[6-(dimethylamino)-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl]methyl}methylcarbamate (67.3 mg, 0.239 mmol), 2-bromo-6-{4-[(2S)-butan-2-yl]-4/-/-1,2,4- triazol-3-yl}pyridine (60 mg, 0.19 mmol), K₃PO₄ (120 mg, 0.564 mmol), Xantphos (21.7 mg, 0.0376 mmol), and Pd2(dba)3 in 1,4-dioxane was heated to 100 °C for 16 h. The reaction was concentrated to dryness. The residue was purified by flash chromatography (Isco, 12 g S1O2, 0- 10% MeOH/DCM) to provide the title compound (87 mg) as a pale yellow oil, which of low purity by LCMS and taken onto the next step without further purification.

Step 6: 2-(6-{4-[(2S)-butan-2-yl]-4H-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6-(dimethylamino)-4-

[(methylamino)methyl]-2,3-dihydro-1/-/-isoindol-1-one

To a solution of te/f-butyl {[2-(6-{4-[(2S)-butan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2-yl)-6- (dimethylamino)-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (89 mg, 0.17 mmol) in DCM (5.0 mL, c = 0.02 M) was added HCI (4 N in 1,4-dioxane, 1 mL, 4 mmol). The mixture was stirred for 3 h. LCMS analysis showed only a trace amount of the desired product. The reaction was concentrated to dryness. The residue was purified by preparative HPLC on a Phenemonex Gemini NX C18 column (150 x 21.1 mm, 5 pm particle size), which was eluted with 35-100% MeCN/H₂0 (+10 mM NH₄OAc) with a flow rate of 40 mL/min to provide Example 10 (8.8 mg, 11% yield, 2 steps) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 8.85 (s, 1 H) 8.54 - 8.60 (m, 1H) 7.95 - 8.03 (m, 1H) 7.76 - 7.87 (m, 1H) 6.83 - 6.90 (m, 1H) 6.15 - 6.30 (m, 1 H) 5.30 - 5.49 (m, 1 H) 5.01 (s, 2H) 3.63 - 3.79 (m, 2H) 2.92 (s, 6H) 2.26 (br. s., 3H) 1.70 - 1.98 (m, 3H) 1.48 (d, J = 6.72 Hz, 3H) 0.76 (s, 3H). m/z (ESI) for (C23H29N7O), 420.2 (M+H)⁺.

Example 11 : 6-methoxy-1-oxo-2-{6-[4-(propan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridin-2-yl}-2,3- dihydro-1/-/-isoindole-4-sulfonamide

Step 1 : 4-bromo-6-methoxy-2-{6-[4-(propan-2-yl)-4/-/-1 ,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro- 1/-/-isoindol-1-one

A mixture of 2-bromo-6-[4-(propan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridine (200 mg, 0.749 mmol), 4-bromo-6-methoxy-2,3-dihydro-1/-/-isoindol-1-one (190 mg, 0.786 mmol), K₂CO₃ (228 mg, 1.65 mmol), Cul (28.5 mg, 0.15 mmol) and A/¹,/\/¹-dimethylethane-1 , 2-diamine (26.4 mg, 0.299 mmol) in MeCN (6.5 ml_, c = 0.12 M) was heated to 120 °C in a microwave for 1.5 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction mixture was filtered and the filter cake was washed with DCM (2x3 ml_). The filter cake was taken up in H2O (10 ml_) and MeCN (5 ml_) and stirred for 10 min. The suspension was filtered and the filter cake was washed with MeCN (2x3 ml_), collected, and dried to provide the title compound (240 mg, 75% yield). ¹H NMR (400 MHz, DMSO-de) d 8.92 (s, 1H), 8.60 (d, J = 8.4 Hz, 1 H), 8.07 (t, J = 7.9 Hz, 1 H), 7.97 - 7.90 (m, 1 H), 7.51 (s, 1 H), 7.37 (s, 1 H), 5.58 (td, J = 6.7, 13.5 Hz, 1 H), 5.00 (s, 2H), 3.89 (s, 3H), 1.61 (d, J = 6.7 Hz, 6H). m/z (ESI) for (CigHisBrNsC^), 428.1 (M+H)⁺.

Step 2: 6-methoxy-1-oxo-2-{6-[4-(propan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1/-/- isoindole-4-sulfonamide

To a vial equipped with a magnetic stir bar was added provide 4-bromo-6-methoxy-2-{6- [4-(propan-2-yl)-4/-/-1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1/-/-isoindol-1-one (240 g, 0.56 mmol), K₂S₂O₅ (249 mg, 1.12 mmol), TBAB (199 mg, 0.616 mmol), HCC>2Na (83.8 mg, 1.23 mmol), Pd(OAc)₂ (6.29 mg, 0.280 mmol), PPh3 (22 mg, 0.0841 mmol), phen (15.1 mg, 0.0841 mmol) and DMSO (3 ml_, c = 0.19). The mixture was degassed by bubbling through with N2 for 10 min. The reaction was heated to 70 °C and stirred at this temperature for 3 h. The reaction was cooled to 0 °C and a saturated solution of NH3 in THF (1 ml_, freshly generated by bubbling through THF with N2 at -60 °C for 15 min) was added. Then a solution of NBS (199 mg, 1.12 mmol) in THF (3 ml_) was added dropwise at 0 °C. The reaction was warmed to 20 °C and stirred for 2 h. LCMS analysis showed -30% remaining starting material with formation of -19% of the desired mass with -20% of the des-Br byproduct. Additional K₂S₂O₅ (249 mg, 1.12 mmol), TBAB (199 mg, 0.616 mmol), HC0₂Na (83.8 mg, 1.23 mmol), Pd(OAc)₂ (6.29 mg, 0.280 mmol), PPh3 (22 mg, 0.0841 mmol), and phen (15.1 mg, 0.0841 mmol) were added to the reaction mixture. The mixture was degassed by bubbling through with N₂ for 10 min and then heated to 70 °C. The reaction was stirred at this temperature for 3.5 h and then cooled to 0 °C. Additional NH₃(g)/THF (1 ml_) was added followed by a solution of NBS (199 mg, 1.12 mmol) in THF (3 ml_) at this temperature. The reaction was warmed to 20 °C and stirred for 1 h. LCMS analysis showed -15% remaining starting material with only a trace increase in product formation. The mixture was diluted with H2O (20 mL) and EtOAc (20 mL). The mixture was stirred for 5 min and then filtered. The filter cake was washed with MeCN (3x2 mL), collected, and dried under vacuum to provide an off-white solid. The residue was purified by preparative HPLC on a DuraShell column (150 x 25 mm, 5 pm particle size) which was eluted with 13-63% MeCN/H20 (+0.05% NH4OH) with a flow rate of 25 mL/min to provide Example 11 (36 mg, 15% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 8.95 (s, 1H), 8.62 (br. d, J = 8.7 Hz, 1 H), 8.10 (br. t, J = 8.1 Hz, 1 H), 7.97 (br. d, J = 7.6 Hz, 1 H), 7.60 (br. d, J = 13.6 Hz, 4H), 5.69 - 5.55 (m, 1H), 5.33 (s, 2H), 3.95 (s, 3H), 1.58 (br. d, J = 6.5 Hz, 6H). m/z (ESI) for (C19H20N6O4S), 429.9 (M+H)⁺.

Example 12: 4-[(methylamino)methyl]-6-[^)-tetrahydrofuran-3-yl]-2-(6-{4-[^)-4,4,4- trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1: tert- butyl [(6-bromo-1-oxo-2,3-dihydro-1/-/-isoindol-4-yl)methyl]methylcarbamate

To a mixture of tert- butyl methyl{[1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,3-dihydro-1/-/-isoindol-4-yl] ethyl}carba ate (7.57 g, 18.8 mmol) in MeOH (150 ml_, c = 0.063 M) was added a solution of CuBr (12.6 g, 56.4 mmol) in H2O (150 ml_). After addition, some precipitate was observed. The mixture was stirred at 65 °C for 23 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass and some undesired deprotection of the Boc group. The mixture was concentrated to remove MeOH. To the mixture was added NaHCOs (9.48 g, 113 mmol). Some blue solid precipitated. B0C2O (6.16 g, 28.2 mmol) was added. The mixture was stirred at 20 °C for 2.5 h. LCMS analysis showed complete Boc protection. The mixture was filtered and the filter cake was washed with EtOAc (100 mL). The biphasic filtrate was separated. The aqueous layer was extracted with EtOAc (3x50 mL). The combined organics were washed with brine (50 mL), dried over Na₂S0₄, filtered, and concentrated to provide a brown gum. The residue was purified by flash chromatography (Biotage, S1O2, petroleum ether/EtOAc = 1:1) to provide the title compound (5.4 g, 81% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-de) d 8.75 (s, 1H), 7.72 (s, 1H), 7.54 (s, 1H), 4.49 (s, 2H), 4.30 (s, 2H), 2.79 (s, 3H), 1.52 - 1.30 (m, 9H). m/z (ESI) for (CisHigBrl ^Os), 355.0 (M+H)⁺ Step 2: tert- butyl {[6-bromo-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1,2,4-triazol-3- yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate

To a solution of terf-butyl [(6-bromo-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl]methylcarbamate (500 mg, 1.41 mmol) in MeCN (10 mL, c = 0.14 M) was added K2CO3 (428 mg, 3.1 mmol) and 2-bromo-6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3- yl}pyridine (472 mg, 1.41 mmol). The mixture was bubbled through with N₂ for 5 min. Then Cul (67 mg, 0.352 mmol) and A/¹,/\/¹-dimethylethane-1, 2-diamine (56 mg, 0.704 mmol) were added. The mixture was bubbled through with N₂ for 5 min. The mixture was heated to 120 °C and stirred at this temperature for 1.5 h under microwave conditions. LCMS analysis showed consumption of the starting material with formation of the desired product mass. To the mixture was added H₂0 (40 mL). The mixture was filtered and the filter cake was washed with H₂0 (10 mL). The filter cake was collected and combined with the crude material obtained from a reaction run in the identical manner with 540 mg tert- butyl [(6-bromo-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl]methylcarbamate (1.52 mmol). To the combined solids was added EtOAc (10 mL) and petroleum ether (15 mL). The mixture was slurried for 10 min and then filtered. The filter cake was collected and dried under vacuum. The solid was purified by preparative HPLC on a Phenomenex Synergi Max-RP column (150 x 50 mm, 10 pm particle size), which was eluted with 50-80% MeCN/H₂0 (+0.225% formic acid) with a flow rate of 120 mL/min. The product-containing fractions were basified to pH ~7 with saturated aqueous NaHCCh and then extracted with EtOAc (2x200 mL). The combined organics were washed with brine (200 mL), dried over Na₂S0₄, filtered and concentrated to provide the title compound (800 mg, 39%, 80% ee). The enantio-enriched material was purified by preparative chiral SFC on a Diacel Chiralcel OJ-H column (250 mm x 30 mm, 5 pm particle size), which was eluted with 25% EtOH in C0₂ (+0.1% NH₄OH) at a flow rate of 60 mL/min to provide the title compound (243 mg, 14% yield, >99% ee) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 9.11 (s, 1H), 8.61 (d, J = 8.5 Hz, 1H), 8.12 (t, J = 8.0 Hz, 1 H), 7.94 (s, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 7.73 - 7.50 (m, 1 H), 6.00 - 5.75 (m, 1 H), 5.22 - 5.06 (m, 2H), 4.59 - 4.48 (m, 2H), 3.28 - 3.13 (m, 1H), 3.05 - 2.92 (m, 1 H), 2.92 - 2.82 (m, 3H), 1.78 - 1.62 (m, 3H), 1.51 - 1.23 (m, 9H). m/z (ESI) for (C^H^BrFsNeOs), 632.9 (M+Na)⁺

Step 3: tert- butyl methyl{[1-oxo-6-(oxolan-3-yl)-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4- triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}carbamate

This reaction was conducted in 5 parallel batches. To each of 5x8 mL vials equipped with a magnetic stir bar was added tert- butyl {[6-bromo-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]- 4/-/-1,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (21.5 g, 0.0353 mmol), 3-bromotetrahydrofuran (7.99 mg, 0.0529 mmol), 2,6-lutidine (7.56 mg, 0.0706 mmol), (TMS)₃SiH (8.77 mg, 0.0353 mmol), DMSO (0.175 mL, c = 0.1 M) and 1 ,4-dioxane (0.175 mL, c = 0.1 M). The photocatalyst (4,4'-di-te/f-butyl-2,2'-bipyridine-K²/\/¹,/\/ )bis{3,5- difluoro-2-[5-(trifluoromethyl)pyridin-2-yl-K/\/]phenyl-KC¹}iridium (0.396 mg, 0.000353 mmol) was added as a solution in DMSO (0.05 ml_) followed by a mixture of 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbbpy) (0.0473 mg, 0.000176 mmol) and NiC 'glyme (0.0388 mg, 0.000176 mmol) as a stock solution in DMSO (0.050 ml_). The mixture was sparged with N₂ for 3 min. The vials were sealed and irradiated for 48 h with blue LEDs (Kessil lamb, 7 cm distance) with fan cooling. LCMS analysis showed formation of the desired product mass. The reactions were combined and concentrated. The crude was purified by preparative SFC on a DuraShell column (150 x 25 mm, 5 pm particle size), eluting with a gradient of 37-77% MeCN/hhO (+0.05 % NhUOH) with a flow rate of 25 mL/min to provide the title compound (19 mg, 18% yield, —1:1 mixture of diasereoisomers) as a white solid m/z (ESI) for (C₃₀H₃₅F₃N₆O₄), 623.3 (M+Na)⁺

Step 4: 4-[(methylamino)methyl]-6-[^)-tetrahydrofuran-3-yl]-2-(6-{4-[^)-4,4,4-trifluorobutan- 2-yl]-4/-/- 1 ,2,4-triazol-3-yl}pyridin-2-yl)-2, 3-dihydro-1 /-/-isoindol- 1 -one hydrochloride

To a solution of tert- butyl methyl{[1-oxo-6-(oxolan-3-yl)-2-(6-{4-[^)-4,4,4-trifluorobutan- 2-yl]-4/-/-1,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}carbamate (19 mg, 0.032 mmol) in MeOH (1.5 mL, c = 0.02 M) was added HCI (4 M in MeOH, 1.5 mL) at 0 °C. The mixture was stirred at 25 °C for 3 h. LCMS analysis showed -40% remaining starting material. The mixture was cooled to 0 °C and additional HCI (4 M in MeOH, 1.5 mL) was added. The mixture was stirred a further 2 h at 25 °C. LCMS analysis showed complete consumption of the starting material. The reaction was concentrated to dryness to provide Example 12 (11.8 mg, 70% yield, -1 :1 mixture of diasereoisomers) as a white solid. ¹H NMR (400 MHz, Methanol-d*) d 9.81 (s, 1H), 8.90 (d, J = 8.5 Hz, 1H), 8.18 (t, J = 7.9 Hz, 1 H), 8.05 - 7.87 (m, 2H), 7.82 (s, 1 H), 6.27 (s, 1 H), 5.39 (s, 2H), 4.36 (s, 2H), 4.27 - 4.04 (m, 2H), 3.97 (q, J = 7.8 Hz, 1 H), 3.82 (dd, J = 8.4, 6.5 Hz, 1 H), 3.69 (q, J = 7.2 Hz, 1 H), 3.27 - 3.09 (m, 2H), 2.87 (s, 3H), 2.57 - 2.40 (m, 1 H), 2.25 - 2.06 (m, 1 H), 1.86 (d, J = 5.2 Hz, 3H). m/z (ESI) for (C₂₅H₂₇F₃N₆O₂), 501.0 (M+H)⁺.

Example 13: 6-(methoxymethyl)-4-[(methylamino)methyl]-2-(6-{4-[^)-4,4,4-trifluorobutan-2- yl]-4/-/-1,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

Step 1: methyl 7-{[(terf-butoxycarbonyl)(methyl)amino]methyl}-3-oxo-2,3-dihydro-1 /-/-isoindole- 5-carboxylate

A mixture of tert- butyl [(6-bromo-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl)methyl] ethylcarba ate (4.3 g, 12.1 mmol), PdC Cdppf) (554 mg, 0.757 mmol), and TEA (3.7 g, 36.3 mmol) in MeOH (100 ml_, c = 0.12 M) was sealed under 50 Psi of CO and heated to 50 °C. The mixture was stirred at this temperature for 24 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The dark red mixture was filtered through a pad of Celite^® and the filter cake was washed with MeOH (250 ml_). The combined filtrate was concentrated to provide a yellow solid. The residue was stirred in EtOAc (30 ml_) at 20 °C for 30 min. The suspension was filtered. The filter cake was washed with EtOAc (20 ml_), collected, and dried to provide a pink solid, which ¹H NMR showed was contaminated with Et₃N_*HBr. The solid was taken up in DCM (200 ml_), washed with water (50 ml_) and brine (50 ml_), dried over Na₂S04, filtered and concentrated to provide the title compound (3.7 g, 91 % yield) as an orange solid. ¹H NMR (400 MHz, DMSO-de) d 9.23 (br. s, 1H), 8.81 (s, 1 H), 8.09 (s, 1 H), 7.98 (br. s, 1 H), 4.55 (s, 2H), 4.43 (s, 2H), 3.89 (s, 3H), 2.79 (s, 3H), 1.56 - 1.29 (m, 9H). m/z (ESI) for (C17H22N2O5), 335.1 (M+H)⁺.

Step 2: tert- butyl {[6-(hydroxymethyl)-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl]methyl}methylcarbamate

To a solution of 7-{[(te/f-butoxycarbonyl)(methyl)amino]methyl}-3-oxo-2,3-dihydro-1/-/-isoindole- 5-carboxylate (3.7 g, 11.1 mmol) in DCM (100 ml_, c = 0.11 M) was added DIBAL-H (1 M in toluene, 44.3 ml_, 44.3 mmol) dropwise at 0-5 °C under N₂. After addition the mixture was stirred at 25 °C for 1 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The reaction was quenched with H2O (5 mL). Anhydrous Na2SC>4 (25 g) was added. The mixture was stirred at 15 °C for 1 h and then the suspension was filtered. The filter cake was stirred with DCM/MeOH (10:1) and then re-filtered. The combined filtrates were concentrated to provide a red gum. The residue was taken up in EtOAc (20 mL) and sonicated for 5 min. Some solids precipitated, which were collected by filtration. The filter cake was washed with EtOAc (5 mL) and DCM (5 mL), collected, and dried to provide the title compound (2.2 g, 65% yield) as a gray solid. ¹H NMR (400 MHz, DMSO-de) d 8.55 (s, 1H), 7.59 - 7.49 (m, 1 H), 7.35 (s, 1 H), 5.39 - 5.29 (m, 1 H), 4.58 (d, J = 5.8 Hz, 2H), 4.48 (s, 2H), 4.29 (s, 2H), 2.76 (s, 3H), 1.57 - 1.26 (m, 9H). m/z (ESI) for (C16H22N2O4), 307.1 (M+H)⁺.

Step 3: tert- butyl {[6-({[terf-butyl(dimethyl)silyl]oxy}methyl)-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl]methyl}methylcarbamate

To a stirred suspension of tert- butyl {[6-(hydroxymethyl)-1-oxo-2,3-dihydro-1/-/-isoindol-4- yl]methyl}methylcarbamate (200 mg, 0.653 mmol) and imidazole (66.7 mg, 0.979 mmol) in dry DCM (10 ml_, c = 0.065 M) was added TBSCI (148 mg, 0.979 mmol) at 0 °C under N2. The solution was stirred at 0 °C for 15 h. TLC analysis showed consumption of the starting material. The mixture was diluted with DCM (30 ml_), washed with brine (10 ml_), dried over Na2SC>4, filtered, and concentrated to provide a brown gum. The residue was purified by flash chromatography (Biotage, S1O2, EtOAc) to provide the title compound (160 mg, 58% yield) as a light brown gum. ¹H NMR (400 MHz, CDCI₃) 67.73 (s, 1 H), 7.40 (s, 1 H), 6.37 (br. s, 1H), 4.81 (s, 2H), 4.52 (br. s, 2H), 4.38 (s, 2H), 2.80 (br. s, 3H), 1.56 - 1.40 (m, 9H), 1.00 - 0.92 (m, 9H), 0.15 - 0.08 (m, 6H).

Step 4: terf-butyl {[6-({[te/f-butyl(dimethyl)silyl]oxy}methyl)-1-oxo-2-(6-{4-[^)-4,4,4- trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1 /-/-isoindol-4- yl]methyl}methylcarbamate

A mixture of terf-butyl {[6-({[terf-butyl(dimethyl)silyl]oxy}methyl)-1-oxo-2,3-dihydro-1/-/- isoindol-4-yl]methyl}methylcarbamate (160 mg, 0.38 mmol), 2-bromo-6-{4-[^)-4,4,4- trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridine (127 mg, 0.38 mmol) and K₃PO₄ (242 mg, 1.14 mmol) in 1,4-dioxane (10 ml_, c = 0.038 M) was evacuated and backfilled with N₂ (3x). Pd₂(dba)₃ (17.4 mg, 0.019 mmol) and Xantphos (44 mg, 0.076 mmol) and the reaction was evacuated and backfilled with N₂ (3x). The mixture was heated to 85 °C and stirred at this same temperature for 2.5 h. TLC (petroleum ether/EtOAc = 1 :2) analysis showed consumption of the starting material. The yellow reaction mixture was cooled to 20 °C. The reaction mixture was filtered through a pad of Celite^®, which was washed with 10% MeOH/DCM (3x20 mL). The filtrate was concentrated to provide a brown solid. The residue was purified by preparatory TLC (petroleum ether/EtOAc = 1:2, R_f = 0.4) to provide the title compound (200 mg, 78% yield) as a white solid. ¹H NMR (400 MHz, CDC ) d 8.77 (dd, J = 8.4, 0.9 Hz, 1 H), 8.39 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.48 (s, 1 H), 6.35 - 6.10 (m, 1H), 5.03 (s, 2H), 4.84 (s, 2H), 4.71 - 4.31 (m, 2H), 3.00 - 2.61 (m, 5H), 1.80 (s, 3H), 1.40 (s, 9H), 0.96 (s, 9H), 0.13 (s, 6H). m/z (ESI) for (C₃₃H₄₅N₆0₄Si), 675.4 (M+H)⁺.

Step 5: tert- butyl {[6-(hydroxymethyl)-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1,2,4- triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate

To a solution of tert- butyl {[6-({[te/f-butyl(dimethyl)silyl]oxy}methyl)-1-oxo-2-(6-{4-[^)- 4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4- yl]methyl}methylcarbamate (200 mg, 0.296 mmol) in THF (10 ml_, c = 0.03 M) was added TBAF (155 mg, 0.593 mmol). The mixture was stirred at 18 h for 75 °C. LCMS analysis showed consumption of the starting material with formation of the product mass. To the reaction mixture was added H2O (30 ml_). The mixture was extracted with EtOAc (2x20 ml_). The combined organics were washed with H2O (30 ml_) and brine (30 ml_), dried over Na₂S0₄, filtered, and concentrated to provide a yellow solid. The residue was purified by flash chromatography (Biotage, S1O2, 0-10% MeOH/EtOAc) to provide the title compound (160 mg, 70% purity, 67% yield) as a white solid, which was taken on without further purification m/z (ESI) for (C₂₇H_3iF₃N₆0₄), 561.3 (M+H)⁺.

Step 6: tert- butyl {[6-(methoxymethyl)-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1,2,4- triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate

A 100 mL 3-neck flask was dried under argon and then charged with a solution of tert- butyl {[6-(hydroxymethyl)-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1,2,4-triazol-3- yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (112 mg, 0.14 mmol, 70% purity) in THF (9 mL, c = 0.014 M). The mixture was cooled to 0 °C and then a solution of Mel (34.4 mg, 0.243 mmol) in THF (1 mL) and solid KOtBu (27.2 mg, 0.243 mmol) were added. After 1 h at 0 °C the reaction was analyzed by LCMS, which showed consumption of the starting material with formation of the desired product mass. To the reaction mixture was added saturated aqueous NH₄CI (20 mL). The mixture was extracted with EtOAc (3x15 mL). The combined organics were washed with brine (30 mL), dried over Na₂S0₄, filtered, and concentrated to dryness. The reside was purified by preparatory TLC (EtOAc, R_f = 0.6) to provide tert- butyl {[6- (hydroxymethyl)-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-1 ,2,4-triazol-3-yl}pyridin-2-yl)- 2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (50 g, 62% yield, 80% ee) as a white solid. The enantio-enriched material was purified by chiral preparatory SFC with a Diacel Chiralpak IC column (250 x 30 mm, 5 pm particle size), which was eluted with 55% MeOH in CO2 (+0.1% NH4OH) with a flow rate of 50 mL/min to provide the title compound (20 mg, 25% yield, >99% ee) as a white solid m/z (ESI) for (C28H33F3N6O4), 575.4 (M+H)⁺.

Step 7: 6-(methoxymethyl)-4-[(methylamino)methyl]-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-

1.2.4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-1-one hydrochloride

To a mixture of terf-butyl {[6-(hydroxymethyl)-1-oxo-2-(6-{4-[^)-4,4,4-trifluorobutan-2-yl]-4/-/-

1.2.4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1/-/-isoindol-4-yl]methyl}methylcarbamate (20 mg, 0.035 mmol) in EtOAc (3 ml_, c = 0.007 M) was added HCI (4 N in EtOAc, 2 ml_) at 0 °C. The mixture was stirred at 25 °C for 1.5 h. LCMS analysis showed consumption of the starting material with formation of the desired product mass. The mixture was concentrated and then dried by lyoplilization to provide Example 13 (14.1 mg, 79% yield) as a white solid. ¹H NMR (400 MHz, DMSO-de) d 9.66 - 9.44 (m, 2H), 9.17 (s, 1 H), 8.67 (d, J = 8.3 Hz, 1 H), 8.13 (t, J = 8.0 Hz, 1H), 7.93 - 7.85 (m, 3H), 6.01 (ddd, J = 4.3, 6.3, 10.5 Hz, 1H), 5.54 - 5.37 (m, 2H), 4.60 (s, 2H), 4.31 - 4.14 (m, 2H), 3.38 (s, 3H), 3.32 - 3.19 (m, 1 H), 3.17 - 3.03 (m, 1 H), 2.63 (t, J = 5.1 Hz, 3H), 1.72 (d, J = 6.5 Hz, 3H). m/z (ESI) for (C23H25F3N6O2), 475.2 (M+H)⁺.

Additional compounds of the invention were prepared by modifications of the methods exemplified herein. Except where otherwise indicated, all compounds having chiral centers were prepared and/or isolated as a single enantiomer having a known relative configuration. Compounds marked “absolute stereochemistry unknown” were typically prepared from racemic intermediates and resolved into single enantiomers by an appropriate chiral preparative SFC method before characterization and testing. Where the absolute stereochemistry is unknown for a pair of enantiomers, the stereochemistry represented in Table 1 is assigned based on the sign of the optical rotation ([a]_D ²⁰) and the relative biological activity, by analogy to compounds having known absolute configurations. Compounds marked “absolute stereochemistry known” were typically prepared from chiral intermediates having known stereochemistry.

Selected compounds and their corresponding characterization data are presented in Table 1 below:

Table 1

For the Examples in Table 1, here stereochemistry is not known, “or1,” or “or2”is at the chiral carbon atom. The bond drawn at that carbon is a representation of the stereochemistry; meaning, the carbon would have that bond configuration drawn or the opposite configuration. Racemic compounds are indicated by an arbitratily drawn stereocenter and the annotation “&1”. Bioloqical Assays and Data

HPK1 biochemical enzyme assay

HPK1 enzyme inhibition was measured using a microfluidic mobility shift assay (MSA). The reactions were conducted in 50 mI_ volumes in 96-well plates, and contained 0.5 nM human full-length recombinant HPK1, 3 mM phosphoacceptor peptide, 5FAM-AKRRRLSSLRA- COOH (CPC Scientific, Sunnyvale, CA), test compound (11-dose 3-fold serial dilutions, 2% DMSO final) or DMSO only, 0.002% Tween-20, 1 mM DTT and 2.5 mM MgCh in 50 mM MOPS (3-(N-morpholino)propanesulfonic acid), pH 7.8, buffer and were initiated by addition of 75 mM ATP, following a 20-min preincubation. The reactions were conducted for 60 min at 37 °C, stopped by the addition of 50 mI_ of 0.015 M EDTA, pH 8, and the extent of reactions (-15-20% conversion with no inhibitor) was determined after electrophoretic separation of the fluorescently labeled peptide substrate and phosphorylated product on an LabChip EZ Reader II (PerkinElmer, Inc., Waltham, MA).

Inhibition of HPK1 was also measured using the fluorescence-based chelation-enhanced fluorescence (CHEF) method (1), using a proprietary fluorescent peptide substrate, in which a cysteine residue is alkylated with a sulfonamido-oxine based derivative to afford an amino acid termed C-Sox (CSx). The assay was conducted similarly as described for the MSA method above, but using 3 mM Ac-[CSx]HSLPRFNR-amide peptide substrate (also known as AQT0178 when purchased from AssayQuant Technologies Inc., Hopkinton, MA) and 45 mM ATP. Initial reaction velocities were determined by following the peptide fluorescence (A_ex = 360 nm, A_em = 500 nm) at 30 °C for 15 min in a T ecan M 1000 plate reader (T ecan Group Ltd. , Mannedorf, Zurich, Switzerland). The inhibition constant ( i) values were calculated by fitting the % conversion based (MSA method) or fluorescence based initial velocities (CHEF method) to the Morrison equation (2) for tight-binding competitive inhibition using non-linear regression method and an experimentally measured ATP K_m (29 mM by MSA and 19 mM by CHEF, respectively). The inhibitors were shown to be ATP-competitive from kinetic and crystallographic studies. HPK1 protein was produced in-house and preactivated by autophosphorylation of enzyme with MgATP as described in the section “Production of recombinant autophosphorylated full-length HPK1”.

Cell Based Assavs

Phospho-SLP-76 (Ser376) Homogeneous Time Resolved Fluorescence Assay

Jurkat cells were seeded at 90,000 cells/well in 90uL of RPMI1640 growth medium containing 10% FBS and incubated at 37°C with 5% CO2 overnight. The following day, compounds were serially diluted from a 10mM top dose for an 11-point 3 fold dilution curve in DMSO. Compounds were intermediately diluted 1 :100 into growth media prior to diluting 1 :10 on cells for final concentration 10mM to 0.1 nM in 0.1% DMSO. After 30 min pre-treatment with compounds, the cells were stimulated using 200pg/ml_ of F(ab)2 complexed anti-CD3 (clone UCTH1) for 15 min at 37°C with 5% CO₂. Stimulation was stopped with ice cold PBS and cells were harvested by centrifugation before lysis in Cisbio lysis buffer (Cisbio, Bedford, MA). Lysates were transferred to white, low-volume plates containing anti-phospho-SLP-76-Cryptate plus anti- phospho-SLP-76-d2 HTRF antibodies and incubated overnight at room temperature protected from light according to the manufacturer’s protocol (Cisbio, Bedford, MA). HTRF was measured on a Perkin Elmer Envision and IC50 values were calculated by concentration-response curve fitting utilizing four-parameter nonlinear regression analyses. Biological activity data for selected compounds is provided in Table 2. The data for the

HPK1 Mobility Shift Assays (MSA) and the similar assay of MSA but with AQT0178 substrate are provided in Table 2 as Ki (mM). The data for the Phospho-SLP-76 (Ser376) Homogeneous Time Resolved Fluorescence (HTRF) assays are provided in Table 2 as IC₅₀ (m).

Table 2.

107

All publications and patent applications cited in the specification are herein incorporated by reference in their entirety. It will be apparent to those of ordinary skill in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

What is claimed is:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, halogen, (Ci-Ce)alkyl, halo(Ci- C₆)alkyl, (Ci-Ce)alkoxy, halo(Ci-C₆)alkoxy, -N(R⁶)(R⁷), -SO2CH₃, (C₃-C₆)cycloalkyl, (C₃- C₆)cycloalkoxy, (4- to 6-membered)heterocycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, (C3-C6)cycloalkyl, (4- to 6- membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, and (C3-Ce)cycloalkoxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkyl, halo(Ci-Ce)alkoxy, (C₃-C₆)cycloalkyl, -N(R⁶)(R⁷);

R⁶and R⁷are each independently selected from the group consisting of hydrogen and (Ci-Ce)alkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, and hydroxy, or R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 8-membered)heterocycloalkyl that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Cr Ce)alkoxy, and halo(Ci-Ce)alkoxy, wherein said (Ci-Ce)alkyl, and halo(Ci-Ce)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, and (CrCe)alkoxy;

R² is: i) hydrogen; ii) -(CH2)_mN(R⁸)(R⁹), wherein m is an integer selected from 0, 1, 2, or 3, and R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, -C(0)(C C₃)alkyl and -C(0)NH(C C₃)alkyl, wherein said (C C₆)alkyl, -C(0)(C Cs)alkyl and -C(0)NH(CrC₃)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, oxo, hydroxy, and (4- to 6-membered)heterocycloalkyl; iii) (Ci-Ce)alkyl, wherein said (Ci-C₆)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, (CrCe)alkoxy, cyano, and hydroxy; iv) a (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (CrCe)alkyl, halo(CrCe)alkyl, (CrCe)alkoxy, and halo(Cr C₆)alkoxy, wherein said (Ci-Ce)alkyl and halo(Ci-Ce)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, and (CrCe)alkoxy; or V) -S0₂-NH₂;

R^2a is selected from the group consisting of hydrogen, halogen, (Ci-Ce)alkyl, halo(Ci- C₆)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, -N(R⁶)(R⁷), (4- to 6-membered)heterocycloalkyl, wherein said (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-C₆)alkyl, and (4- to 6- membered)heterocycloalkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, and (C3-Ce)cycloalkyl;

R³ is selected from the group consisting of hydrogen, halogen, hydroxy, (Ci-Ce)alkyl, halo(Ci-C₆)alkyl, (Ci-Ce)alkoxy, and halo(Ci-Ce)alkoxy;

X is carbon or nitrogen;

R⁴ is a (Ci-Ce)alkyl, (Ci-C₆)alkoxy, -C(O)N(R¹⁰)(R¹¹), (C₆-Cio)aryl, 0-(C₆-Cio)aryl, (C₃- C₆)cycloalkyl, 0-(C₃-C₆)cycloalkyl, NH-(C3-C6)cycloalkyl, a (4- to 6-membered)heterocycloalkyl or a (5- to 10-membered)heteroaryl, wherein said (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C₆-Cio)aryl, O- (Ce-Cio)aryl, (C3-C6)cycloalkyl, 0-(C₃-C₆)cycloalkyl, NH-(C3-C6)cycloalkyl, a (4- to 6- membered)heterocycloalkyl and (5- to 10-membered)heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, (C3-Ce)cycloalkyl, and (4- to 6-membered)heterocycloalkyl, wherein said (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkoxy, and halo(Ci-C₆)alkoxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkoxy, and (C3-Ce)cycloalkyl, wherein the (Ci-Ce)alkoxy, and (C3-Ce)cycloalkyl are optionally substituted with 1 to two halogen; and wherein R¹⁰and R¹¹ are each independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, and (C3-Ce)cycloalkyl, wherein said (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, and (C3-C6)cycloalkyl;

R⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, (Ci-Ce)alkyl, halo(Ci-C₆)alkyl, (Ci-Ce)alkoxy, and halo(Ci-Ce)alkoxy; and a is an integer selected from 0 or 1, provided that when X is nitrogen a is 0, and provided that at least one of R¹, R², and R^2a is other than hydrogen.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a (CrCe)alkyl that is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, wherein the alkyl is optionally substituted with 1 substituent selected from the group consisting of hydroxy, cyano, -N(R⁶)(R⁷), and (CrCe)alkoxy.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is (CrCe)alkoxy that is methoxy, ethoxy, or propan-2-yl-oxy, wherein the alkoxy is substituted with 1 substituent selected from the group consisting of hydroxy, and -N(R⁶)(R⁷).

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a halo(Ci-Ce)alkoxy selected from the group consisting of fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, wherein said fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, cyano, -N(R⁶)(R⁷), (Ci-Ce)alkyl, and (C3-Ce)cycloalkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a (4- to 6-membered)heterocycloalkyl selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a (5- to 6-membered)heteroaryl selected form the group consisting of imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, pyrazinyl, oxazolyl, and thiadiazolyl, each being optionally substituted with 1 to 3 substitutents selected from the group consisting of halogen, hydroxy, cyano, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkoxy, and halo(Ci-C₆)alkoxy.

7. The compound according to claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R² is -(CH2)m-N(R⁸)(R⁹), wherein m is 0, and wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, methyl, hydroxymethyl, ethyl, and hydroxyethyl.

8. The compound according to claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a (5- to 6-membered)heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, hydroxy, (Ci-Ce)alkyl, halo(CrC₆)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, and (C3-Ce)cycloalkyl.

9. The compound according to claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a (4- to 6-membered)heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-Ce)alkoxy, and (C3-C6)cycloalkyl.

10. The compound according to claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X is carbon.

11. The compound according to claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R^2a is hydrogen.

12. The compound according to claims 1-11 , or a pharmaceutically acceptable salt thereof, wherein R³ is hydrogen.

13. A pharmaceutical composition comprising a compound of any of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

14. A method for the treatment of abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of claims 1 to 14, or a pharmaceutically acceptable salt thereof.