EA044841B1 - 2,3-DIHYDRO-1H-PYRROLO[3,4-c]PYRIDIN-1-ONE DERIVATIVES AS HPK1 INHIBITORS FOR THE TREATMENT OF CANCER - Google Patents

Description

Field of invention

The present invention relates to compounds of formulas I, II or III, and their pharmaceutically acceptable salts, pharmaceutical compositions that contain such compounds and salts, and their use. The compounds, salts and compositions of the present invention are useful for treating or normalizing abnormal cell proliferative disorders such as cancer.

Prerequisites for creating the invention

Hematopoietic precursor kinase 1 (HPK1), also known as mitogen-activated protein kinase 1 (MAP4K1), is a member of the mammalian Ste20-like serine/threon kinase family that acts through the JNK and ERK signaling pathways. HPK1 is primarily expressed in hematopoietic organs and cells (eg, T cells, B cells, and dendritic cells), suggesting a potential role for HPK1 in the regulation of signaling in hematopoietic cell lines, 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, when the T cell receptor (TCR) is activated, HPK1 kinase is applied to the plasma membrane, resulting in full activation of the kinase.

This full activation of the kinase leads to HPK1 phosphorylation of the SLP76 adapter protein, which ultimately leads to destabilization of the TCR signaling complex, which further interferes with the mitogen-activated protein (MAP) kinase signaling events required for T-cell activation and proliferation. (Hernandez, et al., The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function, Open Cell Reports 25, 80-94, October 2, 2018). HPK1 kinase has also been shown to negatively regulate T cell signaling by the PGE2 receptor in a PKA mode dependent manner. In addition, HPK1 kinase has been reported to play a role in: i) activation-induced cell death (AICD) and JNK activation; ii) regulating leukocyte function-associated antigen-1 (LFA-1) integrin activation on T cells by direct competition with adhesion-promoting and degranulation-promoting protein (ADAP) to bind to the SLP76 SH2 domain; and iii) regulating activation using nuclear factor κB (NF-κB) signaling through interaction with IKK-α and -β. The study also showed that HPK1 negatively regulates MAP kinase pathway signaling and Ap-1 transcription in T cells. (Hernandez, et al. 2018).

Research to date on HPK1 kinase suggests that HPK1 plays a role in enhancing T cell responses and enhancing antitumor immunity.

The essence of the invention

The present invention provides, in part, the compounds of formulas I, II and III, and pharmaceutically acceptable salts thereof. Such compounds can inhibit HPK1 kinase activity, thereby exerting biological functions. Also provided are pharmaceutical compositions and medicaments that contain the compounds or salts of the present 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 for using the foregoing.

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

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, halogen(C1C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)alkoxy, -N( ^R6 )( ^R7 ) and (C3- _C6 )cycloalkyl, wherein said ( _C1 - _C6 )alkyl, halogen( _C1 - _C6 )alkyl and ( _C3 - _C6 )cycloalkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C ₁ C ₆ )alkyl and (C ₁ -C ₆ )alkoxy;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C1C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, ( C1-C6)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 which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C1- _C6 )alkyl, halogen( _C1 - _C6 )alkyl _, ( _C1 - _C6 )alkoxy and halogen( _C1C6 )alkoxy, wherein said ( _C1 -C ₆ )alkyl and halogen(C ₁ -C ₆ )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano,

- 1 044841 (C1-Cb)alkyl and ( _C1 - _C6 )αalkoxy;

R ^1a is selected from the group consisting of hydrogen and halogen.

R ² represents:

i) -(CH ₂ ) _m N(R ⁸ )(R ⁹ ), in which m is an integer selected from 0, 1, 2, or 3, and R ⁸ and R ⁹ are each independently selected from the group, which consists of hydrogen and (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C1-C6)alkoxy, cyano and hydroxy, or ^R8 and ^R9 , taken together with the nitrogen to which they are attached, form a (4- to 6-membered) heterocycloalkyl which is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C1- _C6 )alkyl, halogen( _{C1- C6} )alkyl, ( _C1 - _C6 )alkoxy and halogen( _C1 - _C6 )alkoxy, wherein said ( _C1 - _C6 )alkyl and halogen (C ₁ -C ₆ )alkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano and (C1C ₆ )alkoxy;

ii) (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkoxy, - N(R ⁶ )(R ⁷ ), cyano and hydroxy, wherein R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C ₁ -C ₆ )alkyl; or iii) (4- to 6-membered) heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C ₁ -C ₆ )alkyl, halogen (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy, wherein said (C ₁ -C ₆ )alkyl and halogen(C ₁ -C ₆ )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano and (C1C ₆ )alkoxy;

R ³ is selected from the group consisting of hydrogen, halogen, hydroxy, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy;

X represents carbon or nitrogen;

R ⁴ represents (4- to 6-membered) heterocycloalkyl or (5- to 10-membered) heteroaryl, wherein said (4- to 6-membered) heterocycloalkyl and (5- to 10-membered) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, oxo, hydroxy, -N(R ¹⁰ )(R ¹¹ ), (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)alkoxy and -(CH2)n(C3-C6)cycloalkyl, wherein said (C1-C6)alkyl and halogen(C1-C6)alkyl are optionally substituted from one to three substituents selected from the group consisting of halogen, hydroxy, cyano and (C1-C6)alkoxy, and in which n is an integer selected from 0, 1 or 2; and wherein R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen and (C 1 -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from a group that consists of halogen and hydroxy;

R ⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy; and a is an integer selected from 0 or 1, with the proviso that when X is nitrogen, a is 0.

In another embodiment, the invention provides a pharmaceutical composition that contains a compound of any one of the formulas described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients.

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

In another embodiment, the invention provides a method of treating abnormal cell growth, particularly cancer, in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The compounds of the present invention may be administered as single agents, or may be administered in combination with other anticancer therapeutic agents, in particular standard treatment agents that are appropriate for a particular type of cancer.

In a further embodiment, the invention provides a method of treating abnormal cell growth, particularly cancer, in a subject in need thereof, which comprises administering to the subject a specified amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a specified amount of an additional anticancer therapeutic agent , which together are effective in treating said abnormal cell growth.

In another embodiment, the invention relates to a compound according to the invention, or a pharmaceutically acceptable salt thereof, for use as a medicine, in particular

- 2 044841 medicinal products for the 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, particularly 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 provides a pharmaceutical composition for use in treating abnormal cell growth in a subject in need thereof, the composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the invention provides for the use of a compound of any one of the formulas described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of abnormal cell growth in a subject.

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

In some embodiments, the methods and uses result in one or more of the following effects: (1) inhibition of cancer cell proliferation; (2) inhibition of cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibition of cancer cell metastasis; (5) inhibition of angiogenesis; (6) enhanced T cell responses; or (7) increasing antitumor activity.

In another embodiment, the invention provides a method of treating HPK1-related disorders and enhancing the immune response in a subject, which comprises administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective to treat the disorder, particularly cancer. In some embodiments, the disorder is a cancer that is characterized by amplification or overexpression of HPK1 kinase.

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

It should be understood that both the foregoing general description and the following detailed description are illustrative and explanatory only, and do not limit the invention claimed.

In addition, each of the embodiments that describe the invention below includes within its scope pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase or a pharmaceutically acceptable salt thereof, as intended herein, covers all compounds described herein.

Detailed description

Definitions and explanations.

The present invention can be more easily understood with reference to the following detailed description of the preferred embodiments of the invention and the examples included herein. It should be understood that the terminology used herein is intended to describe specific embodiments only and is not intended to be limiting. It is further understood that, unless specifically defined herein, terminology used herein is to be given its generally accepted meaning as known in the relevant art.

As used herein, terms in the singular include references to the plural unless otherwise indicated. For example, a substituent includes one or more substituents.

The term approximately refers to a relative term that means from about plus or minus 10% of the nominal value to which it refers, in one embodiment, to about plus or minus 5%, in another embodiment, to about plus or minus 2% . For the industry of the disclosure presented, this level of approximation is appropriate unless the value is specifically stated to require a more restrictive range.

As used herein, the term "n-membered" when n is an integer generally describes the number of ring-forming atoms in a fragment where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring, and thiazole is an example of a 5-membered heteroaryl ring.

- 3 044841

At various places in the present description, substituents in the compounds of the invention are disclosed in groups or ranges. The invention is specifically intended to include each distinct subcombination of members of such groups and ranges. For example, the term ''C _{1_6} αlkyl'' is specifically intended to include C1 alkyl ( _methyl ), C2 alkyl (ethyl), C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl. In another example, the term 5- to 6-membered heteroaryl group is specifically intended to include any 5- to 6-membered heteroaryl group.

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

The invention described herein can accordingly be practiced in the absence of any element(s) not specifically described herein. Thus, for example, in each example herein, any of the terms which contains, which consists essentially of, and which consists of may be replaced by either of the other two terms.

The term (C ₁ -C ₆ )alkyl, as used herein, refers to a saturated branched or straight chain alkyl group that contains from 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl , isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, npentyl, isopentyl, neopentyl and n-hexyl. (C ₁ -C ₆ )alkyl may be optionally substituted, in which one or more hydrogen atoms are substituted with a substituent selected from the group consisting of halogen, cyano, hydroxy, -SF5, nitro, -(C ₁ -C ₆ ) alkoxy and -N(R ⁶ )(R ⁷ ), in which R ⁶ and R ⁷ are each independently selected from hydrogen and (C ₁ -C ₆ )alkyl. For example, a (C ₁ -C ₆ )alkyl moiety may be substituted with one or more halogen atoms to form a halogen(C ₁ C ₆ )alkyl. Illustrative examples of halogen(C ₁ -C ₆ )alkyl include, but are not limited to, fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, and pentafluoroethyl. Other illustrative examples of substituted (C ₁ -C ₆ )alkyl include, but are not limited to, cyanobutyl and ethoxyethyl.

The term halogen(C ₁ -C ₆ )alkyl, as used herein, refers to a (C ₁ -C ₆ )alkyl group as defined above, wherein the alkyl group is substituted with one or more halogen atoms. For example, halogen(C ₁ -C ₆ )alkyl may be selected from fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl.

The term (C ₂ -C ₆ )alkenyl refers to an aliphatic hydrocarbon that has from 2 to 6 carbon atoms, and which has at least one carbon-carbon double bond, including straight chain or branched chain groups that have at least at least one carbon-carbon double bond. Illustrative examples include, but are not limited to, ethenyl, 1-propenyl, 2propenyl (alyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. When the compounds of the invention contain a (C ₂ -C ₆ )alkenyl group, the compound may exist as a pure E (entgegen) form, a pure Z (zusammen) form, or any mixture thereof. (C ₂ -C ₆ )alkenyl may be optionally substituted, wherein one or more hydrogen atoms are substituted substituents selected from the group consisting of halogen, cyano, hydroxy, -SF5, nitro, -(C ₁ C ₆ )alkoxy , and -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ are each independently selected from hydrogen and (C1C ₆ )alkyl.

The term (C ₂ -C ₆ )alkynyl refers to an aliphatic hydrocarbon that has from two to six carbon atoms, and which has at least one carbon-carbon triple bond, including straight chain or branched chain groups that have, at least one carbon-carbon triple bond. Illustrative examples include, but are not limited to, ethenyl, propynyl, butynyl, pentynyl and hexynyl. (C ₂ -C ₆ )alkynyl may be optionally substituted, wherein one or more hydrogen atoms are substituted with a substituent selected from the group consisting of halogen, cyano, hydroxy, -SF5, nitro, -(C ₁ -C ₆ ) alkoxy and -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ are each independently selected from hydrogen and (C ₁ -C ₆ )alkyl.

The term (C ₁ -C ₆ )alkoxy, as used herein, refers to a (C ₁ -C ₆ )alkyl group, as defined above, attached to the generic molecular moiety via an acid atom

- 4 044841 kind. Illustrative examples of (C ₁ -C ₆ )alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy and hexyloxy. (C ₁ -C ₆ )αalkoxy may be optionally substituted, wherein one or more hydrogen atoms are substituted, selected from the group consisting of halogen, cyano, hydroxy, -SF5, nitro, -(C ₁ -C ₆ ) alkoxy and -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ are each independently selected from hydrogen and (C ₁ -C ₆ )alkyl. For example, (C ₁ -C ₆ )alkoxy may be substituted with one or more halogen atoms to form halogen(C ₁ -C ₆ )alkoxy. Illustrative examples of halogen(C ₁ -C ₆ )alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy.

The term halogen(C ₁ -C ₆ )alkoxy as used herein refers to a (CiC ₆ )alkoxy group as defined above, wherein the alkoxy group is substituted with one or more halogen atoms. For example, halogen(C ₁ -C ₆ )alkoxy may be selected from fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy.

The term (C ₁ -C ₆ )alkylthio, as used herein, refers to a (C ₁ -C ₆ )alkyl group, as defined above, attached to the parent molecular moiety via a sulfur atom. Representative examples of (C ₁ -C ₆ )alkylthio include, but are not limited to, methylthio, ethylthio, propylthio and the like. (C ₁ -C ₆ )alkylthio may be optionally substituted, wherein one or more hydrogen atoms are substituted by a substituent selected from the group consisting of halogen, cyano, hydroxy, -SF5, nitro, -(C ₁ -C ₆ ) alkoxy and -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ are independently selected from hydrogen and (C ₁ -C ₆ )alkyl.

As used herein, the term (C ₃ -C ₆ )cycloalkyl refers to a carbocyclic substituent obtained by removing hydrogen from a saturated carbocyclic molecule having from 3 to 6 carbon atoms. Cycloalkyl may be a monocyclic ring, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. (C ₃ C ₆ )cycloalkyl may be optionally substituted, wherein one or more hydrogen atoms are substituted when one or more hydrogen atoms are substituted with a substituent selected from the group consisting of halogen, cyano, hydroxy, -SF5, nitro, -( C ₁ -C ₆ )alkoxy and -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ are independently selected from hydrogen and (C ₁ -C ₆ )alkyl.

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

Examples of heterocycloalkyl rings include, but are not limited to, azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl , thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanil, tetrahydrodiazinyl, oxazinyl, oxathiazinyl. Additional 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 , 1,3thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl, 1,2tetrahydrodiazin-2-yl, 1,3 -tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, 2-oxopiperidinyl (eg 2oxo-piperidin-1-yl), azabicyclo[2.2.1]heptyl and the like. One specific example of heterocycloalkyl is 2-oxo-1,3-oxazolidin-3-yl. Heterocycloalkyl may be optionally substituted, wherein one or more hydrogen atoms are substituted with a substituent selected from the group consisting of halogen, cyano, hydroxy, -SF5, nitro, -(C ₁ -C ₆ )alkoxy and -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ are each independently selected from hydrogen and (C ₁ -C ₆ )alkyl.

(C ₆ -C ₁ o)aryl refers to a monocyclic or annelated ring polycyclic all-carbon aromatic group that has a conjugated pi-electron system containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

As used herein, the term heteroaryl refers to an aromatic carbocyclic system containing one, two, three or four heteroatoms independently selected from

- 5 044841 oxygen, nitrogen and sulfur, and having one, two or three rings, and such rings can be fused, where fused is defined above. Ring (5- to 10-membered) heteroaryl refers to a heteroaryl ring having from 5 to 10 ring atoms, in which at least one of the ring atoms is nitrogen and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen. Ring (5-6 membered) heteroaryl refers to a heteroaryl ring having from 5 to 6 ring atoms, in which at least one of the ring atoms is nitrogen and the remaining ring atoms are 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-triazole or 1,2,4triazole), pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, dihydropyrrolotriazolyl and oxadiazolyl. More specific examples of heteroaryls include imidazolyl, 1H-pyrazolyl, thiadiazolyl or triazolyl.

It should be understood that heteroaryl may optionally be annealed with a cycloalkyl group, or with a heterocycloalkyl group, as defined herein.

The heteroaryl substituent can be attached via a nitrogen atom of appropriate valence or via any carbon atom. The heteroaryl unit may optionally be substituted with one or more substituents on a nitrogen atom of the appropriate valency or on any available carbon atom. (5-6 membered)heteroaryl may be optionally substituted when one or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, -SF ₅ , nitro, -(C ₁ -C ₆ )alkoxy and -N(R ⁶ )(R ⁷ ), in which R ⁶ and R ⁷ are independently selected from hydrogen and (C ₁ -C ₆ )alkyl. The substituent can be attached to a heteroaryl motif at any available carbon atom or to a heteroatom when the heteroatom is nitrogen having the appropriate valence.

A halogen or halogen atom as used herein refers to a chlorine, fluorine, bromine or iodine atom.

Hydroxy or hydroxyl, as used herein, denotes an -OH group.

Cyano, as used herein, denotes the -CN group, which, in addition, |—c=l can be represented as ’

Nitro, as used herein, denotes a -NO ₂ group.

Optional/optionally substituted, as used herein, means that the substitution is optional, and therefore includes both unsubstituted and substituted atoms and molecules/fragments. Substituted atom or moiety means that any hydrogen on a specified atom or motif may be replaced by a choice from a specified group of substituents (up to and including each hydrogen atom on a specified atom or motif is replaced by a selection from a specified group of substituents), provided that the normal valence of the specified atom or motif is not exceeded and that the substitution results in a stable compound. For example, if the methyl group (ie -CH3) is optionally substituted, then up to 3 hydrogen atoms per carbon atom may be replaced by substituent groups.

Optionally substituted, as used herein, means that the substitution is optional, and therefore includes both unsubstituted and substituted atoms and molecules. Substituted atom or motif means that any hydrogen on the specified atom or motif can be replaced by a choice from the specified group of substituents (up to the point that each hydrogen atom on the specified atom or motif is replaced by a choice from the specified group of substituents), provided that the normal valence of the specified atom or motif is not exceeded and that the substitution results in a stable compound. For example, if the methyl group (ie -CH3) is optionally substituted, then up to 3 hydrogen atoms per carbon atom may be replaced by substituent groups.

The patient or subject is a warm-blooded animal 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 contained in the preparation and/or with the mammal being treated with it.

The term therapeutically effective amount, as used herein, refers to that amount of a compound that is administered that will alleviate, to a certain extent, one or more symptoms of the disorder being treated. With respect to the treatment of an HPK1 kinase-mediated disorder (eg, cancer), a therapeutically effective amount refers to that amount that has the effect of alleviating 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 tumor size (2) inhibiting (i.e. slowing to some extent, preferably stopping) tumor metastasis (3) inhibiting to some extent (ie, slowing to some extent, essentially stopping) tumor growth or tumor invasiveness and/or (4) alleviating to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer.

The term treatment, as used herein, unless otherwise specified, means reversing, alleviating, inhibiting the progression 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 specified, refers to the effect of treatment as treatment is defined herein. The term treatment also includes adjuvant and neo-adjuvant treatment of a subject.

Isomer means stereoisomer and geometric isomer as defined below.

Stereoisomer refers to compounds that have one or more chiral centers, each of which can exist in an 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 can exist in cis, trans, anti, entgegen (E) and zusammen (Z) forms, as well as mixtures thereof.

As used herein, unless otherwise indicated, the point of attachment of the substituent may be at any suitable position of the substituent. For example, pyridinyl (or pyridyl) may 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 specifying the atom by which such moiety is linked to the substituent, then the substituent may be attached through any corresponding atom in such moiety. For example, in an optionally substituted (5- to 10-membered) heteroaryl, the heteroaryl substituent may be bonded to any carbon atom on the heteroaryl subunit or to a heteroatom of the heteroaryl as valency permits. Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

This description uses the terms substituent, radical, and group interchangeably.

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

Connections

The compounds of formula I, as described above, contain an azalactam (2,3-dihydro-Spyrrolo[3,4-c]pyridin-1-one) core, the pyrole ring being attached via its nitrogen atom to a 6-membered heteroaryl (pyridine or pyrimidine) which is substituted with R ⁴ and optionally with R ⁵ substituent.

In one embodiment, in Formula I as described above, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C ₁ - C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 halogens.

In another embodiment, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each methyl.

In another embodiment, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each ethyl.

In another embodiment, R ¹ is -N(R ⁶ )(R ⁷ ), and one of R ⁶ and R ⁷ is hydrogen and the other is methyl.

In another embodiment, R ¹ is -N(R ⁶ )(R ⁷ ), and one of R ⁶ and R ⁷ is methyl and the other is ethyl.

In yet another embodiment, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ taken together with the nitrogen to which they are attached form a (4- to 8-membered) heterocycloalkyl, which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy. When R ⁶ and R ⁷ taken together form a (4- to 8-membered) heterocycloalkyl, the heterocycloalkyl may be selected from the group consisting of azetidinyl, pyrrolidinyl and azabicyclo[2.2.1]heptyl.

In certain embodiments, R ¹ is azetidinyl, optionally substituted with one to three substituents selected from the group consisting of halogen, (C1C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy.

In certain embodiments, R ¹ is pyrolidinyl, optionally substituted with one to three substituents selected from the group consisting of halogen, (C1C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, and halogen(C ₁ -C ₆ )alkoxy.

In certain other embodiments, R ¹ is (C ₃ -C ₆ )cycloalkyl, wherein said (C ₃ -C ₆ )cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy. When R ¹ is (C ₃ -C ₆ )cycloalkyl, (C ₃ -C6)cycloalkyl is cyclopropyl.

In yet another embodiment, R ¹ is (C ₁ -C ₆ )alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

In another embodiment, R ¹ represents hydrogen.

It should be understood that any of the above subfamilies (embodiments) of R ¹ can be combined together with any of the subfamilies for R ^1a , R ² , R ³ , R ⁴ , R ⁵ , a and X, as described above and hereinafter .

In another embodiment, in Formula I as described above, R ² is -(CH ₂ ) _m N(R ⁸ )(R ⁹ ), in which m is 1, and one of R ⁸ and R ⁹ is hydrogen, and the other is methyl.

In another embodiment, R ² is -(CH ₂ ) _m N(R ⁸ )(R ⁹ ), in which m is 1 and R ⁸ and R ⁹ are both hydrogen.

In certain other embodiments, R ² is 4- to 6-membered heterocycloalkyl, and heterocycloalkyl is azetidinyl.

It should be understood that any of the above subfamilies (embodiments) of R ² can be combined together with any of the subfamilies for R ¹ , R ^1a , R ³ , R ⁴ , R ⁵ , a and X, as described above and hereinafter .

In another embodiment, in Formula I, as described above, R ³ is hydrogen.

In yet another embodiment, in Formula I, as described above, R ⁴ is a (5- to 6-membered) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, -N(R ¹⁰ )(R ¹¹ ), (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)alkoxy, and -(CH2)n(C3- C6)cycloalkyl, wherein n is an integer selected from 0, 1 or 2; and wherein R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen and (C 1 -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from group, which consists of halogen and hydroxy. When R ⁴ is (5- to 6-membered) heteroaryl, the heteroaryl may be 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, or pyrazolyl.

In another embodiment, R ⁴ is a (4- to 6-membered) heterocycloalkyl, optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, oxo, hydroxy, -N(R ¹⁰ )( R ¹¹ ), (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxy, halogen(C1C6)alkoxy and -(CH2)n(C3-C6)cycloalkyl, in which n is an integer a number selected from 0, 1 or 2; and wherein R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen and (C 1 -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from group which consists of halogen and hydroxy, when R ⁴ represents (4- to 6-membered) heterocycloalkyl, the heterocycloalkyl may be oxazolidinyl, optionally substituted with an oxo substituent.

It should be understood that any of the above subfamilies (embodiments) of R ⁴ can be combined together with any of the subfamilies for R ¹ , R ^1a , R ² , R ³ , R ⁵ , a and X, as described above and hereinafter .

In yet another embodiment, in Formula I, as described above, X is nitrogen and a is 0.

In another embodiment, X is carbon, a is 1, and R ⁵ is hydrogen or halogen. When R ⁵ represents a halogen, R ⁵ may represent a fluorine atom.

It should be understood that any of the above subfamilies (embodiments) X may be combined together with any of the subfamilies for R ¹ , R ^1a , R ² , R ³ , R ⁴ , R ⁵ , and a as described above and hereinafter document.

In other embodiments, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ^1a represents H;

R ¹ is (C1-C6)alkyl, halogen(C1-C6)alkyl, -N( ^R6 )( ^R7 ), and (C3- _C4 )cycloalkyl, wherein said ( _C3 - _C4 )cycloalkyl is optionally substituted with one (C ₁ -C ₆ )alkyl;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C1C ₆ )alkyl; or

R ⁶ and R ⁷ are taken together with the nitrogen to which they are attached to form a (4- to 8-membered) heterocycloalkyl, which is an optionally substituted one to three (C1C ₆ )alkyl or halogen(C ₁ -C ₆ )alkyl;

R ² is -(CH2)mN(R ⁸ )(R ⁹ ), in which m is 1, and R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen and (C ₁ -C ₆ ) alkyl;

R ³ represents H;

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X represents carbon;

R ⁵ represents hydrogen;

a represents 1; And

R ⁴ is (5-membered)heterocycloalkyl or (6-membered)heteroaryl, each optionally substituted with 1 to 3 substituents selected from oxo, (C ₁ -C ₆ )alkyl, optionally substituted with hydroxy, halogen (C ₁ -C ₆ )alkyl and -( _CH2 ) _n ( _C3 - _C6 )cycloalkyl, in which n is 0 or 1.

In another embodiment, the invention provides a compound of formula I

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, halogen(C1C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)alkoxy, -N( ^R6 )( ^R7 ) and (C3- _C6 )cycloalkyl, wherein said ( _C1 - _C6 )alkyl, halogen( _C1 - _C6 )alkyl and ( _C3 - _C6 )cycloalkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, ( _CrC6 )alkyl and ( _C1 - _C6 )alkoxy _;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C1C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, ( C1-C6)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 which is optionally substituted with one to three substituents selected from the group which consists of halogen, (C1- _C6 )alkyl, halogen( _C1 - _{C6 )} alkyl, ( _{C1- C6} )alkoxy, and halogen( _C1C6 )alkoxy, wherein said (C ₁ -C ₆ )alkyl and halogen(C ₁ -C ₆ )alkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy;

R ^1a represents H;

R ² is CH2N(R ⁸ )(R ⁹ ), wherein R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen and a (C 1 -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, ( _C1C6 )alkoxy, cyano and hydroxy, or ^R8 and ^R9 , taken together with the nitrogen to which they are attached, form (from 4- to 6-membered)heterocycloalkyl, which is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, ( C ₁ -C ₆ )alkoxy, and halogen(C ₁ -C ₆ )alkoxy, wherein said (C ₁ -C ₆ )alkyl and halogen(C ₁ -C ₆ )alkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano and (C ₁ -C ₆ )alkoxy; And

R ³ represents H;

X represents carbon;

R ⁵ represents hydrogen;

a represents 1; And

R ⁴ represents (4- to 6-membered) heterocycloalkyl or (5- to 10-membered) heteroaryl, wherein said (4- to 6-membered) heterocycloalkyl and (5- to 10-membered) heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, oxo, hydroxy, -N(R ¹⁰ )(R ¹¹ ), (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)alkoxy, and -(CH2)n(C3-C6)cycloalkyl, wherein said (C1-C6)alkyl and halogen(C1-C6)alkyl are optionally substituted from one up to three substituents selected from the group consisting of halogen, hydroxy, cyano and (C1-C6)alkoxy, and in which n is an integer selected from 0, 1 or 2; and wherein R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen and (C 1 -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from group, which consists of halogen and hydroxy.

In another embodiment, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of (C1-C4)alkyl, CF3, -N( ^R6 )( ^R7 ) and (C3- _C4 )cycloalkyl, wherein said ( _C3 - _C4 )cycloalkyl is optionally substituted with one CH ₃ ;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C ₁ C ₃ )alkyl; or

R ⁶ and R ⁷ , taken together with the nitrogen to which they are attached, form a (4- to 5-membered) heterocycloalkyl which is optionally substituted with one to two CH ₃ substituents;

R ² is CH2N(R ⁸ )(R ⁹ ), in which R ⁸ is hydrogen and R ⁹ is selected from the group consisting of hydrogen and CH3; And

R ⁴ is (6-membered)heterocycloalkyl or (6-membered)heteroaryl, wherein said (6-membered)heterocycloalkyl is 1,3-oxazolidin-3-yl, and said (5-membered)heteroaryl is 3-pyrazolyl or triazolyl, each optionally substituted with 1 to 2 substituents selected from the group consisting of oxo, (C ₁ -C ₅ )alkyl, halogen(C ₁ -C ₅ )alkyl and -CH ₂ -cyclopropyl.

In another embodiment, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of (C1-C4)alkyl, CF3, -N( ^R6 )( ^R7 ), and (C3- _C4 )cycloalkyl, wherein said ( _C3 - _C4 )cycloalkyl is optionally substituted with one CH ₃ ;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (CiC ₃ )alkyl; or

R ⁶ and R ⁷ , taken together with the nitrogen to which they are attached, form a (4- to 5-membered) heterocycloalkyl which is optionally substituted with one to two CH ₃ substituents;

R ² is CH2N(R ⁸ )(R ⁹ ), wherein R ⁸ is hydrogen and R ⁹ is selected from the group consisting of hydrogen and CH3; And

R ⁴ is (5-membered)heterocycloalkyl or (6-membered)heteroaryl, wherein said (5-membered)heterocycloalkyl is 2-oxo-1,3-oxazolidin-3-yl, optionally substituted with 1 CH ₃ , CH ₂ F, CHF ₂ , or CF ₃ , and said (6-membered) heteroaryl is 1Hpyrazolyl or triazolyl, optionally substituted with 1 to 2 substituents selected from the group consisting of (C ₁ -C ₅ )alkyl, halogen( C ₁ -C ₅ )alkyl and -CH ₂ -cyclopropyl.

In another embodiment, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ are each independently selected from the group consisting of from hydrogen and (C ₁ -C ₃ )alkyl.

In another embodiment, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ⁶ )(R ⁷ ), wherein R ⁶ and R ⁷ taken together with the nitrogen to which they attached to form a (4- to 5-membered) heterocycloalkyl which is azetidinyl or pyrrolidinyl, and said heterocycloalkyl is optionally substituted with one to two CH3 substituents.

In another embodiment, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of -N(R ⁶ )(R ⁷ ) and (C ₃ -C ₄ )cycloalkyl, wherein said (C ₃ -C ₄ )cycloalkyl is optionally substituted with one CH ₃ ;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C ₁ C ₃ )alkyl; or

R ⁶ and R ⁷ taken together with the nitrogen to which they are attached form a (4- to 5-membered) heterocycloalkyl which is optionally substituted with one to two substituents selected from the group consisting of CH ₃ or halogen(C ₁ )alkyl;

R ² is -CH2N(R ⁸ )(R ⁹ ), wherein R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen and CH3; And

R ⁴ is (6-membered)heterocycloalkyl or (6-membered)heteroaryl, wherein said (5-membered)heterocycloalkyl is 2-oxo-1,3-oxazolidin-3-yl, optionally substituted with 1 substituent selected from group which consists of CH3, CHF2- and CH2F, and said (5-membered)heteroaryl is imidazolyl, N-pyrazolyl, thiadiazolyl or triazolyl, optionally substituted with 1 to 2 substituents independently selected from the group which consists of (C ₁ -C ₅ )alkyl, halogen(C ₁ -C ₆ )alkyl and -(C ₄ -C ₅ )cycloalkyl, wherein said (C ₁ -C ₅ )alkyl is optionally substituted with one hydroxy.

In another embodiment, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ represents -N(R ⁶ )(R ⁷ );

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C1C ₃ )alkyl; or

R ⁶ and R ⁷ taken together with the nitrogen to which they are attached form pyrrolidinyl-1-yl, optionally substituted with 1 to 2 CH3;

R ² is -CH2N(R ⁸ )(R ⁹ ), wherein R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen and CH3; And

R ⁴ is triazol-3-yl substituted with 1 to 2 substituents independently selected from the group consisting of CH ₃ -, CH ₃ -CH ₂ -, and CH ₃ -CH ₂ -CH ₂ -.

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The compounds of the invention are relative to a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:

R ^1a represents H;

R ³ represents H;

a represents 1;

X represents carbon; And

R ⁵ represents hydrogen;

provides the structure represented

ABOUT

I ) ^N= \

4 ^R4 wherein R ¹ , R ² and R ⁴ are as defined herein.

In another embodiment, the present invention is directed to any one or more of the following compounds:

6-(dimethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triαzol-3-yl]pyridin-2yl} - 2,3-dihydro-1H-pyrrolo[3,4ω]pyridin-1-one;

4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2-yl ]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-6-[(2R)-2-methylpyrrolidinyl-1-yl]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2 -yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2R) -2methylpyrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4ω]pyridin-1-one;

4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3yl)pyridine -2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-2-[6-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2S)-2methylpyrolidinyl- 1-yl]-2,3-dihydro-1H-pyrrolo[3,4-g]pyridin-1-one;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to compounds of formula II

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, halogen(C1C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)αalkoxy, -N(R ⁶ )(R ⁷ ) and (C3- _C6 )cycloalkyl, wherein said ( _C3 - _C6 )cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, ( _C1 - _C6 )alkyl, and (C ₁ -C ₆ )alkoxy;

^R6 and ^R7 are each independently selected from the group consisting of hydrogen and (CrC6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy, or ^R6 and ^R7 , taken together with the nitrogen to which they are attached, form a (4- to 8-membered) heterocycloalkyl, which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C1- _C6 )alkyl, halogen( _C1 - _C6 )alkylα, ( _C1 - _C6 )alkoxy and halogen( _C1 - _C6 )alkoxy;

R ² represents:

i) -(CH ₂ )mN(R ⁸ )(R ⁹ ), wherein m is an integer selected from 0, 1, 2, or 3, and R ⁸ and R ⁹ are each independently selected from the group that consists of hydrogen and (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy, or R ⁸ and R ⁹ taken together with nitrogen to which they are attached form a (4- to 6-membered) heterocycloalkyl which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C1C6)alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen (C ₁ -C ₆ )alkoxy; or ii) (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen (C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen (C ₁ -C ₆ )alkoxy;

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R ⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1 _- C6)alkoxy and halogen(C1 _- C6)alkoxy; And

R ¹² is selected from the group consisting of (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl and -(CH ₂ ) _n (C ₃ C ₆ )cycloalkyl, in which n is the integer 0 or 1.

In another embodiment, in Formula II, as described above, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C ₁ - C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 halogen.

In another embodiment of Formula II, R ¹ is -N(R ⁶ )(R ⁷ ), and (R ⁶ ) and (R ⁷ ) are each independently methyl.

In another embodiment of Formula II, R ¹ is -N(R ⁶ )(R ⁷ ), and (R ⁶ ) and (R ⁷ ) are each independently ethyl.

In another embodiment of Formula II, R ¹ is -N(R ⁶ )(R ⁷ ), and one of (R ⁶ ) and (R ⁷ ) is hydrogen and the other is methyl.

In another embodiment of Formula II, R ¹ is -N(R ⁶ )(R ⁷ ), and one of (R ⁶ ) and (R ⁷ ) is methyl and the other is ethyl.

In yet another embodiment of Formula II, R ¹ is -N(R ⁶ )(R ⁷ ) and R ⁶ and R ⁷ taken together with the nitrogen to which they are attached form a (4- to 8-membered) heterocycloalkyl which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )αalkoxy and halogen( C ₁ C ₆ )alkoxy. When R ⁶ and R ⁷ taken together form a (4- to 8-membered) heterocycloalkyl, the heterocycloalkyl may be selected from the group consisting of azetidinyl, pyrrolidinyl and azabicyclo[2.2.1]heptyl.

In certain embodiments of Formula II, R ¹ is azetidinyl, optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, ( C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy.

In certain embodiments of Formula II, R ¹ is pyrolidinyl, optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, ( C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy.

In certain other embodiments of Formula II, R ¹ is (C3C6)cycloalkyl, wherein said (C3-C6)cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C1-C6 )alkyl and (C1C6)alkoxy. When R ¹ is (C3-C ₆ )cycloalkyl, (C ₃ -C ₆ )cycloalkyl is cyclopropyl.

In yet another embodiment of Formula II, R ¹ is (C ₁ -C ₆ )alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

In another embodiment of Formula II, R ¹ is hydrogen.

It should be understood that any of the above subfamilies (embodiments of Formula II) R ¹ can be combined together with any of the subfamilies for R ² , R ⁵ , and R ¹² as described above and hereinafter for Formula II.

In another embodiment, in Formula II as described above, R ² is (CH ₂ ) _m N(R ⁸ )(R ⁹ ), in which m is 1, and one of (R ⁸ ) and (R ⁹ ) is hydrogen, and the other is methyl.

In another embodiment of Formula II, R ² is -(CH ₂ ) _m N(R ⁸ )(R ⁹ ), in which m is 1, and (R ⁸ ) and (R ⁹ ) are both hydrogen.

In certain other embodiments of Formula II, R ² is 4- to 6-membered heterocycloalkyl, and heterocycloalkyl is azetidinyl.

It should be understood that any of the above subfamilies (embodiments of Formula II) R ² can be combined together with any of the subfamilies for R ¹ , R ⁵ , and R ¹² as described above and hereinafter of Formula II.

In another embodiment, in Formula II, as described above, R ¹² represents (C ₁ -C ₆ )alkyl selected from the group consisting of ethyl, propyl, isopropyl, butyl and tert-butyl.

In another embodiment of Formula II, R ¹² is a halogen(C ₁ -C ₆ )alkyl selected from the group consisting of fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluorobutanyl and trifluoropentanyl.

In yet another embodiment of Formula II, R ¹² is -(CH2)n(C3C ₆ )cycloalkyl, in which n is 1, and (C ₃ -C ₆ )cycloalkyl is cyclopropyl.

In some embodiments, the compound of Formula II has absolute stereochemistry as shown in Formula II-A or II-B

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or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ⁵ , and R ¹² are as defined for formula II.

Each of the embodiments described herein in accordance with Formula II is also applicable to the compounds of Formula II-A and II-B.

In another embodiment, the present invention is directed to compounds of formula III

or a pharmaceutically acceptable salt thereof, in which:

R ¹ is selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, halogen(C1C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)alkoxy, -N( ^R6 )( ^R7 ) and (C3-C6)cycloalkyl, wherein said (C3- _C6 )cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, ( _C1 - _C6 )alkyl and (C ₁ -C ₆ )alkoxy;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C1C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy , or R ⁶ and R ⁷ , taken together with the nitrogen to which they are attached, form a (4- to 8-membered) heterocycloalkyl which is optionally substituted with one to three substituents selected from the group consisting of halogen, ( C1- _C6 )alkyl, halogen( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy and halogen( _C1 - _C6 )alkoxy;

R ² represents:

i) -(CH ₂ )mN(R ⁸ )(R ⁹ ), wherein m is an integer selected from 0, 1, 2, or 3, and R ⁸ and R ⁹ are each independently selected from the group that consists of hydrogen and (C1-C6)αalkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and hydroxy, or ^R8 and ^R9 , taken together with nitrogen to which they are attached form a (4- to 6-membered) heterocycloalkyl, which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C1C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen (C ₁ -C ₆ )alkoxy; or ii) (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen (C ₁ -C ₆ )alkoxy; R ⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ C ₆ )alkoxy and halogen (C ₁ -C ₆ ) alkoxy; And

R ¹² is selected from the group consisting of (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl and -(CH ₂ )n(C ₃ C ₆ )cycloalkyl.

In another embodiment, in Formula III, as described above, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C ₁ - C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 halogens.

In another embodiment of Formula III, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each methyl.

In another embodiment of Formula III, R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each ethyl.

In another embodiment of Formula III, R ¹ is -N(R ⁶ )(R ⁷ ), and one of R ⁶ and R ⁷ is hydrogen and the other is methyl.

In another embodiment of Formula III, R ¹ is -N(R ⁶ )(R ⁷ ), and one of R ⁶ and R ⁷ is methyl and the other is ethyl.

In yet another embodiment of Formula III, R ¹ is -N(R ⁶ )(R ⁷ ) and R ⁶ and R ⁷ taken together with the nitrogen to which they are attached form a (4- to 8-membered) heterocycloalkyl which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )αalkoxy and halogen( C ₁ - 13 044841

C6)alkoxy. When R6 and ^R7 taken together form a (4- to 8-membered) heterocycloalkyl, the heterocycloalkyl may be selected from the group consisting of azetidinyl, pyrrolidinyl and azabicyclo[2.2.1]heptyl.

In certain embodiments of Formula III, R ¹ is azetidinyl, optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, ( C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy.

In certain embodiments of Formula III, R ¹ is pyrolidinyl, optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, ( C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy.

In certain other embodiments of Formula III, R ¹ is (C3C6)cycloalkyl, wherein said (C3-C6)cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, (C1-C6 )alkyl and (QC6)alkoxy. When R ¹ represents (C3-C ₆ )cycloalkyl, where (C ₃ -C ₆ )cycloalkyl represents cyclopropyl.

In yet another embodiment of Formula III, R ¹ is (C ₁ -C ₆ )alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

In another embodiment of Formula III, R ¹ is hydrogen.

It should be understood that any of the above subfamilies (embodiments of Formula III) R ¹ can be combined together with any of the subfamilies for R ² , R ⁵ , and R ¹² as described above and hereinafter for the formula.

In another embodiment, in Formula III as described above, R ² is (CH ₂ )mN(R ⁸ )(R ⁹ ), in which m is 1, and one of (R ⁸ ) and (R ⁹ ) is hydrogen, and the other is methyl.

In another embodiment of Formula III, R ² is -(CH2)mN(R ⁸ )(R ⁹ ), in which m is 1 and R ⁸ and R ⁹ are both hydrogen.

In certain other embodiments of Formula III, R ² is 4- to 6-membered heterocycloalkyl, and heterocycloalkyl is azetidinyl.

It should be understood that any of the above subfamilies (embodiments of Formula III) R ² can be combined together with any of the subfamilies for R ¹ , R ⁵ , and R ¹² as described above and hereinafter for the formula.

In another embodiment, in Formula III as described above, R ¹² is (C ₁ -C ₆ )alkyl selected from the group consisting of ethyl, ethyl, propyl, propyl, isopropyl, butyl and tert-butyl.

In another embodiment of Formula III, R ¹² is a halogen(C ₁ -C ₆ )alkyl selected from the group consisting of fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluorobutanyl and trifluoropentanyl.

In yet another embodiment of Formula III, R ¹² is -(CH ₂ ) _n (C ₃ C ₆ )cycloalkyl, in which n is 1, and (C ₃ -C ₆ )cycloalkyl is cyclopropyl.

In some embodiments, the compound of formula III has the absolute stereochemistry as shown in formula III-A or III-B or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ⁵ , and R ¹² are as defined for formula III.

Each of the embodiments described herein in accordance with Formula III are also applicable to the compounds of Formula III-A and III-B.

In another aspect, the invention provides a compound selected from the group consisting of:

- 14 044841

4-[(methylamino)methyl]-6-(pyrolidinyl-1-yl)-2-(6-{4-[(25)-4,4,4-trifluorobutan-2yl]-4H-1,2,4 -triazol-3-yl}pyridin-2-yl)-2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-4-[(methylamino)methyl]-2-(6-{4-[(25)-4,4,4-trifluorobutan-2-yl]4H-1,2,4-triazol- 3-yl}pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

2-{6-[4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-6(dimethylamino)-4-[(methylamino)methyl]-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

2-(6-{4-[(25)-butan-2-yl]-4H-1,2,4-triazol-3-yl}pyridin-2-yl)-6-(dimethylamino)-4[( methylamino)methyl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-2,3-dihydro -1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-4-[(methylamino)methyl]-2-{6-[(45)-4-methyl-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-2-{6-[4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}6-(dimethylamino)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(dimethylamino)-2-{6-[5-(propan-2-yl)-1H-pyrazol-4-yl]pyridin2-yl}-2,3-dihydro-1H-pyrrolo [3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(dimethylamino)-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(dimethylamino)-2-(6-{4-[(25)-4,4,4-trifluorobutan-2-yl]-4H-1,2,4triazol-3-yl} pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-4-[(methylamino)methyl]-2-(6-{4-[^)-1,1,1-trifluoropentan-3-yl]4H-1,2,4-triazol-3 -yl}pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-4-[(methylamino)methyl]-2-(6-{4-[^)-1,1,1-trifluoropentan-3-yl]4H-1,2,4-triazol-3 -yl}pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-2-{5-fluoro-6-[5-(propan-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-4[(methylamino)methyl]-2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(azetidin-1-yl)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2 -yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-[(2B,4B)-2,4-dimethylazetidin-1-yl]-2-{6-[4-(propan-2-yl)-4H-

1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

6-[(1h,4h)-7-azabicyclo[2.2.1]hept-7-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2yl)-4H-1 ,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-cyclopropyl-2-{6-[(45)-4-methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro-1H -pyrrolo[3,4-c]pyridin-1-one;

6-[(2B,55)-2,5-dimethylpyrolidinyl-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2yl)-4H-1,2,4 -triazol-3-yl]pyridin-2-yl}-2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(diethylamino)-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4- 15 044841

[(methylamino)methyl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-[(2C4K)-2,4-dimethylazetidin-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)4H-1,2,4- triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(dimethylamino)-2-{6-[(45)-4-methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro -1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-cyclopropyl-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro -1H-pyrrolo[3,4-c]pyridin-1-one;

6-(azetidin-1-yl)-4-[(methylamino)methyl]-2-{6-[(45)-4-methyl-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl }-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-[(2C45)-2,4-dimethylazetidin-1-yl]-2-{6-[4-(propan-2-yl)-4H-

1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(dimethylamino)-2-{6-[5-(propan-2-yl)-1H-1,2,3-triazol-1yl]pyridin-2-yl}-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-6-(propan-2-yl)-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2 -yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-cyclopropyl-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-[(2C4A-2,4-dimethylazetidin-1-yl]-2-{6-[(45)-4-methyl-2-oxo1,3-oxazolidin-3-yl]pyridine -2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-cyclopropyl-4-[(methylamino)methyl]-2-{6-[(45)-4-methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(diethylamino)-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-Zyl]pyridin-2-yl}-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-2-{6-[(48)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-6(propan-2-yl)- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(diethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(azetidin-1-yl)-2-{6-[(48)-4-methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-[(2C5A-2,5-dimethylpyrolidinyl-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2yl)-4H-1,2,4-triazol- 3-yl]pyridin-2-yl}-2,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

4-(aminomethyl)-6-(1-methylcyclopropyl)-2-{6-[(48)-4-methyl-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-6-(1-methylcyclopropyl)-2-{6-[(48)-4-methyl-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-[ethyl(methyl)amino]-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4triazol-3-yl]pyridin-2 -yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-2-{6-[(4H-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin2-yl}-4-[(methylamino)methyl]-2 ,3-dihyde rho-1H-pyrrolo[3,4-c]pyridin-1-one;

6-methyl-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-(dimethylamino)-4-[(methylamino)methyl]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2-yl]-2,3-dihydro -1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-6-(1-methylcyclopropyl)-2-{6-[4-(propan-2-yl)-4H-1,2,4triazol-3-yl]pyridin-2-yl }-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-{6-[4-(propan-2-yl)-4H-1,2,4triazol-3-yl ]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

2-{6-[(4H-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-6(dimethylamino)-4-[(methylamino)methyl]- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-tert-butyl-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

- 16 044841

4-(aminomethyl)-6-tert-butyl-2-{6-[(45)-4-methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro -1H-pyrrolo[3,4-c]pyridin-1-one;

6-tert-butyl-4-[(methylamino)methyl]-2-{6-[(45)-4-methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-amino-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-τpeτ-bytyl-4-[(methylamino)methyl]-2-(6-{4-[(3ξ)-1,1,1-τpiφτopπentan-3-yl]-4H1,2,4-triazol-3 -yl}pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}6-(trifluoromethyl) -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

6-[(2^45)-2D-dimethylazetidin-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)4H-1,2,4- triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from the group consisting of the compounds listed in table. 1, including examples 1 and 53 inclusive, or pharmaceutically acceptable salts thereof. In another aspect, the invention provides a compound selected from the group consisting of the compounds illustrated in Examples 1-53 herein, or pharmaceutically acceptable salts thereof. In another aspect, the invention relates to any one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof.

The compounds of the invention have been optimized for selectivity against HPK1 kinase.

A pharmaceutical composition refers to a mixture of one or more 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 contains 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 one of the formulas described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients.

In some embodiments, the pharmaceutical composition further comprises at least one additional anticancer therapeutic agent or palliative agent. In some such embodiments, the at least one additional agent is an anticancer therapeutic agent, as described below. In some such embodiments, the combination provides an additive, more additive, or synergistic anticancer effect.

In one embodiment, the invention provides a method of treating abnormal cell growth in a subject in need thereof, which comprises 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 of treating abnormal cell growth in a subject in need thereof, which comprises 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 together are effective in treating said abnormal cell growth.

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. The compounds of the invention may be administered as single agents, or may be administered in combination with other anticancer therapeutic agents, in particular standard treatment agents that are appropriate for a particular type of cancer.

In some embodiments, the methods result in one or more of the following effects: (1) inhibition of cancer cell proliferation; (2) inhibition of cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibition of cancer cell metastasis; (5) inhibition of angiogenesis; (6) enhanced T cell responses; or (7) increasing antitumor activity.

- 17 044841

In another aspect, the invention provides a method of treating a disorder mediated by HPK1 kinase activity in a subject, such as certain types of cancer, which comprises administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective to treat the disorder.

Unless otherwise indicated, all references herein to compounds of the invention include references to salts, solvates, hydrates, and complexes thereof, as well as solvates, hydrates, and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled variants thereof.

The compounds of the invention may exist in the form of pharmaceutically acceptable salts, such as, for example, acid addition salts and basic salt addition compounds of one of the formulas set forth herein. As used herein, the term pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness and properties of the output compound. The phrase pharmaceutically acceptable salt(s) as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the formulas disclosed herein.

For example, the compounds of the invention, which are basic in nature, are capable of forming various salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, in practice it is desirable to first 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 the base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention can be prepared by treating the base compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent medium or an appropriate organic solvent such as methanol or ethanol. Evaporation of the solvent yields the desired solid salt. 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.

Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds that form non-toxic acid addition salts, that is, salts that contain pharmacologically acceptable anions such as 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'methylenebis(2 hydroxy-3-naphthoate)] salts.

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butine-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, wherekanoate, dihydrochloride, dihydrogen phosphate, edetate, edislate, estolate, esylate, ethyl succinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsanilate, glycolatulate, heptanoate , hexine-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methyl sulfate, monohydrogen phosphate , mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate, triethiodide and valerate.

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, aluminum and lithium.

The compounds of the invention, which include a basic component such as an amino group, can form pharmaceutically acceptable salts with various amino acids other than the above acids.

Those compounds of the invention which are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, in particular sodium and potassium salts. All these salts are obtained by generally accepted methods. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds herein. These salts can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide and the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution that contains the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanol solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same way as before. In both cases, it is advantageous to use stoichiometric amounts of reactants to ensure completeness of the reaction and maximum yield of the desired end product.

Chemical bases that can 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, salts derived from such pharmacologically acceptable cations, such as addition salts of alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium or water-soluble amine, such as N-methylglucamine (meglumine), and lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines.

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

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

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

One skilled in the art will appreciate that the free base compounds of the invention, which have basic functionality, can be converted into acid addition salts by treatment with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the invention can be converted back to the corresponding free bases by treatment with a stoichiometric excess of a suitable base such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent, and at a temperature of from about 0°C to about 100°C . The free-base form can be isolated using conventional methods such as organic solvent extraction. In addition, the acid addition salts of the compounds of the invention can interconvert by taking advantage of differential salt solubilities, volatility or acidity of the acids, or by treatment with a suitably loaded ion exchange resin. For example, the exchange may be influenced by the reaction of the salt of the compounds of the invention with a slight stoichiometric excess of acid with a lower pK than that of the acid component of the output salt. This transformation is typically carried out at a temperature from about 0°C to the boiling point of the solvent that is used as the process medium. Similar exchanges are possible with basic addition salts, usually mediated by 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 depend on the humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term solvate is used herein to describe a molecular complex that contains a compound of the invention and one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term hydrate is used when the solvent is water. Pharmaceutically acceptable solvates according to the invention include hydrates and solvates, wherein the crystallization solvent may be isotopically substituted, for example, D ₂ O, d6-acetone, d ₆ DMSO.

Also included within the scope of the invention are complexes such as chelates, the complexes comprising a drug-host wherein, unlike the above solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes that contain two or

- 19 044841 more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric quantities. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 1975, 64 (8):

1269-1288, Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety.

The invention further relates to prodrugs of the compounds of the formulas provided herein. Thus, certain derivatives of the compounds of the invention, which may have little or no pharmacological activity themselves, may, when administered to a patient, be converted into the compounds of the invention, for example, by hydrolytic cleavage. Such derivatives are called prodrugs. Additional information on the use of prodrugs can 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 entirety.

Prodrugs according to the invention can, for example, be obtained by replacing the corresponding functionality present in the compounds according to the invention with certain fragments known to one skilled in the art in the prior art as pro-fragments as described, for example, in Design of Prodrugs H Bundgaard (Elsevier, 1985) , the disclosure of which is incorporated herein by reference in its entirety.

Some limiting examples of prodrugs according to the invention include:

(i) when the compound contains carboxylic acid (-COOH) functionality, its ester, for example, replacing hydrogen with (C ₁ -C ₈ )alkyl;

(ii) when the compound contains alcohol functionality (-OH), its ether, for example, replacing hydrogen with (C ₁ -C ₆ )alkanoyloxymethyl; and a phosphorus ether group; and (iii) when the compound contains a primary or secondary amino functionality (-NH ₂ or -NHR, where R^H), its amide, for example, the replacement of one or both hydrogens with an acceptably metabolically labile group such as an amide, carbamate, urea, phosphonate , sulfonate and the like.

Additional examples of group substitution in accordance with the above examples and examples of other types of prodrugs can be found in the above references.

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

Also included within the scope of the invention are metabolites of compounds of the formulas described herein, that is, compounds that are formed in vivo upon administration of a drug.

The compounds of the formulas provided herein may have asymmetric carbon atoms. Carbon-carbon bonds of compounds according to the invention can be depicted herein using a solid line (λ solid wedge) or a dotted wedge 1) The use of a solid line to depict bonds with asymmetric carbon atoms is intended to show that all possible stereoisomers (for example, specific enantiomers, racemic mixtures, etc.) at such a carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is intended to indicate that only the stereoisomer shown is included. The possibility exists that the compounds of the invention may contain more than one asymmetric carbon atom. In these compounds, the use of a solid line to represent bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers that are intended are included. For example, unless otherwise stated, it is intended that the compounds of the invention may 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 a compound, is intended to indicate that a mixture of diastereomers is present.

The compounds of the invention which have chiral centers may exist as stereoisomers such as racemates, enantiomers or diastereomers.

Stereoisomers of the compounds of the formulas herein may 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 which exhibit more than one type of isomer; and mixtures thereof (such as racemates and diastereomeric pairs).

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

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If any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) as above, where one homogeneous crystal form is obtained that contains both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate, where the two crystal forms are obtained in equimolar amounts, each containing one enantiomer.

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

In addition, some of the compounds of the invention may form atropisomers (eg, substituted biaryls). Atropoisomers are conformational stereoisomers that occur when rotation around a single bond in a molecule is limited or significantly slowed, resulting in asymmetrical steric interactions with other parts of the molecule and substituents on both ends of the single bond. The interconversion of atropisomers is slow enough to allow separation and isolation under predetermined conditions. The energy barrier to thermal racemization can be determined by steric inhibition of free rotation of one or more bonds, forming a chiral axis.

When the compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. The cis/trans isomers can be separated using conventional methods well known to one skilled in the art, such as chromatography and fractional crystallization.

Conventional methods for preparing/isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC) or supercritical chiral chromatography (SFC).

Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as 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 can be separated using chromatography and/or fractional crystallization, and one or both diastereoisomers are converted to the corresponding pure enantiomer(s) using methods well known to one skilled in the art in the art. .

The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase that consists of hydrocarbons, typically heptane or hexane, that contains from 0 to 50% isopropanol, typically 2 to 20%, and 0 to 5% alkylamine, typically 0.1% diethylamine. Concentrating the eluate gives an enriched mixture.

Stereoisomeric conglomerates can be separated using conventional methods known to one skilled in the art 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 the compounds described herein can be described in terms of enantiomeric excess (e.i.), which indicates the degree to which a sample contains one enantiomer in greater quantities than the other. The racemic mixture has an e.i. 0%, then if the only completely pure enantiomer has an ee. 100%. Likewise, diastereomeric purity can be described in terms of diastereomeric excess (d.i.).

The present invention further includes isotopically labeled compounds that are identical to those listed in one of the provided formulas, but in fact are those in which one or more atoms are replaced by an atom that has an atomic mass or mass number different from the atomic mass or mass number that are commonly found in nature.

The isotopically labeled compounds of the present invention can generally be prepared using conventional methods known to one skilled in the art, or using methods similar to those described herein using an appropriate isotopically labeled reagent instead of an unlabeled reagent, which is used otherwise.

Examples of isotopes that can be introduced into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Specific isotopically labeled compounds according to the invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are introduced, are

- 21 044841 useful in drugs and/or studies of substrate distribution in tissue. Labeled tritium, ie, ³ H, and carbon-14, ie, ¹⁴ C isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium, i.e., ^2H , may provide specific therapeutic benefits that result in potentially greater metabolic stability, such as a potential increase in in vivo half-life or a potential reduction in required dosing and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following the procedures disclosed in the Schemes and/or Examples and Preparations below by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds of the invention intended for pharmaceutical use can be administered in the form of crystalline or amorphous products, or mixtures thereof. They can be obtained, for example, in the form of solid tampons, powders or films, using methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radiofrequency drying can be used for this purpose.

Therapeutic methods and applications

The invention further provides therapeutic methods and uses that include the administration of 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 of treating abnormal cell growth in a mammal, which comprises 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 of treating cancer in a subject, which includes administering to the subject a specified amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a specified amount of an additional anticancer therapeutic agent, an amount of which together is effective in treating said cancer.

The compounds of the invention include compounds of any of the formulas described herein, or a pharmaceutically acceptable salt thereof.

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

In another embodiment, the invention provides a method of inhibiting the invasiveness of cancer cells in a subject, which comprises administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cellular invasiveness.

In another embodiment, the invention provides a method of inducing apoptosis in cancer cells in a subject, which comprises administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to induce apoptosis.

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

HPK1 polynucleotides and polypeptides are known in the art (Hu et al. (1996) Genes Dev. 10: 2251-2264, which is incorporated herein by reference). HPK1 polypeptides contain various conserved structural motifs. HPK1 polypeptides contain an amino-terminal Ste20-like kinase domain that spans amino acid residues 17-293, which includes an ATP binding site from amino acid residues 23-46. The kinase domain is accompanied by four pro-rich line (PR) motifs that serve as binding sites for proteins that contain SH3, 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 tyrosine phosphorylation at position 381, located between PR1 and PR2, mediates binding to SLP-76 in T cells or BLNK in B cells via the SLP-76 or BLNK SH2 domain and is required for kinase activation. The citron homology domain found at the C terminus of HPK1, approximately including residues 495–800, may act as a regulatory domain and may be involved in macromolecular interactions.

The compounds disclosed herein directly bind to HPK1 and inhibit its kinase activity. In some embodiments, the disclosed compounds reduce, inhibit, or otherwise reduce HPK1-mediated phosphorylation of SLP76 and/or

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Gads. The compounds disclosed herein may or may not be a specific inhibitor of HPK1. 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 (eg, other serine/threonine kinases). In some embodiments, the disclosed compounds specifically inhibit the activity of serine/threonine kinase HPK1.

The compounds disclosed herein can be used in a method of inhibiting HPK1. Such methods include contacting HPK1 with an effective amount of a compound disclosed herein. The term contacting refers to bringing a compound into sufficient proximity to an isolated HPK1 enzyme or a cell that expresses HPK1 (eg, T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit HPK1 activity. The compound can contact HPK1 in vitro or in vivo by administering the compound to a subject.

Any method known in the art for measuring HPK1 kinase activity can be used to determine whether HPK1 is inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or measuring further biological effects of HPK1 kinase activity. , such as recruitment of 14-3-3 proteins to phosphorylate SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from microclusters that contain LAT, or activation of T or B cells.

The compounds disclosed herein may be used to treat an HPK1-dependent disorder (eg, cancer). As used herein, HPK1-dependent disorder is a pathological condition in which HPK1 activity is required for the development or maintenance of the pathological condition.

The compounds disclosed herein also find use for enhancing the immune response in a subject in need thereof. Such methods include administering an effective amount of a compound disclosed herein (ie, a compound of formula I, II or III or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof). The term enhancement of the immune response refers to the improvement of any immunogenic response to an antigen. Non-limiting examples of improvements in immunogenic response to antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (eg, CD4 T cells, CD8 T cells), enhancement of T cells (eg, CD4 T cells, CD8 T cells). cells). T cell proliferation, enhanced B cell proliferation, increased T cell and/or B cell survival, enhanced antigen presentation by antigen presenting cells (e.g., antigen cells), increased antigen clearance, increased production of cytokines by T cells (e.g., interleukin- 2), increased resistance to prostaglandin E2-induced immune suppression and enhanced priming and/or cytolytic activity of CD8 T cells. In some embodiments, CD8 T cells in a subject have enhanced priming, activation, proliferation, and/or cytolytic activity relative to administration of a compound of Formula I, II, III, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, CD8 T cell priming is characterized by increased expression of CD44 and/or increased cytolytic activity in CD8 T cells. In some embodiments, CD8 T cell activation is characterized by an increased frequency of γ-IFN ⁺ CD8 T T cells. In some embodiments, the CD8 T cell is an antigen-specific T cell.

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

In some embodiments, serum levels of IL-10 cytokines and/or IL8 chemokines, the human homolog of murine CS, in a subject are reduced relative to administration of a compound of Formula I, II, III or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

Recruitment of the TCR leads to the activation of HPK1, which functions as a negative regulator of the TCR-induced AP-1 response pathway. HPK1 is thought to negatively regulate T cell activation by reducing the stability of signaling microclusters by phosphorylating SLP76 on Ser376 (Di Bartolo et al. (2007) JEM 204: 681-691) and Gads on Thr254, leading to the recruitment of 14-3-3 proteins, which bind to phosphorylated SLP76 and Gads, releasing the SLP76-Gads-14-3-3 complex with LAT-containing microclusters, leading 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 decreased immune response to antigenic stimulation. This term includes general elements of exhaustion and/or energy in which antigen recognition may occur but further immune response is ineffective to control infection or tumor growth.

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The term dysfunctional, as used herein, also includes one that is difficult to respond to treatment or one that does not respond to antigen recognition, in particular, an impaired ability to translate antigen recognition into effective functions

T cells, such as proliferation, cytokine production (eg, IL-2, IFN gamma) and/or killing of target cells.

The term anergy refers to a state of insensitivity to antigenic stimulation due to incomplete or insufficient signals transmitted through the T-cell receptor (eg, increased intracellular Ca in the absence of ras activation). T cell anergy can also occur upon antigen stimulation in the absence of costimulation, causing the cell to become refractory to subsequent antigen activation even in the context of costimulation. A state of non-response that can be replaced by the presence of interleukin-2. Anergic T cells are not susceptible to clonal expansion and/or acquisition of effector functions.

The term exhaustion refers to T cell exhaustion, a state of T cell dysfunction that results from prolonged TCR signaling that occurs in many chronic infections and cancer. It differs from anergy in that it does not arise from incomplete or insufficient signaling, but from persistent signaling. It is defined by poor effector function, persistent 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 (eg, immunoregulatory cytokines) and intrinsic cellular negative regulatory (co-stimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

T cell enhancement means to induce, cause, or stimulate T cells to have sustained or enhanced biological function, or to renew or reactivate exhausted or inactive T cells. Examples of enhanced T cell function include: increased secretion of cytokines (eg, interferon gamma, IL-2, IL-12, and TNFa), increased proliferation, increased antigen response (eg, viral, pathogen, or tumor clearance) relative to preintervention levels and increased production of effector granules by CD8 T cells, such as granzymes B.

Accordingly, the compounds of formulas I, II, III or pharmaceutically acceptable salts, prodrugs, metabolites or derivatives thereof disclosed herein are useful for the treatment of dysfunctional T cell disorders. T cell dysfunctional disorder is a disorder or condition of T cells that is characterized by a decreased response to antigenic stimulation. In a specific embodiment, a dysfunctional T cell disorder is a disorder that is specifically associated with increased HPK1 kinase activity. In another embodiment, a dysfunctional T cell disorder is one in which the T cells are anergic or have a reduced ability to secrete cytokines, proliferate, or perform cytolytic activity. In a particular aspect, decreased sensitivity results in ineffective control of the pathogen or tumor that expresses the immunogen. Examples of dysfunctional T cell disorders that are characterized by dysfunction of T cells include unresolved acute infection, chronic infection, and tumor immunity.

Thus, the compounds disclosed herein can be used to treat conditions where increased immunogenicity is desired, for example, enhancing tumor immunogenicity for the treatment of cancer. Immunogenicity refers to the ability of a certain substance to trigger an immune response. Tumors are immunogenic, and tumors that enhance immunogenicity promote clearance of tumor cells by the immune response.

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

In one aspect, a method provided herein for treating cancer in a subject in need thereof comprises administering to the subject an effective amount of a compound of Formula I, II, III, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the subject has melanoma. Melanoma can be early stage or advanced stage. In some embodiments, the subject has rectal cancer. Colorectal cancer can be early or late stage. In some embodiments, the subject has non-small cell lung cancer. Non-small cell lung cancer can be early or late stage. In some embodiments, the subject has pancreatic cancer. Pancreatic cancer can be early stage or advanced stage. In some embodiments, the subject has a hematologic malignancy. Hematologic malignancy can be early or late stage. In some embodiments, the subject has ovarian cancer. Ovarian cancer can be early or late stage. In some embodiments, the subject has breast cancer. Breast cancer can be early or late stage. In some embodiments, the subject has renal cell carcinoma. Renal cell carcinoma can be early or late stage. In some embodiments, the cancer increases the level of T cell infiltration.

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

The treatments disclosed herein may result in a partial or complete response. As used herein, complete response or CR refers to resolution of all target lesions; partial response or PR denotes at least a 30% reduction in the sum of long diameters (SLD) of the target lesions, taking the output SLD as a reference; and stable disease or SD refers to not enough reduction in target lesions to be eligible for PR, not enough increase to be eligible for PD, taking as reference the lowest level of SLD since the start of treatment. As used herein, overall response rate (ORR) refers to the sum of the complete response (CR) and partial response (PR) rates.

The treatment methods disclosed herein may result in an increase in progression-free survival and overall survival of a subject administered an HPKI antagonist. The term progression-free survival (PFS) as used herein refers to the length of time during and after treatment during which the treatment of a disease (eg, cancer) does not deteriorate. Progression-free survival may include the amount of time patients experienced a complete or partial response, as well as the amount of time patients 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 specified time.

In frequent embodiments of the methods provided herein, the abnormal cell growth is a cancer that is characterized by amplification or overexpression of HPK1 kinase. In some embodiments of the methods provided herein, a subject is identified as having a cancer that is characterized by amplification or overexpression of HPK1 kinase.

In frequent embodiments of the methods provided herein, the abnormal cell growth is a cancer, where 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, gastric cancer (ie gastric) and thyroid cancer glands. 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 such embodiments, the cancer is characterized by amplification or overexpression of HPK1 kinase.

In some embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer. In some such embodiments, the cancer is breast cancer or ovarian cancer that is characterized by amplification or overexpression of HPK1 kinase. In some such embodiments, the cancer is (a) breast cancer or ovarian cancer; (b) which is characterized by amplification or overexpression of HPK1 kinase.

In some embodiments, the cancer is ovarian cancer. In some such embodiments, ovarian cancer is characterized by amplification or overexpression of HPK1 kinase.

In other embodiments, the cancer is breast cancer, including, for example, EP-positive/HP-positive/positive breast cancer, HEP2-negative breast cancer; ER-positive/HR-positive breast cancer, HEP2-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 that exhibits primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the above, the breast cancer is characterized by amplification or overexpression of HPK1 kinase.

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

The terms abnormal cellular growth and hyperproliferative disorder are used interchangeably in this application.

Abnormal cell growth, as used herein, unless otherwise noted, refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous).

Abnormal cell growth includes abnormal growth of: (1) tumor cells (tumors) that exhibit increased expression of HPK1 kinase; (2) tumors that proliferate by activating aberrant HPK1 kinase; (3) tumors that are characterized by amplification or overexpression of HPK1 kinase; and (4) 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 agents other than a compound of the invention that are or may 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, protein tyrosine kinase and/or serine/threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or derivatives oligonucleotides, cytotoxic and immuno-oncological agents.

As used herein, cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cellular growth. Cancer refers to solid tumors, named after the type of cells that form them, cancers of the blood, bone marrow or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Examples of blood cancers include leukemia, lymphoma, and myeloma. Cancer includes a primary cancer, which begins in a specific location in the body, metastatic cancer, which spreads from the site where it started to other parts of the body, recurrence of the original primary cancer after remission, and a second primary cancer, which is a new primary cancer in a person with a history of a previous cancer of a different type from the most recent type.

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. In some such embodiments, the cancer is characterized by amplification or overexpression of HPK1 kinase.

Forms and dosage regimens

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

Dosing regimens may be adjusted to provide the optimal desired response. For example, may be administered in a single bolus dose, may be administered in multiple divided doses over a period of time, or the dose may be proportionally decreased or increased as indicated by the requirements of the therapeutic situation. This is particularly preferred for formulating parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units that are acceptable as unit dosages for mammalian subjects when the mammal is being treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Specification for

- 26 044841 unit dosage forms according to the invention are dictated by and directly depending on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations that are inherent in the field of formulation of such active compound in the treatment of sensitivity in individuals.

Thus, one skilled in the art would appreciate, based on the disclosure provided herein, that the dosage and dosage schedule are adjusted in accordance with methods well known in the therapeutic field. That is, the maximum permissible dose can be easily determined, and further, an effective amount that provides a noticeable therapeutic effect in the patient can be determined, and which may be temporarily required for the administration of each agent to provide a noticeable therapeutic effect in the patient. Accordingly, while specific dosage and dosage schedules are illustrated herein, these examples are not in any way limiting the dosage and dosage schedule that may be provided to a patient in the practice of the present invention.

It should be noted that dosage volumes may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular subject, specific dosage regimens must be adjusted over a period of time in accordance with the individual need and professional judgment of the subject to whom the composition is administered or monitored, and that the dosage ranges set forth herein are are illustrative only and are not intended to limit the scope or practice of the claimed composition. For example, dosages 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 covers dose escalation in the same patient, which is determined by a qualified specialist. Determination of appropriate dosages and schedules of administration of a chemotherapeutic agent is well known in the art and should be readily apparent to those of ordinary skill in the art as provided by the teachings disclosed herein.

The amount of a compound of the invention that is administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the prescribing decisions of the physician. However, effective dosage ranges from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg person, this would be an amount of from about 0.05 to about 7 g/day, preferably from about 0.1 to about 2.5 g/day. In some cases, dosage levels below the lower end of the stated range may be more than sufficient, while in other cases even larger doses can be administered without causing any harmful side effects, provided such large doses are first divided into several smaller doses for administration throughout the day.

Compositions and routes of administration

As used herein, a pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to the body and does not reduce the biological activity and properties of the active compound that is administered.

The pharmaceutically acceptable carrier may include any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will depend largely on factors such as the particular route of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage dosage form.

Acceptable pharmaceutical carriers include inert diluents or excipients, water and various organic solvents (such as hydrates and solvates). Pharmaceutical compositions may, if necessary, contain additional ingredients such as flavoring agents, binders, excipients and the like. Thus, for oral administration, tablets that contain various excipients such as citric acid can be used 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, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are useful for tabletting. Solid compositions of this type may also be used 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 for oral administration are desired, the active compound therein may be combined with various sweetening or flavoring agents, coloring agents 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, such as a tablet, capsule, dragee, powder, sustained release composition, solution or suspension, for parenteral injection, such as a sterile solution, suspension or emulsion, for topical administration, such as an ointment or cream, or for rectal administration, such as a suppository.

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

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

Pharmaceutical compositions suitable for delivering the compounds of the invention and methods for their production will be apparent to one skilled in the art from the prior art. Such compositions and methods for their production 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 can be administered orally. Oral administration may involve swallowing, such that the compound enters the gastrointestinal tract, or may involve either buccal or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

Compositions suitable for oral administration include solid compositions such as tablets, capsules that contain particles, liquids or powders, lozenges (including liquid-filled), chewable, multi- and nano-particles, gels, solid solution, liposome, films (including mucoadhesive ), vaginal suppositories, sprays and liquid compositions.

Liquid compositions include suspensions, solutions, syrups and elixirs. Such compositions 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 compositions may also be prepared by dissolving a solid, for example from a sachet.

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

For tablet dosage forms, depending on the dose, the active ingredient may comprise from 1 to 80% by weight of the dosage form, more preferably from 5 to 60% by weight of the dosage form. In addition to the active ingredient, tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl hydroxypropylcellulose, starch, pregelatinized starch and sodium alginate. Typically, the disintegrant will comprise from 1 to 25% by weight, preferably from 5 to 20% by weight of the dosage form.

Binders are typically used to impart cohesive properties to the tablet composition. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants are typically present at 0.2 to 5% by weight of the tablet, and glidants are typically present at 0.2 to 1% by weight of the tablet.

The tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants are usually present in an amount of from 0.25 to 10% by weight, preferably from 0.5 to 3% by weight of the tablet.

Other common ingredients include antioxidants, colors, flavoring agents, preservatives, and flavor masking agents.

Exemplary tablets contain up to about 80 wt.% active ingredient, 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.

- 28 044841

Tablet mixtures can be compressed directly or using a roller press to form tablets. Blends for tablets or similar blends may also be wet-, dry-, or melt-granulated, melt-congealed, or extruded prior to tabletting. The final composition may include one or more layers and may be coated or uncoated; or encapsulated.

The composition of the tablets is discussed in detail in Pharmaceutical Dosage Forms: Tablets, Vol. 1, 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 compositions for oral administration can be formulated as immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

Suitable modified release compositions are described in US Pat. No. 6,106864. Details of other suitable release technologies such as high energy dispersions and osmotic particles 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 disclosure of these references is incorporated herein by reference in its entirety.

Parenteral administration

The compounds of the invention can also be administered directly into the bloodstream, into a muscle or into an internal organ. Acceptable routes of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intragastric, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion devices.

Compositions for parenteral administration are usually aqueous solutions which may contain excipients/excipients such as salts, carbohydrates and buffering agents (preferably pH 3 to 9), but for some applications they may be more suitable as sterile non-aqueous solutions or in dried form for use in combination with a suitable carrier such as sterile, pyrogen-free water.

The preparation of parenteral compositions under sterile conditions, for example by lyophilization, can be easily accomplished using standard pharmaceutical methods well known to those skilled in the art.

The solubility of the compounds of the invention used in the preparation of parenteral solutions can be increased through the use of suitable formulation methods, such as the inclusion of solubility enhancing agents.

Compositions for parenteral administration may be formulated as immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Thus, the compounds of the invention may be formulated as a solid, semi-solid or thixotropic liquid for administration as an implanted depot providing a modified release of the active compound. Examples of such compositions include drug-coated stents and PGLA microspheres.

The compounds of the present invention can also be administered topically to the skin or mucous membrane, that is, dermal or transdermal. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, capsules, implants, sponges, fibers, dressings and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be included; see, for example, J Pharm Sci, 88(10), 955-958 by Finnin and Morgan (October 1999). Other methods of local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless injection (eg, Powderject™, Bioject™, etc.). The disclosure of these references is incorporated herein by reference in its entirety.

Compositions for topical use may be formulated as immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the present invention can also potentially be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry mixture with lactose, or as a particulate mixed component, for example, mixed with phospholipids such as phosphatidylcholine ) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, nebulizer (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- 29 044841 heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent such as chitosan or cyclodextrin.

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

Before 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 can be achieved by any suitable comminution method such as spiral jet milling, fluidized bed jet milling, supercritical fluid nanoparticle processing, high pressure homogenization or spray drying.

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

A suitable solution composition for use in an aerosol dispenser using electrohydrodynamics to produce a fine mist may contain from 1 to 20 mg of a compound of the invention per actuation, and the actuation volume may vary from 1 to 100 μl. A typical composition includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Suitable flavoring agents, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to the present compositions of the invention for inhalation/nasal administration.

Compositions for inhalation/intranasal administration can be formulated to provide immediate and/or modified release, using, for example, poly(DL-lactic acid-glycolic acid (PGLA). Modified release compositions include delayed, sustained, intermittent, controlled, targeted and programmable release.

Compositions for inhalation/intranasal administration can be formulated as immediate and/or modified release using, for example, poly(DL-lactic glycolic acid (PGLA). Modified release compositions include delayed, sustained, pulsed, controlled, targeted and programmed release .

In the case of dry powder and aerosol inhalers, the standard dosage is determined by a valve that delivers a metered amount. Units in accordance with the invention are typically adapted to administer a metered dose or injection containing the desired amount of a compound of the invention. The total daily dose may be administered as a single dose or, usually more commonly, in divided doses throughout the day.

The compounds of the present invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is the traditional suppository base, but various alternatives can be used if necessary.

Compositions for rectal/vaginal administration can be formulated as 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 directly into the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other compositions suitable for ocular and auricular administration include ointments, biodegradable (eg, absorbable gel sponges, collagen) and non-biodegradable (eg, silicone) implants, wafers, lenses, and particulate or vesicular systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer such as gellan gum may be included along with a preservative such as benzalkonium chloride. Such compositions can also be delivered by iontophoresis.

Compositions for ocular/ear administration may be formulated as immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

- 30 044841

Other technologies

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

Drug-cyclodextrin complexes, for example, can generally be used for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes could potentially be used. As an alternative to direct complexation with the active substance, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in PCT publications WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entirety.

Dosage

The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the attending physician. However, an effective dose will typically range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 0.01 to about 35 mg/kg/day, as a single or divided dose. For a 70 kg person this would be from about 0.07 to about 7000 mg/day, preferably from about 0.7 to about 2500 mg/day. In some cases, dosage levels below the lower end of the above range may be more than sufficient, while in other cases even larger doses can be used without causing any harmful side effects, with such large doses usually divided into several smaller doses to administration throughout the day.

Set of parts

Since it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, which is within the scope of the present invention, two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, can be conveniently combined in the form of a kit , suitable for co-administration of the composition. Thus, the kit of the present invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention, and means for separately storing said compositions, such as a container, a divided bottle or a divided foil pouch. An example of such a set is the well-known blister pack used for packaging tablets, capsules and the like.

The kit of the present invention is particularly suitable for the administration of different dosage forms, for example, oral and parenteral, for the administration of individual compositions at different dosing intervals, or for titrating individual compositions against each other. To make it easier to follow the rules, the kit usually includes instructions for use and may be equipped with a so-called instructional insert.

Combination therapy

As used herein, the term combination therapy refers to the administration of a compound of the present invention together with at least one additional pharmaceutical or drug (eg, anticancer agent), either sequentially or simultaneously.

As noted above, the compounds of the present invention can be used in combination with one or more additional anticancer agents. The effectiveness of the compounds of the present invention in certain tumors may be enhanced by combination with other approved or investigational cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are not regulated in tumors , and other immune enhancing agents such as PD1 antagonists and others.

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

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

- 31 044841 one to three) anticancer therapeutic agents.

In specific 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, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src/Abl, RTK/Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK4/CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2 or Hsp90, or immunomodulatory agents, such as PD1 or PD-L1 antagonists, OX40 agonists or 41BB agonists.

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

Synthesis methods

The compounds of formula I, II and III can be prepared by the methods described below, together with synthetic methods known in the field of organic chemistry, or modifications and transformations that are generally known to those skilled in the art. The starting materials used herein are commercially available or can be prepared by conventional methods known in the art [such as those described in standard references such as the Compendium of Organic Synthetic Methods, Vol. I-XIII (published by Wiley-Interscience)]. Preferred methods include, but are not limited to, the methods 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 in question. This can be achieved using 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 Wiley & Sons, 1999, which are incorporated herein by reference.

The compounds of formula I, II and III or pharmaceutically acceptable salts thereof can be prepared in accordance with the reaction schemes discussed herein below. Unless otherwise noted, substituents in the diagrams are as defined above. One skilled in the art will understand that R ¹³ is a substituent that is formed outside of R ⁴ . Non-limiting examples of R ¹³ include (C1C6)alkyl, optionally substituted hydroxy, halogen (C1-C6)alkyl and -(CH2)n(C3-C6)cycloalkyl, where n is 0 or 1. Non-limiting examples of (C1-C6-alkyl for R ¹³ in the diagrams below include CH3-, _CH3CH2- and CH3-CH2-CH2-.

Isolation and purification of the products is carried out according to standard procedures known to a chemist of ordinary skill.

One skilled in the art will appreciate that the various symbols, superscripts, and subscripts used in the diagrams, methods, and examples are for convenience of presentation and/or to reflect the order in which they are introduced in the diagrams and are not intended to necessarily correspond to symbols , superscript or subscript in the attached claims. In addition, one of ordinary skill in the art will appreciate that in many cases the compounds presented will be mixtures and enantiomers that can be separated at various stages of the synthesis schemes using conventional techniques such as, but not limited to, crystallization, normal phase chromatography, reverse -phase chromatography and chiral chromatography to obtain individual enantiomers. The diagrams depict methods used in the synthesis of compounds according to the present invention. They do not limit the scope of the invention in any way.

The compounds of the present invention are prepared in accordance with typical procedures presented herein, and modifications thereof known to those skilled in the art.

The following abbreviations are used in all examples: Ac denotes acetyl, AcO or OAc denotes acetoxy, ACN denotes acetonitrile, aq. stands for water, atm. denotes atmosphere(s), BOC, Boc or boc denotes N-tert-butoxycarbonyl, Bn denotes benzyl, Bu denotes butyl, nBu denotes normal butyl, tBu denotes t-butyl, DBU denotes 1,8-diazabicyclo[5.4.0]undec -7-ene, Cbz stands for benzyloxycarbonyl, DCM (CH2C12) stands for methylene chloride, d.i. stands for diastereomeric excess, DEA stands for diethylamine, DIPEA stands for diisopropylethylamine, DMA stands for Ν,Ν-dimethylacetamide, DME stands for 1,2dimethoxyethane, DMF stands for Ν,Ν-dimethylformamide, DMSO stands for dimethyl sulfoxide, EDTO stands for ethylenediaminetetraacetic acid, e.n. denotes enantiomeric excess, Et denotes ethyl, EtOAc denotes ethyl acetate, EtOH denotes ethanol, HOAc or AcOH denotes acetic acid, i-Pr or 'Pr denotes isopropyl, IPA denotes isopropyl alcohol, LAH denotes lithium aluminum hydride, LHMDS denotes lithium hexamethyldisilazide (lithium bis( trimethylsilyl)amide), mCPBA = meta-chloroperoxybenzoic acid, Me = methyl, MeOH = methanol, MS = MS, MTBE = methyl tert-butyl ether, NCS = N-chlorosuccinimide, Ph = phenyl, TBHP

- 32 044841 denotes tert-butyl hydroperoxide, TBME denotes methyl tert-butyl ether, TFO denotes trifluoroacetic acid, THF denotes tetrahydrofuran, SFC denotes supercritical liquid chromatography, TLC denotes thin layer chromatography, Rf denotes retention factor, ~ denotes approximately, rt denotes retention time, h denotes hours, min denotes mines, eq. denotes equivalents, us. stands for saturated.

Preparation of synthetic intermediates

Intermediate 1: 2-bromo-6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridine.

Step 1: 6-bromopyridine-2-carbohydrazide (1a) hn-nh _{2 1a}

To a solution of methyl 6-bromo-2-pyridinecarboxylate (16.0 g, 74.0 mmol) in methanol (120 ml) was added hydrazine monohydrate (5.23 g, 88.8 mmol, 85%), and the mixture was stirred for 16 hours at ambient temperature. The resulting solution was concentrated to approximately half volume and then triturated by adding 40 ml of methyl tert-butyl ether and stirring for 10 minutes. The resulting white solid was filtered and dried in vacuo to give the title compound (15 g, 94%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (b.s., 1H), 8.13 (dd, J=0.9, 7.5 Hz, 1H), 7.76-7.71 (m , 1H), 7.64 (dd, J=0.9, 8.0 Hz, 1H), 4.08 (br.s, 2H). m/z (ESI) for (C ₆ H ₆ BrN ₃ O) 217.5 (M+H)+.

Step 2: N'-[(6-bromopyridin-2-yl)carbonyl]-N,N-dimethylhydrαzonoformamide (1b) ^HN 'N

NMe _{2 1b}

A solution of 6-bromopyridine-2-carbohydrazide (1a) (15.0 g, 69.4 mmol) in dimethylformamide dimethyl acetal (80 ml) was stirred at 80°C for 16 hours. The resulting mixture was concentrated under reduced pressure to give a residue. Methyl tert-butyl ether (60 ml) was added to this residue and the resultant was stirred for 40 minutes, the resulting yellow solid was filtered and dried to give the title compound (16 g, 85%).

1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.06 (s, 1H), 8.01-7.97 (m, 1H), 7.91 (t, J= 7.7 Hz, 1H), 7.80 (dd, J=1.0, 7.8 Hz, 1H), 2.84 (s, 6H). m/z (ESI) for ^HncBr^O) 272.7 (M+H)+.

Step 3: 2-bromo-6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridine (intermediate 1) ΒΓ^Ν^γ ^Ν ' _Ν ' Intermediate connection 1

N'-[(6-bromopyridin-2-yl)carbonyl]-N,N-dimethylhydrazonoformamide (1b) (16.0 g, 59.0 mmol) and iso-propylamine (12.0 g, 200 mmol) were dissolved in acetic acid (33 ml) and acetonitrile (130 ml). After the observed smoke emission had subsided, the resulting solution was stirred at 95°C for 16 hours. The reaction mixture was combined with another batch of this reaction (5 g scale) and concentrated in vacuo. The resulting material was diluted with water (130 ml) and adjusted to pH 7 with 1 N. aqueous sodium hydroxide (120 ml). The resulting mixture was then extracted with ethyl acetate (2x150 ml) and the combined organic layer was washed with water (2x130 ml) and concentrated in vacuo. The crude product was purified by column chromatography (0-100% ethyl acetate in petroleum ether) to give the title compound as a yellow solid (16.9 g, average yield 82%).

1H NMR (400 MHz, CDCl3) δ 8.42-8.34 (m, 1H), 8.28 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.8 Hz , 1H), 7.52 (d, J=7.8 Hz, 1H), 5.57 (sept., J=6.7 Hz, 1H), 1.56 (d, J=6.5 Hz, 6H). m/z (ESI) for (SchHntsBe^) 268.8 (M+H)+.

Intermediate 2: tert-butyl ((6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin4-yl)methyl)(methyl)carbamate.

Step 1: 4-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (2a)

- 33 044841

N-bromosuccinimide (5.43 g, 30.5 mmol) and azobisisobutyronitrile (453 mg, 2.76 mmol) were added to a solution of methyl 2-chloro-3-methylpyridine-4-carboxylate (5.12 g, 27.61 mmol ) in carbon tetrachloride (35 ml, 0.8 M). The resulting mixture was heated at 80°C for 18 hours. The mixture was cooled to room temperature, filtered, and the solid was washed with carbon tetrachloride (10 ml). The filtrate was diluted with DCM (100 ml) and washed with saturated aqueous sodium bicarbonate (100 ml). The aqueous layer was extracted with DCM (100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a pale brown oil, which was dissolved in 7N. ammonia in methanol (39 ml, 276 mmol). The reaction mixture was allowed to stir at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in DCM (100 ml) and washed with saturated aqueous sodium bicarbonate solution (100 ml). The aqueous layer was extracted with DCM (100 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as an off-white solid (4.58 g, 98%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (d, J=4.89 Hz, 1H), 7.75 (d, J=5.01 Hz, 1H), 6.70 (br.s , 1H), 4.54 (s, 2H). m/z (APCI+) for (C ₇ H ₅ ClN ₂ O) 168.7 (M+H) ⁺ .

Step 2: Methyl 1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (2b)

4-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin1-one (2a) (787 mg, 4.67 mmol), methanol (30 ml) were placed in a 100 ml high pressure reactor. potassium acetate (913 mg, 9.30 mol), and palladium tetra(triphenylphosphine) (168 mg, 0.145 mmol). The vessel was pressurized with carbon monoxide gas (4 bar) and the reaction mixture was heated for 4 hours at 100°C. The resulting mixture was filtered and the resulting solid was washed with methanol. The solid was then collected and dried to give the title compound as a brown solid (744 mg, 83%), which was used without purification.

1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.87 (d, J=4.77 Hz, 1H), 7.93 (d, J=4.77 Hz, 1H ), 4.71 (s, 2H), 3.93 (s, 3H). m/z (APCI+) for (C ₉ H ₈ N ₂ O ₃ ) 193.0 (M+H) ⁺ .

Step 3: 2-(tert-butyl)4-methyl 1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,4-dicarboxylate (2c)

Triethylamine (0.81 ml, 5.81 mmol), di-tert-butyl dicarbonate (1.07 g, 4.65 mmol) and 4-dimethylaminepyridine (48.3 mg, 0.387 mmol) were added to the methyl-1-oxo- 2,3-dihydro-1Hpyrrolo[3,4-c]pyridine-4-carboxylate (2b) (744 mg, 3.87 mmol) in DCM (4.0 mL, 1M). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (30 ml) and extracted with DCM (2x30 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (30-100% ethyl acetate in heptane) to give the title compound as a pale yellow solid (74 mg, 66%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.98 (d, J=4.89 Hz, 1H), 8.02 (d, J=4.89 Hz, 1H), 5.21 (s, 2H) , 4.11 (s, 3H), 1.65 (s, 9H). m/z (APCI+) for (C ₁₄ H ₁₆ N ₂ O ₅ ) 293.3 (M+H) ⁺ .

Step 4: 2-(tert-butoxycarbonyl)-4-(methoxycarbonyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4c]pyridine 5-oxide (2d)

Urea hydrogen peroxide (1.14 g, 12.1 mmol) was added to a solution of 2-(tert-butyl)4-methyl 1oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2, 4-dicarboxylate 2c (1.68 g, 5.76 mmol) in acetonitrile (38 ml, 0.15 M). The mixture was cooled to 0°C, then trifluoroacetic anhydride (1.6 ml, 11.5 mmol) was added dropwise. The resulting mixture was stirred at 0°C and then allowed to warm to room

- 34 044841 temperature and stirred for 2 hours. The mixture was quenched with 10% aqueous sodium thiosulfate (80 ml) and extracted with DCM (2x80 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a white solid (2.23 g, 125% ~80% purity by weight). m/z (APCI+) for (C ₁₄ H ₁₆ N ₂ O ₆ ) 308.9 (M+H)+.

Step 5: 2-(tert-butyl)4-methyl 6-chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2,4dicarboxylate (2e)

2,6-lutidine (0.34 ml, 2.90 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-4(methoxycarbonyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine 5-oxide (2d) (1.05 g, 2.90 mmol) in DCM (29 ml, 0.1 M) at 0°C, then add phosphorus(V)oxychloride (0.54 ml, 5. 79 mmol) and DMF (0.14 ml, 1.74 mmol). The resulting mixture was stirred at 0°C and then allowed to warm to room temperature. After 2 h, RC-MS showed only the starting material and phosphorus(V)oxychloride (0.32 ml, 3.47 mmol) and DMF (0.14 ml, 1.74 mmol) were added to react and the reaction mixture was left to stir at room temperature for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (100 ml) and extracted with DCM (2x100 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (30-100% ethyl acetate in heptane) to give the title compound as a white solid (722 mg, 76%). (Contains about 8% methyl 6-chloro-2-formyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate by 1H NMR).

^1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H) 5.07 (s, 2H) 4.00 (s, 3H) 1.55 (s, 9H). m/z (APCI+) for (C14H15ClN2O5) 328.9 (M+H)+.

Step 6: Methyl 6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (2f)

Solution 4 N. HCl in dioxane (7.0 mL, 29.0 mmol) was added to the 2-(tert-butyl)4-methyl 6chloro-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine solution -2,4-dicarboxylate (2e) (722 mg, 2.21 mmol) in DCM (20 ml) and methanol (5 ml). The mixture was stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure and the resulting material was azeotroped with toluene, then further concentrated in vacuo to give the title compound as an off-white solid (520 mg, 90%) .

1H NMR (400 MHz, DMSO-a ₆ ) δ 9.28 (s, 1H) 8.04 (s, 1H) 4.68 (s, 2H) 3.94 (s, 3H). m/z (APCI+) for (C ₉ H ₇ ClN ₂ O ₃ ) 226.90 (M+H)+.

Step 7: 6-chloro-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (2g)

A 2.0 M solution of lithium borohydride in THF (8.8 mL, 17.7 mmol) was added to the suspension of methyl 6-chloro-1oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (2f) (1.0 g, 3.80 mmol) in THF (60 ml, 0.074 M) at 0°C. The mixture was stirred at 0°C for 1 hour, then quenched with an aqueous solution of 1N. HCl (0.5 ml). The mixture was diluted with water (100 ml) and extracted with 20% isopropanol in DCM (4x100 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a white solid (795 mg, 91%).

1H NMR (400 MHz, DMSO-66) δ 9.05 (b.s., 1H) 7.60 (s, 1H) 5.59 (t, J=5.93 Hz, 1H) 4.72 (d, J=5.75 Hz, 2H) 4.56 (s, 2H). m/z (APCI+) for (C8H ₇ ClN2O2) 199.0 (M+H)+.

Step 8: tert-butyl ((6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl)methyl)(methyl)carbamate (intermediate 2)

- 35 044841

Methanesulfonyl chloride (0.04 ml, 0.483 mmol) was added to a suspension of 6-chloro-4-(hydroxymethyl)2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (2d) (48.0 mg, 0.240 mmol) in DCM (6.0 ml, 0.02 M) at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. A 2M solution of methylamine in THF (1.21 mL, 2.42 mmol) was added and the mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure and the residue was taken up in DCM (6 mL). Di-tert-butyl dicarbonate (66.6 mg, 0.290 mmol) and triethylamine (0.10 ml, 0.725 mmol) were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (20 ml) and extracted with DCM (2x20 ml ). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (50-100% ethyl acetate in heptane) to give the title compound as an off-white solid (40 mg, 53%).

1H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 4.68 (s, 2H), 4.54 (br. s, 2H), 2.94 (s, 3H), 1, 50 (sh. s., 9H). m/z (APCI+) for (C _m Н18СШзОз) 312.0 (M+H)+.

Intermediate 3: tert-butyl ((6-(dimethylamino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-4-yl)methyl)(methyl)carbamate.

Step 1: Methyl 6-(dimethylamino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (3a)

A mixture of dimethylamine hydrochloride (30.8 mg, 0.377 mmol), triethylamine (0.14 ml, 1.03 mmol) and methyl 6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxylate α 2f (77.7 mg, 0.34 mmol) in DMF (2 ml) was heated to 80°C. After stirring at this temperature for 24 hours, the reaction was not complete. Dimethylamine hydrochloride (30.8 mg, 0.377 mmol) and trimethylamine (0.14 ml, 1.03 mmol) were added and the mixture was left stirring at 80°C for 24 hours. Volatiles were removed under reduced pressure. The residue was taken into water (10 ml) and extracted with DCM (2x10 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (0-10% methanol in DCM) to give the title compound as a pale brown oil (35 mg, 43%).

1H NMR (400 MHz, CDCl ₃ ) δ 7.17 (s, 1H) 4.71 (s, 2H) 4.06 (s, 3H) 3.22 (s, 6H). m/z (APCI+) for (C11H13N3O3) 236.0 (M+H)+.

Step 2: 6-(dimethylamino)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (3b)

Lithium borohydride (0.27 mL, 0.536 mmol, 2.0 M in THF) was added to a solution of methyl 6(dimethylamino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4 -carboxylate (3a) (35 mg, 0.130 mmol) in THF (5.0 ml, 0.03 M) at 0°C. The resulting mixture was stirred at 0°C, then allowed to warm to room temperature and stirred for 18 hours. The mixture was quenched with water (15 ml) and extracted with 10% methanol in DCM (2x15 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as an off-white solid (24 mg, 78%), which was used without purification, m/z (APCI+) for (C ₁₀ H ₁₃ N ₃ O ₂ ) 208.1 (M+H)+.

Step 3: tert-butyl ((6-(dimethylamino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl)methyl)(methyl)carbamate (Intermediate 3)

- 36 044841

I

Vos Intermediate 3

To a solution of 6-(dimethylamino)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (3b) (24 mg, 0.120 mmol) in DCM (16, 0 ml) triethylamine (0.08 ml, 0.579 mmol) and methanesulfonyl chloride (0.02 ml, 0.232 mmol) were added at 0°C, the mixture was stirred at 0°C for 30 min, a 1 M solution of methylamine in THF (1.2 ml, 1.16 mmol), and the reaction mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was taken up in DCM (10 ml) and triethylamine (0.08 ml, 0.579 mmol) was added, and di-tert-butyl dicarbonate (39.1 mg, 0.174 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (15 ml) and extracted with 10% methanol in DCM (2x15 ml). The combined organic layer was dried over anhydrous sodium sulfate. filtered and concentrated. The crude material was purified by column chromatography (0-10% methanol in DCM) to give the title compound as a white foam (17 mg, 46%).

^1H NMR (400 MHz, CDCl3) δ 6.83 (s, 1H), 6.61 -6.44 (m, 1H), 4.50 (br.s., 2H), 4.41-4, 31 (m, 2H), 3.12 (s, 6H), 2.97-2.89 (m, 3H), 1.51-1.39 (s, 9H). m/z (APCI+) for (C16H24N4O3) 321.0 (M+H) ⁺ .

Alternatively, intermediate 3 was prepared as follows.

Step 1: 2-chloro-6-(dimethylamino)-N,N-dimethylpyridine-4-carboxamide (3c)

Cl Zs

To a 3.0 L round bottom flask charged with methyl 2,6-dichloropyridine-4-carboxylate (58.0 g, 281 mmol) under N2 atmosphere was added N,N-dimethylamine (38.1 g, 845 mmol) at 0- 10°C. THF (200 ml) was added. A solution of i-PrMgCl (2.0 M in THF, 352 ml, 704 mmol) was added over 3 hours, maintaining the reaction temperature at 0-10°C. The reaction mixture was stirred for an additional 10 minutes at 0°C, and then at 25°C for 18 hours. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was cooled in an ice bath and quenched by adding cold saturated aqueous NH ₄ Cl (500 ml), maintaining the reaction temperature <20°C. EtOAc (500 ml) was added and the layers were separated. The aqueous layer was extracted with EtOAc (500 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting oil was dissolved in heptane (200 ml) and concentrated on a rotary evaporator to form solids. The suspension was stirred for 0.5 h and the solids were collected by filtration, the filter cake was washed with hexanes (3x50 ml). The filter cake was suspended in 1:20 EtOAc/petroleum ether (100 ml) and the solids were collected by filtration. The filter cake was washed with 1:20 EtOAc/petroleum ether (3x30 ml) and then dried in vacuo to give 2-chloro-6-(dimethylamino)-N,N-dimethylpyridin-4-carboxamide (51 g, 80% yield) as light yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 6.49 (d, J=0.7 Hz, 1H), 6.35 (d, J=0.9 Hz, 1H), 3.13-3.09 ( m, 9H), 2.98 (s, 3H); m/z (ESI+) for (C ₁₀ H ₁₄ ClN ₃ O), 227.9 (M+H) ⁺ .

Step 2: 2-chloro-6-(dimethylamino)-3-formyl-N,N-dimethylpyridine-4-carboxamide (3d)

This transformation was carried out in two parallel reactions. POCl ₃ (85.9 g, 560 mmol) was added to a round bottom flask containing DMF (250 ml) at 15-25°C with stirring. The mixture was stirred at 15-25°C for 15 minutes, and then 2-chloro-6-(dimethylamino)-N,Ndimethylpyridine-4-carboxamide (25.5 g, 112 mmol) was added. The mixture was stirred at 50°C for 16 hours. XMS analysis showed consumption of the starting material to form the mass of the desired product. The two reactions were combined and then quenched by slowly pouring into cold saturated aqueous Na ₂ CO ₃ solution, maintaining pH ~9. The mixture was extracted with EtOAc (4x1.0 L). The combined organic layers were washed with brine (5x600 ml), dried over Na2SO4, filtered and concentrated. The crude product was combined with two additional reactions carried out in an identical manner with 7.5 g and 5.0 g of 2-chloro-6-(dimethylamino)-N,N-dimethylpyridinium-4-carboxamide. The material was loaded into EtOAc (200 ml) and suspended for 20 minutes. The suspension was filtered. Filter

- 37 044841 the layered cake was washed with EtOAc (2x50 ml). The filter cake was suspended in 1:1 petroleum ether/EtOAc (80 ml) for 20 min. The suspension was filtered and the filter cake was washed with 1:1 petroleum ether/EtOAc (60 ml). The filtered cake was dried in a vacuum. The combined filtrate was concentrated to dryness. The residue was suspended in 1:1 petroleum ether/EtOAc (100 ml) for 30 min. The suspension was filtered and the filter cake was washed with 1:1 petroleum ether/EtOAc (2x50 ml) and dried under vacuum. The combined dried solids were suspended in petroleum ether (200 ml) for 10 minutes, and the solids were collected by filtration. The filtered cake was washed with petroleum ether (100 ml) and then concentrated in vacuo. The combined filtrate was concentrated in vacuo to ~50 mL and then allowed to stand for 2 days. The resulting solids were collected by filtration and the filter cake was washed with 3:2 petroleum ether/EtOAc (2x50 ml). The solids were combined to give 2-chloro-6-(dimethylamino)-3formyl-N,N-dimethylpyridine-4-carboxamide (52 g, 73% yield) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.21 (d, J=0.6 Hz, 1H), 6.28 (d, J=0.6 Hz, 1H), 3.19 (s, 6H ), 3.13 (s, 3H), 2.77 (s, 3H); m/z (ESI+) for (CnH^ClN^), 255.9 (M+H) ⁺ .

Step 3: tert-butyl yl]methyl}methylcarbamate (3e) {[6-(dimethylamino)-4-(dimethylcarbamoyl)-3-formylpyridinium-2-

A mixture of tert-butyldimethylcarbamate (3.41 g, 23.5 mmol) and N,N,N,N-tetramethylenediamine (3.27 g, 28.2 mmol) in 135 ml THF was cooled to -55°C under N ₂ . A solution of s-BuLi (1.4M in cyclohexane, 20.1 mL, 28.2 mmol) was added while maintaining the solution temperature <-52°C (internal). The mixture was stirred for an additional 30 minutes at -55°C, and then treated with a solution of ZnCl ₂ (1.9M in 2methyltetrahydrofuran, 14.8 ml, 28.2 mmol), maintaining the reaction temperature <-52°C. The solution was stirred for an additional 40 minutes to -55°C and then warmed to room temperature to obtain a solution of {[(tert-butoxycarbonyl)(methyl)amino]methyl}(chlorido)zinc (c=0.195M). A portion of the pre-prepared zincate solution (90.2 mL, 17.6 mmol) was transferred to an oven-dried 250 mL round bottom solution under N2 and concentrated to dryness to obtain a white foam. The flask was filled again with N2. A separate flask was charged with 2-chloro-6-(dimethylamino)-3-formyl-N,Ndimethylpyridine-4-carboxamide (3.0 g, 10 mmol), PdCl ₂ (dppf) (0.858 g, 1.17 mmol), 1,4-dioxane (50 ml) and H2O (0.159 g, 8.8 mmol). The suspension was cannulated into a flask containing zincate, and the mixture was then stirred at 80°C for 80 minutes. X-ray MS analysis indicated the formation of the desired mass of product with some remaining starting material. An additional aliquot of {[(tert-butoxycarbonyl)(methyl)amino]methyl}(chlorido)zinc solution (2.0 mL) was added and the mixture was stirred at 80°C for 20 minutes. No additional conversion was observed. The reaction mixture was cooled to 0°C and quenched by adding saturated aqueous NH ₄ Cl (10 ml) and H2O (20 ml). The mixture was stirred at 0°C for 20 minutes and then filtered through a pad of celite. The filtrate was extracted with EtOAc (4x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (80 g SiO ₂ , 0-100% EtOAc/heptane. The resulting white foam was triturated with MTBE and concentrated in vacuo to give tert-butyl {[6-(dimethylamino)-4(dimethylcarbamoyl)-3 -formylpyridin-2-yl]methyl}methylcarbamate (3.8 g, 95% yield) as a light yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 9.84 (d, J=6.8 Hz, 1H), 6.45 (s, 1H), 4.71 (s, 2H), 3.15 (s , 6H), 2.99 (s, 3H), 2.90 (s, 3H), 2.75 (s, 3H), 1.33 (d, J=69.8 Hz, 9H); m/z (ESI+) for (C ₁₈ H ₂₈ N ₄ O ₄ ), 365.3 (M+H) ⁺ .

Step 4: tert-butyl {[6-(dimethylamino)-4-(dimethylcarbamoyl)-3-{(E)-[(2-methylpropan-2sulfinyl)imino]methyl}pyridin-2-yl]methyl}methylcarbamate (3f

To a solution of tert-butyl {[6-(dimethylamino)-4-(dimethylcarbamoyl)-3-formylpyridin-2yl]methyl}methylcarbamate (3.0 g, 8.0 mmol) and (R)-(+)-2- Methyl 2-propanesulfinamide (1.2 g, 9.88 mmol)

- 38 044841 titanium(IV) ethoxide (5.63 g, 24.7 mmol) was added to THF (40 ml). The mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature, diluted with DCM (50 ml), and quenched by adding saturated aqueous NaHCO ₃ (20 ml). The solution was stirred vigorously for 20 minutes and then filtered through a pad of celite. Celite was washed with DCM (3x). The combined filtrate was dried over Na2SO4, filtered, and concentrated. The residue was purified using flash chromatography (80 g SiO ₂ , 0-100% EtOAc/heptane) to give tert-butyl {[6-(dimethylamino)-4(dimethylcarbamoyl)-3-{(E)-[(2-methylpropane- 2-sulfinyl)imino]methyl}pyridin-2yl]methyl}methylcarbamate (3.89 g, 97% yield) as a colorless foam.

1H NMR (400 MHz, DMSO-th ₆ ) δ 8.39 (s, 1H), 6.46 (s, 1H), 4.77-4.55 (m, 2H), 3.12 (s, 6H ), 2.95 (s, 3H), 2.93 (s, 3H), 2.74 (s, 3H), 1.41 (s, 4H), 1.20 (s, 5H), 1.12 (s, 9H); m/z (ESI+) for (C ₂₂ H ₃₇ N ₅ O ₄ S), 468.4 (M+H)+.

Step 5: tert-butyl {[6-(dimethylamino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl]methyl} methylcarbamate

In a round bottom flask, in

Intermediate 3 is loaded with tert-butyl {[6-(dimethylamino)-4(dimethylcarbamoyl)-3-{(E)-[(2-methylpropane-2-sulfinyl)imino]methyl}pyridin-2yl]methyl}methylcarbamate ( 3.89, 8.32 mmol) under N2, THF (42 mL) was added. The mixture was cooled to 0°C and then treated with a solution of LiBH4 (2.0 M in THF, 4.37 ml, 8.73 mmol). The mixture was stirred at 0°C for 1 hour, and then a solution of NaOMe (25% in MeOH, 17.1 ml, 74.9 mmol) was added at the same temperature. The reaction mixture was allowed to slowly warm to room temperature and stirred for 16 hours. LCMS analysis indicated consumption of the starting material to form the desired mass of product. The mixture was diluted with DCM and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified using flash chromatography (80 g SiO ₂ , 0-100% EtOAc/heptanes) to give intermediate 3 (1.7 g, 64% yield) as a colorless foam.

1H NMR (400 MHz, DMSO-06) δ 8.68 (s, 1H), 6.68 (s, 1H), 4.42 (s, 2H), 4.23 (s, 2H), 3.06 (s, 6H), 2.86 (s, 3H), 1.36 (m, 9H); RX-MS m/z (ESI+) for (C ₁₆ H ₂₄ N ₄ O ₃ ), 321.2 (M+H)+.

Intermediate 4: 2-bromo-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine

Step 1: N'-acetyl-6-bromopyridine-2-carbohydrazide (4a)

To a solution of 6-bromopyridine-2-carbohydrazide (1a) (1.5 g, 6.94 mmol) in DCM (23 mL) at 0°C was added TEA (1.4 mL, 10.4 mmol) and acetyl chloride (0 .56 ml, 7.8 mmol).

The resulting solution was stirred at 20°C for 58 hours. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (SiO ₂ , 0-100% ethyl acetate/petroleum ether) to give N'-acetyl-6-bromopyridine-2- carbohydrazide as a white solid (1.0 g, 56%), ¹ H NMR (400 MHz, DMSO-06) δ 10.41 (d, J=1.6 Hz, 1H), 10.02 (d, J=1.6 Hz, 1H), 8.04 (dd, J=7.5, 1.2 Hz, 1H), 7.97 (t, J=7.7 Hz, 1H), 7.91 ( dd, J=7.9, 1.2 Hz, 1H), 1.92 (s, 3H); m/z (ESI) for (C ₈ H ₈ BrN ₃ O ₂ ), 257.9 (M+H)+.

Step 2: 2-bromo-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine

Br

Intermediate 4

To a solution of N'-acetyl-6-bromopyridine-2-carbohydrazide (4a) (240 mg, 0.93 mmol) in DCM (6 mL) and MeCN (6 mL) was added TEA (0.78 mL, 5.6 mmol ) and p-toluenesulfonyl chloride (195 mg, 1.0 mmol). The resulting solution was stirred at 20°C for 5 hours. The reaction mixture was concentrated in vacuo and the resulting material was purified by flash chromatography (SiO ₂ , 0-10% methanol/DCM) to give 2-39 044841 bromo-6-(5-methyl -1,3,4-oxadiazol-2-yl)pyridine as a white solid (80 mg, 36%).

1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=7.6 Hz, 1H), 8.00 (t, J=7.8 Hz, 1H), 7.90 (d, J =8.0 Hz, 1H), 2.63 (s, 3H); m/z (ESI) for (C ₈ H ₆ BrN ₃ O), 241.5 (M+H)+.

Intermediate 5: 2-bromo-6-(1,3,4-oxadiazol-2-yl)pyridine

A solution of 6-bromopyridine-2-carbohydrazide (1a) (1.0 g, 4.63 mmol) in HC(OEt) ₃ (4.0 ml) was stirred at 120°C for 18 hours. The reaction mixture was cooled to room temperature , and HC(OEt) ₃ (4.0 ml) was added. The reaction mixture was allowed to stir at 140°C for 3 hours, then at 135°C for 16 hours, 150°C for 16 hours and 135°C for 19 hours. LCMS analysis with minimal starting material remaining to form the desired mass product. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (SiO ₂ , 1:10 EtOAc/petroleum ether) to give intermediate 5 (400 mg, 38% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.05-7.98 (m, 1H), 7 .92 (d, J=8.0 Hz, 1H); m/z (ESI) for (C^Br^O), 225.8, 227.8 (M+H)+.

Intermediate 6: 2-bromo-6-(1,3,4-thiadiazol-2-yl)pyridine

Step 1: 6-bromo-N'-formylpyridine-2-carbohydrazide (6a)

Pure formic acid (3.2 g, 69.4 mmol) was added to Ac ₂ O (5.9 g, 57.9 mmol) under N2 atmosphere. The mixture was stirred at 60°C for 1 hour and then cooled to room temperature. THF (20.0 ml) was added. The solution was transferred to a solution of 6-bromopyridine-2-carbohydrazinide (1a) (5.0 g, 23.1 mmol) in THF (40 ml) at 0°C. The mixture was stirred at 15°C for 3 hours. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was concentrated to dryness. The residue was suspended in DCM (50 ml) and the solids were collected by filtration. The filter cake was washed with DCM (50 mL) and dried in vacuo to give 6-bromo-N-formylpyridine-2-carbohydrazide (6a) (3.7 g, 65% yield) as a white solid.

1H NMR (400 MHz, DMSO-66) δ 10.17 (s, 2H), 8.13-8.00 (m, 2H), 7.98-7.90 (m, 1H), 7.86 ( dd, J=7.9, 1.0 Hz, 1H); m/z (ESI) for (C ₇ H ₆ BrN ₃ O ₂ ), 245.7 (M+H)+.

Step 2: 2-bromo-6-(1,3,4-thiadiazol-2-yl)pyridine

Intermediate 6

To a solution of 6-bromo-N'-formylpyridine-2-carbohydrazide (6a) (4.2 g, 17.4 mmol) in xylenes (420 ml) was added phosphorus pentasulfide (2.3 g, 10.4 mmol). The mixture was stirred at 140°C for 45 minutes. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , 1:1 petroleum ether/EtOAc). The grain product was purified using flash chromatography (SiO ₂ , 1:3 EtOAc/petroleum ether) to give intermediate 6 (587 mg, 14% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.32 (dd, J=7.7, 0.9 Hz, 1H), 8.03-7.97 (m, 1H), 7.86 (dd, J=7.9, 0.9 Hz, 1H).; m/z (ESI) for (C^Br^S), 243.8 (M+H)+.

Intermediate 7: tert-butyl [(6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin4-yl)methyl]carbamate

Step 1: (6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl methanesulfonate (7a)

- 40 044841

A solution of 6-chloro-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (2.0 g, 10.1 mmol) and TEA (3.1 mg , 30.2 mmol) in THF (50.0 ml) under N ₂ was cooled to 0°C and then treated dropwise with MsCl (1.73 g, 15.1 mmol). The mixture was stirred at 0°C for 2 hours. X-ray MS analysis showed consumption of the starting material. The reaction mixture was diluted with EtOAc (150 ml). The mixture was washed with H2O (50 ml), with aqueous NaHCO ₃ (50 ml), and brine (2x50 ml), dried over Na ₂ SO ₄ , filtered, and concentrated to give (6-chloro-1-oxo-2, 3-dihydro-1H-pyrrolo[3,4c]pyridin-4-ul)methylmethanesulfonate (2.0 g, 72% yield) as gray solid, m/z (ESI+) for (C9H9ClN2O4S), 276.9 (M+H)+.

Step 2: 4-(azidomethyl)-6-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (7b)

(6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate solution (2.0 g, 7.23 mmol), 18-crown-6 (191 mg, 0.723 mmol), and NaN ₃ (705 mg, 10.8 mmol) in MeCN (70 ml) were stirred at 10°C for 20 hours. RC-MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was diluted with H ₂ O (50 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 4-(azidomethyl)-6-chloro-2,3-dihydro-1Hpyrrolo[3,4-c]pyridine -1-one (1.62 g, >99% yield) as a light brown solid, m/z (ESI+) for (C8H6ClN5O), 223.7 (M+H)+.

Step 3: 4-(aminomethyl)-6-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (7c)

A solution of 4-(azidomethyl)-6-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (1.62 g, 7.23 mmol) and PPh ₃ (2.84 mg, 10.8 mmol) in a mixture of THF (40.0 ml) and H ₂ O (4.0 ml) was stirred at 20°C for 6 hours. X-ray MS analysis showed consumption of the starting material. A solution of HCl (4.0M in EtOAc, 50 ml) was added and the mixture was extracted with H ₂ O (2x30 ml). The combined aqueous layers were basified with solid NaHCO ₃ to pH ~8 to obtain an aqueous solution of 4-(aminomethyl)-6-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1one (c ~0.12M , 60 ml), which was used directly for the next step.

Step 4: tert-butyl [(6-chloro-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate

TEA (620 mg, 6.03 mmol) and DXM (10 ml). The mixture was cooled to 10°C and Boc ₂ O (790 mg, 3.62 mmol) was added. The mixture was stirred at 15°C for 1.5 hours. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The mixture was diluted with DCM (50 ml) and washed with H2O (25 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was diluted with DCM (5 ml). Petroleum ether (15 ml) was added and the mixture was stirred at 10°C for 15 minutes to obtain a suspension. The solids were collected by filtration and the filter cake was dried in vacuo to give intermediate 7 (809 mg, 90% yield) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.62 (s, 1H), 7.50 (bt, J=6.0 Hz, 1H), 4 .46 (s, 2H), 4.34

- 41 044841 (d, J=6.0 Hz, 2H), 1.40 (s, 9H); m/z (ESI+) for (C ₁₃ H ₁₆ ClN ₃ O ₃ ), 197.9 (M-Boc+H) ⁺ .

Intermediate 8: tert-butyl methyl{[6-(1-methylcyclopropyl)-1-oxo-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-4-yl]methyl}carbamate

Step 1: Ethyl 3-cyano-2-hydroxy-6-(1-methylcyclopropyl)pyridine-4-carboxylate (8a)

A mixture of 2-cyanoacetamide (10.0 g, 119 mmol) and TEA (12.0 g, 119 mmol) in EtOH (50 ml) was heated to 65 °C (internal) until the solids dissolved and then ethyl 3-(1methylcyclopropyl)-3-oxopropanoate (24.6 g, 124 mmol) was added. The mixture was stirred at 65°C for 2 hours. TLC analysis (1:10 EtOAc/petroleum ether) showed consumption of the starting material. The reaction mixture was cooled to 10°C. The resulting precipitate was collected by filtration. The filter cake was washed with MTBE (3x10 ml) and vacuum dried. The filtrate was concentrated to dryness. The residue was diluted with EtOH (10 ml) and MTBE (30 ml) was added. The resulting precipitate was collected by filtration. The filter cake was washed with EtOH (5 ml) and MTBE (2x10 ml) and dried in vacuum. The solids were combined to give ethyl 3-cyano-2-hydroxy-6-(1-methylcyclopropyl)pyridine-4carboxylate (25.0 g, 85% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ 12.74 (b.s., 1H), 6.63 (b.s., 1H), 4.36 (q.v., J=7.1 Hz, 2H), 1.45 - 1.27 (m, 6H), 1.16-1.06 (m, 2H), 0.92-0.75 (m, 2H).

Step 2: Ethyl 2-chloro-3-cyano-6-(1-methylcyclopropyl)pyridine-4-carboxylate (8b)

To a solution of ethyl 3-cyano-2-hydroxy-6-(1-methylcyclopropyl)pyridine-4-carboxylate (24.0 g, 97.5 mmol) in MeCN (487 ml) was added dropwise POCl ₃ (74.7 g , 487 mmol) at 30°C. The mixture was stirred at 65°C for 60 hours. TLC analysis (EtOAc) showed consumption of the starting material. The solution was concentrated to remove residual POCl ₃ . The residue was poured onto ice and made alkaline with NaHCO ₃ to pH ~8. The mixture was extracted with EtOAc (2x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (1:10 EtOAc/petroleum ether) to give ethyl 2-chloro-3-cyano-6-(1-methylcyclopropyl)pyridine-4-carboxylate (21.9 g, 85% yield) as light -yellow solid.

1H NMR (400 MHz, chloroform-d) δ 7.79 (s, 1H), 4.50 (q, J=7.2 Hz, 2H), 1.55 (s, 3H), 1.50- 1.40 (m, 5H), 1.03 (sq., J=3.9 Hz, 2H); m/z (ESI+) for (C ₁₃ H ₁₃ ClN ₂ O ₂ ), 264.9 (M+H) ⁺ .

Step 3: 4-chloro-6-(1-methylcyclopropyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (8c)

Raney's Ni (2.0 g 34, 1 mmol). The black mixture was stirred at 30°C under H ₂ at 30 psi for 48 hours. TLC analysis (1:10 EtOAc/petroleum ether) showed consumption of the starting material. The mixture was filtered through a pad of celite. The filter cake was washed with MeOH (250 ml). The combined filtrate was concentrated to dryness. The residue was suspended in EtOAc (5 ml) for 20 minutes and the suspension was filtered. The filter cake was washed with EtOAc (2 ml) and dried in vacuo to give 4-chloro-6-(1-methylcyclopropyl)-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one (1.1 g , 52% yield) as a gray solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (b.s., 1H), 7.23-7.05 (m, 1H), 4.56-4.34 (m, 2H), 1 .55 (b.s., 3H), 1.391.11 (m, 2H), 0.99-0.66 (m, 2H); m/z (ESI+) for (ScIcC^O), 222.8 (M+H) ⁺ .

Step 4: tert-butyl methyl{[6-(1-methylcyclopropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- 42 044841

c]pyridin-4-yl]methyl} carbamate

N.H.

Intermediate 8

Mixture of 4-chloro-6-(1-methylcyclopropyl)-2,3-dihydro-1H-pyrrolo[3,4-e]pyridin-1-one (1.0 g, 4.49 mmol), sodium [( tert-butoxycarbonyl)(methyl)amino]acetate (1.9 g, 8.98 mmol), NiCl ₂ dimethoxyethane (197 mg, 0.898 mmol), pyridin-2-yl-N-cyanoamidine (131 mg, 0.898 mmol) , and iridium(III) bis[2-(2,4difluorophenyl)-5-methylpyridin-N,C ₂₀ ]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate (22.8 mg, 0. 0225 mmol) in DMF (135 ml) was pumped out and N2 (3x) was added again. The mixture was irradiated with two 72 W magenta LED strips in a flow (8 ml/min) at ambient temperature for 7 h with fan cooling. The reaction mixture was concentrated to dryness. The residue was purified using flash chromatography (5 g SiO ₂ , 30-80% EtOAc/petroleum ether) to give intermediate 8 (856 mg, 58% yield) as an off-white solid.

1H NMR (400 MHz, DMSO- _d6 ) δ 8.86 (b.s., 1H), 7.45 (s, 1H), 4.59-4.40 (m, 2H), 4.35 ( s, 2H), 2.84 (s, 3H), 1.52 (s, 3H), 1.47-1.31 (m, 5H), 1.31-1.10 (m, 6H), 0 .86-0.81 (m, 2H); m/z (ESI+) for (C ₁₈ H ₂₅ N ₃ O ₃ ), 332.1 (M+H)+.

Intermediate 9: 4-chloro-6-[ethyl(methyl)amino]-2,3-dihydro-1H-pyrrolo[3,4e]pyridin-1-one

Step 1: Ethyl 2-chloro-6-[ethyl(methyl)amino]pyridine-4-carboxylate (9a)

A solution of ethyl 2,6-dichloropyridine-4-carboxylate (1.61 g, 7.34 mmol) and N-methylethanamine (1.30 g, 22.0 mmol) in DMF (3.0 ml) was stirred at 80°C within 3 hours, X-ray MS analysis showed consumption of the starting material. The reaction mixture was concentrated to dryness. The residue was purified using flash chromatography (12 g SiO ₂ , 0-100% EtOAc/heptane) to give ethyl 2-chloro-6[ethyl(methyl)amino]pyridine-4-carboxylate (1.65 g, 93% yield ) in the form of a colorless oil.

1H NMR (400 MHz, CDCI3) δ 7.03 (d, J=0.9 Hz, 1H), 6.96 (d, J=0.9 Hz, 1H), 4.39 (q, J= 7.1 Hz, 2H), 3.61 (sq., J=7.1 Hz, 2H), 3.09 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H); m/z (APCI+) for (CiiHisCINzOz), 243.1 (M+H)+.

Step 2: Ethyl 2-chloro-6-[ethyl(methyl)amino]-3-formylpyridine-4-carboxylate (9b)

To DMF (508 mg, 6.95 mmol), under N ₂ atmosphere, was added POC13 (800 mg, 5.22 mmol). The mixture was stirred at room temperature for 20 minutes, and then a solution of ethyl 2-chloro-6[ethyl(methyl)amino]pyridine-4-carboxylate (1.65 g, 6.39 mmol) in DCM (25.5 ml) was added ). The mixture was stirred at reflux for 20 hours under N2 atmosphere. The mixture was cooled to room temperature, and quenched by slowly pouring into saturated aqueous NaHCO ₃ solution (100 ml). The mixture was stirred for 10 min and then extracted with EtOAc (2x80 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (24 g SiO ₂ , 0-100% EtOAc/heptane) to give ethyl 2-chloro-6-[ethyl(methyl)amino]-3formylpyridine-4-carboxylate (1.51 g, 82% yield ) as a light yellow solid.

1H NMR (400 MHz, CDCI3) δ 10.17 (s, 1H) 6.37 (s, 1H) 4.43 (sq., J=7.09 Hz, 2H) 3.67 (b.d., J=4.03 Hz, 2H) 3.16 (d, J=9.29 Hz, 3H) 1.39 (t, J=7.15 Hz, 3H) 1.23 (t, J=7.09 Hz, 3H); m/z (APCI+) for (C^H^CMO3), 271.1 (M+H)+.

Step 3: 4-chloro-6-[ethyl(methyl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

- 43 044841

A mixture of ethyl 2-chloro-6-[ethyl(methyl)amino]-3-formylpyridine-4-carboxylate (1.33 g, 4.91 mmol) and NH3 solution (7.0 N in MeOH, 7.01 ml, 49.1 mmol) was stirred for 1 hour at room temperature. The mixture was concentrated to dryness. The residue was dissolved in DCM (10.0 ml) and TFO (5.59 g, 49.1 mmol) and Et ₃ SiH (1.14 g, 1.57 mmol) were added. The mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (100 ml) and washed with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate 9 (823 mg, 74% yield) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 6.82 (s, 1H) 6.41 (b.s., 1H) 4.37 (s, 2H) 3.63 (sq., J=7.09 Hz , 2H) 3.10 (s, 3H) 1.19 (t, J=7.09 Hz, 3H); m/z (APCI+) for (CuH^C^O), 226.1 (M+H)+.

Intermediate 10: 4-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one

Step 1: {2-chloro-6-[(2R)-2-methylpyrrolidinyl-1-yl]pyridin-4-yl}(piperidin-1-yl)methanone (10a)

A solution of (2,6-dichloropyridin-4-yl)(piperidin-1-yl)methanone (600 mg, 2.32 mmol) and (2R)-2methylpyrrolidinyl (591 mg, 6.95 mmol) in DMF (1.5 ml) was stirred at 100°C for 16 hours. XMS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was cooled to room temperature, diluted with H ₂ O and extracted with DCM (3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (24 g SiO ₂ , 0-20% EtOAc/heptane) to give {2-chloro-6[(2R)-2-methylpyrrolidinyl-1-yl]pyridin-4-yl}(piperidine -1-yl)methanone (664 mg, 93% yield).

¹ H NMR (400 MHz, Chloroform-d) δ 6.44 (d, J=1.0 Hz, 1H), 6.21 (d, J=1.0 Hz, 1H), 4.12 (sq. , J=7.1 Hz, 1H), 3.72-3.62 (m, 2H), 3.54 (ddd, J=10.5, 7.6, 2.9 Hz, 1H), 3, 40-3.28 (m, 2H), 2.10-2.04 (m, 2H), 1.75-1.62 (m, 4H), 1.26 (t, J=7.2 Hz, 1H), 1.21 (d, J=6.3 Hz, 2H); m/z (APCI+) for (C^Cl^O), 308.2 (M+H)+.

Step 2: 2-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1-carbonyl)pyridine-3carbaldehyde (10b)

To a solution of DMF (473 mg, 6.47 mmol) in DCM (3.0 ml) was added POCl ₃ (992 mg, 6.47 mmol). The mixture was stirred for 10 min, and then a solution of {2-chloro-6-[(2R)-2-methylpyrrolidinyl-1yl]pyridin-4-yl}(piperidin-1-yl)methanone (664 mg, 2.16 mmol) in DCM (3.0 ml). The mixture was stirred at reflux for 15 hours. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was concentrated to dryness and slowly poured into saturated aqueous NaHCO ₃ (30 ml). The mixture was extracted with DCM (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (24 g SiO ₂ , 0-40% EtOAc/heptane) to give 2-chloro-6-[(2R)2-methylpyrolidinyl-1-yl]-4-(piperidin-1-carbonyl )pyridine-3-carbaldehyde (568 mg, 78% yield).

1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 5.99 (s, 1H), 4.13-4.65 (m, 1H), 3.68-3.83 (m, 1H), 3.55-3.68 (m, 2H), 3.35-3.55 (m, 1H), 2.98-3.20 (m, 2H), 1.88-2.17 ( m, 3H), 1.71-1.83 (m, 2H), 1.55-1.67 (m, 3H), 1.461.55 (m, 1H), 1.31-1.42 (m, 1H), 1.17-1.26 (m, 3H); m/z (APCI+) for (Q^ClN^), 336.1 (M+H)+.

Step 3: N-[(E)-{2-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1-carbonyl)pyridin-3yl}methylidene]-2-methylpropane -2-sulfinamide (10c)

- 44 044841

Mixture of 2-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1-carbonyl)pyridine-3carbaldehyde (432 mg, 1.29 mmol), (R)-(+ )-2-methyl-2-propanesulfinamide (187 mg, 1.54 mmol), and titanium(1U) ethoxide (880 mg, 3.86 mmol) in THF (10.0 ml) were stirred at 45°C for 16 h. X-ray MS analysis showed ~25% of the remaining starting material. Additional batches of (R)-(+)-2methyl-2-propanesulfinamide (62.4 mg, 0.515 mmol), and titanium(IV) ethoxide (293 mg, 1.29 mmol) were added and the mixture was stirred at 50°C in within 16 hours. X-ray MS analysis showed consumption of the starting substance. The reaction mixture was cooled to room temperature. The mixture was diluted with DCM and washed with NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give N-[(E)-{2-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1carbonyl)pyridine -3-yl}methylidene]-2-methylpropan-2-sulfinamide (495 mg, 88% yield) as a white gum, which was used without further purification, m/z (APCI+) for (C ₂₁ H ₃₁ ClN ₄ O ₂ S), 440.2 (M+H)+.

Step 4: 4-chloro-6-[(2R)-2-methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Solution of N-[(E)-{2-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1-carbonyl)pyridin-3yl}methylidene]-2-methylpropan-2 -sulfinamide (495 mg, 1.13 mmol) in THF (15.0 ml) was cooled to 0°C and then a solution of LiBH ₄ (2.0 M in THF, 620 ml, 1.24 mmol) was added. The mixture was stirred at 0°C for 2 hours, and then a solution of NaOMe (25% in MeOH, 2.5 ml, 10.1 mmol) was added. The reaction mixture was allowed to warm to room temperature and then stirred for 16 hours. The reaction mixture was diluted with DCM (60 ml) and washed with saturated aqueous NH4Cl (60 ml) and brine (60 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified using flash chromatography (24 g SiO ₂ , 50-100% EtOAc/heptane) to give intermediate 10 (199 mg, 70% yield) as a colorless foam.

^1H NMR (400 MHz, chloroform-d) δ 6.68 (s, 1H), 6.45 (s, 1H), 4.35 (s, 2H), 4.21-4.14 (m, 1H ), 3.58 (ddd, J=10.5, 7.6, 2.8 Hz, 1H), 3.39 (sq., J=8.9 Hz, 1H), 2.13-1.97 (m, 2H), 1.75 (dt, J=5.2, 2.6 Hz, 1H), 1.23 (d, J=6.3 Hz, 3H). One hydrogen atom is envisioned to be overlapped by the water peak; m/z (APCI+) for (C12H14ClN ₃ O), 252.3 (M+H)+.

Intermediate 11: 4-chloro-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-1-one

Step 1: 2-chloro-N,N-dimethyl-6-[methyl(nropan-2-yl)amino]pyridin-4-carboxamide (11a) o ¹

Cl 11a

A mixture of 2,6-dichloro-N,N-dimethylpyridine-4-carboxamide (30.0 g, 137 mmol) and N-methylpropan-2amine (50.1 g, 685 mmol) in MeCN (120 ml) was distributed between three hermetically sealed reaction vessels and stirred each time at 100°C for 60 hours. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixtures were combined and concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , 1:1 EtOAc/petroleum ether) to give 2-chloro-N,N-dimethyl-6-[methyl(propan-2-yl)amino]pyridin-4carboxamide (30, 5 g, 87% yield) as a yellow solid.

1H NMR (400 MHz, chloroform-d) δ 6.45 (d, J=0.9 Hz, 1H), 6.31 (d, J=1.0 Hz, 1H), 4.82 (p, J =6.8 Hz, 1H), 3.08 (s, 3H), 2.97 (s, 3H), 2.83 (s, 3H), 1.16 (d, J=6.7 Hz, 6H ); m/z (ESI+) for (C _p Н18СШ ₃ О), 255.9 (M+H)+.

- 45 044841

Step 2: 2-chloro-3-formyl-N,N-dimethyl-6-[methyl(propαn-2-yl)amino]pyridin-4-carboxamide (11b)

ci about Hb

To a solution of DMF (21.9 g, 299 mmol) in DCE (120 ml) POCl ₃ (45.9 g, 299 mmol) was added dropwise at 5-15°C. The mixture was stirred at room temperature for 15 minutes and 2-chloro-N,Ndimethyl-6-[methyl(propan-2-yl)amino]pyridin-4-carboxamide (25.5 g, 99.7 mmol) was added. The reaction mixture was stirred at 65°C for 16 hours. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was cooled to room temperature and added dropwise to saturated aqueous Na ₂ CO ₃ (900 ml). The mixture was extracted with DCM (2x300 ml). The combined organic layers were washed with brine (5x500 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (SiO ₂ , 1:1 EtOAc/petroleum ether) to give 2-chloro-3-formyl-N,N-dimethyl-6-[methyl(propαn-2yl)amino]pyridin-4- carboxamide (23.7 g, 84% yield) as a brown solid.

1H NMR (400 MHz, CDCI3) δ 10.19 (s, 1H), 6.25 (br.s., 1H), 3.12 (s, 3H), 3.02-2.85 (m, 3H ), 2.77 (s, 3H), 1.22 (b.d., J=6.5 Hz, 6H); m/z (ESI+) for (C^H^C^Oz), 283.9 (M+H)+.

Step 3: 2-chloro-N,N-dimethyl-3-{(E)-[(2-methylpropane-2-sulfinyl)imino]methyl}-6[methyl(propan-2-yl)amino]pyridin-4 -carboxamide (11c)

about 11c

Mixture of 2-chloro-3-formyl-N,N-dimethyl-6-[methyl(propan-2-yl)amino]pyridin-4-carboxalamide (23.7 g, 83.5 mmol), (R)- (+)-2-methyl-2-propanesulfinamide (12.1 g, 100 mmol), and titanium(IV) ethoxide (38.1 g, 167 mmol) in THF (250 ml) were stirred at 50°C for 20 h. X-ray MS analysis showed the consumption of the starting material with the formation of the mass of the desired product. The reaction mixture was concentrated to dryness. The residue was stirred with saturated aqueous NaHCO ₃ (300 ml) for 30 minutes. The mixture was filtered. The filter cake was washed with H2O (3x80 ml) and petroleum ether (3x50 ml) and dried in vacuo to give 2-chloro-N,N-dimethyl-3-{(E)-[(2-methylpropane-2-sulfinyl)imino] methyl}6-[methyl(propan-2-yl)amino]pyridin-4-carboxamide (32.3 g, >99% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 6.74 (s, 1H), 5.36-5.10 (m, 1H), 3.30 (s, 3H) , 3.26 (s, 3H), 3.10 (s, 3H), 1.54 (d, J=6.7 Hz, 6H), 1.49 (s, 9H); m/z (ESI+) for (C1 ₇ H2 ₇ ClN4O2S), 387.2 (M+H)+.

Step 4: 4-chloro-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

CI Intermediate 11

A solution of 2-chloro-N,N-dimethyl-3-{(E)-[(2-methylpropane-2-sulfinyl)imino]methyl}-6-[methyl(propan2-yl)amino]pyridin-4-carboxamide ( 32.3 g, 83.5 mmol) in THF (200 ml) was cooled to 0°C and LiBH ₄ (1.82 g, 83.5 mmol) was added. The mixture was stirred at room temperature for 1 hour. X-ray MS analysis showed consumption of the starting material. NaOMe (165 g, 919 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filter cake washed with EtOAc (3x200 ml). The combined filtrate was concentrated to dryness. The residue was dissolved in DCM (300 ml) and washed with H2O (500 ml). The aqueous layer was extracted with DCM (2x300 ml). The combined organic layers were washed with brine (500 ml), dried over Na2SO4, filtered and concentrated. The solid was suspended in a mixture of DCM (50 ml) and petroleum ether (120 ml) for 30 minutes. Solids were collected by filtration. The filter cake was dried under vacuum to provide Intermediate 11 (11.3 g, 56% yield) as an off-white solid.

1H NMR (400 MHz, Chloroform-d) δ 7.19 (s, 1H), 6.79 (s, 1H), 4.82 (p, J=6.7 Hz, 1H), 4.35 (d , J=1.2 Hz, 2H), 2.88 (s, 3H), 1.18 (d, J=6.7 Hz, 6H); m/z (ESI+) for (C11H14CIN3O), 239.9 (M+H)+.

Intermediate 12: 2-bromo-6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridine

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N'-[(6-bromopyridin-2-yl)carbonyl]-N,N dimethylhydrazonoformamide (2.0 g, 7.4 mmol), ethylamine (0.5 ml, 333 mg, 7.4 mmol) was loaded into the flask. , acetic acid (3 ml) and MeCN (15 ml, 0.5 M). The solution was heated for 16 hours at 95°C. The reaction mixture was diluted with EtOAc (10 ml) and H ₂ O (10 ml). Solid K ₂ CO ₃ was added until the pH of the aqueous layer was pH ~8. The layers were separated and the aqueous layer was extracted with EtOAc (3x30 ml). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was suspended in EtOAc (0.3 ml) and petroleum ether (3 ml) for 5 min. The solids were collected by filtration to give Intermediate 12 (1.5 g, 80%) as a light yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.19 (dd, J=7.7, 0.9 Hz, 1H), 7.99-7.90 (m, 1H), 7.79 (dd, J=8.0, 0.9 Hz, 1H), 4.47 (sq., J=7.2 Hz, 2H), 1.38 (t, J=7, 2 Hz, 3H); m/z (APCI+) for (C ₉ H ₉ BrN ₄ ), 252.7 (M+H) ⁺ .

Intermediate 13: 2-bromo-6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridine

A mixture of N'-[(6-bromopyridin-2-yl)carbonyl]-N,N-dimethylhydrazonoformamide (1b) (29.0 g, 106.8 mmol) and propan-1-amine (31.6 g, 534 mmol) in MeCN (440 ml) and acetic acid (110 ml) were stirred at 95°C for 16 hours. RC-MS analysis showed consumption of the starting material to form the mass of the desired product. The reaction mixture was concentrated to dryness. The residue was loaded into H ₂ O (50 ml) and basified to pH ~9 with 1 N. NaOH (~500 ml). The mixture was extracted with EtOAc (3x150 ml). The combined organic layers were washed with brine (150 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was suspended with EtOAc (50 ml) for 10 min and the solid was collected by filtration. The filter cake was washed with petroleum ether (2x50 ml) and dried in vacuo to give intermediate 13 (21.0 g, 74% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.20 (dd, J=0.7, 7.8 Hz, 1H), 7.98-7.91 (m, 1H), 7.78 (dd, J=0.7, 8.0 Hz, 1H), 4.45-4.36 (m, 2H), 1.77 (six, J=7.4 Hz, 2H ), 0.87 (t, J=7.4 Hz, 3H); m/z (ESI+) for (C ₁₀ H ₁₁ BrN ₄ ), 266.7 (M+H)+.

Intermediate 14: 2-bromo-6-[4-(pentan-3-yl)-4H-1,2,4-triazol-3-yl]pyridine

A mixture of N'-[(6-bromopyridin-2-yl)carbonyl]-N,N-dimethylhydrazonoformamide (1b) (3.10 g, 11.4 mmol) and pentan-3-amine (2.99 g, 34 .4 mmol) in MeCN (24 ml) and acetic acid (6 ml) were stirred at 95°C for 16 hours. RC-MS analysis showed consumption of the starting material to form the mass of the desired product. The solution was concentrated to dryness. The residue was taken into EtOAc (100 ml) and washed with saturated aqueous NaHCO ₃ (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (SiO ₂ , 1:1 DCM/EtOAc) to give intermediate 14 (2.3 g, 68% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.16 (d, J=7.7 Hz, 1H), 7.98-7.92 (m, 1H), 7 .78 (d, J=7.9 Hz, 1H), 5.01 (tt, J=8.5, 5.8 Hz, 1H), 1.85 (ddt, J=14.1, 8.5 , 7.2 Hz, 4H), 0.73 (t, J=7.4 Hz, 6H); m/z (ESI+) for (C12H15BrN4), 295.0 (M+H) ⁺ .

Intermediate 15: 2-bromo-6-{4-[(2S)-butan-2-yl]-4H-1,2,4-triazol-3-yl}pyridine

A mixture of N'-[(6-bromopyridin-2-yl)carbonyl]-N,N-dimethylhydrazonoformamide (1b) (4.40 g, 16.2 mmol) and (2S)-butan-2-amine (1, 25 g, 17.0 mmol) in MeCN (100 ml) and acetic acid (25 ml) were stirred at 90°C for 16 hours. X-ray MS analysis showed consumption of the starting material. The solution was concentrated to dryness. The residue was partitioned between EtOAc (50 ml) and Na2CO3 (50 ml). The organic layer was washed with brine (2x30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (120 g SiO ₂ , 1-5% MeOH/EtOAc) to give intermediate 15 (3.0 g, 66% yield) as a light yellow oil.

^1H NMR (400 MHz, chloroform-d) δ 8.33 (s, 1H), 8.30 (dd, J=7.8, 0.9 Hz, 1H), 7.72-7.67 (m , 1H), 7.53 (dd, J=7.9, 0.9 Hz, 1H), 5.42 (g, J=6.9 Hz, 1H), 1.87 (ddq, J=30, 1, 14.1, 7.2 Hz, 2H), 1.56 (d, J=6.9 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); m/z (ESI+) for (ScH^Br^), 282.8 (M+H)+.

Intermediate 16: 6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine £1 _N η ₂ ν ν^Ύ'\

Step 1: 6-aminopyridine-2-carbohydrazide (16a) ⁿ

Ek AS .k η ₂ ν ν^^ 'νη ₂ O 16a

To a solution of methyl 6-aminopyridine-2-carboxylate (100 g, 657 mmol) in MeOH (1.0 L) was added N2H4-H2O (69.7 g, 1.18 mol). The mixture was stirred at reflux for 5 hours. A significant amount of white precipitate formed. TLC analysis (1:10 MeOH/DCM) showed consumption of the starting material. The reaction mixture was filtered. The filter cake was washed with EtOAc (3x100 ml) and dried in vacuo to give 6-aminopyridine-2-carbohydrazide (95.4 g, 95% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.53-7.46 (m, 1H), 7.08 (dd, J=7.3, 0.9 Hz, 1H), 6.58 (dd, J=8.4, 0.9 Hz, 1H), 6.06 (s, 2H), 4.45 (d, J=4.7 Hz, 2H); m/z (ESI) for (C6H8N4O), 152.8 (M+H)+.

Step 2: N'-(6-{(2E)-2-[(dimethylamino)methylidene]hydrazinecarbonyl}pyridin-2-yl)-N,Ndimethylmethanimidamide (16b)

L n \ A AC / Ν^Ν Ν ^^ NN ¹ O ¹ 16b

A mixture of 6-aminopyridine-2-carbohydrazide (95.4 g, 627 mmol) in N,Ndimethyldimethoxymethylamine (500 ml) was stirred at reflux for 18 hours. TLC analysis (1:10 MeOH/DCM) showed consumption of the starting material substances. The reaction mixture was concentrated to dryness. The residue was suspended in a mixture of EtOAc (100 ml) and petroleum ether (200 ml) at 15°C for 5 minutes. The solids were collected by filtration and the filter cake was dried in vacuo to give N'-(6-{(2E)-2-[(dimethylamino)methylidene]hydrazinecarbonyl}pyridin-2-yl)-N,N-dimethylmethanimidamide (156 g, 95% yield) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 9.94 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.77 (dd, J=7.4, 0.9 Hz, 1H), 7.69-7.62 (m, 1H), 7.03 (dd, J=8.1, 0.9 Hz, 1H), 3.11 (s, 3H), 3.10 (s, 3H), 2.95 (s, 6H); m/z (ESI) for (C12H18N6O), 263.0 (M+H)+.

Step 3: 6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine |n ₂ mCDu% / Intermediate 16

To a solution of N'-(6-{(2E)-2-[(dimethylamino)methylidene]hydrazinecarbonyl}pyridin-2-yl)-N,Ndimethylmethanimidamide (100 g, 381 mmol) in PhMe (800 ml) was added propane-1 -amine (113 g, 1.91 mol) and acetic acid (160 g, 2.67 mol). The mixture was stirred at 90-100°C (internal) for 24 hours. X-ray MS analysis showed consumption of the starting material. The reaction mixture was cooled to room temperature. The mixture was brought to pH ~10-11 by adding 50% aqueous NaOH and then washed with H2O. The aqueous layer was extracted with 5:1 DCM/THF (3x). The combined organic layers were concentrated to dryness. The residue was concentrated with EtOAc (3x). The solids were suspended in 1:2 EtOAc/heptanes for 30 min. Solids were collected by filtration. The filter cake was dried under vacuum to provide Intermediate 16 (25.6 g, 76% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.53 - 7.47 (m, 1H), 7.22 (d, J=7.0 Hz, 1H), 6 .52 (d, J=8.0 Hz, 1H), 6.15 (s, 2H), 4.48 (t, J=7.2 Hz, 2H), 1.67 (g, J=7, 4 Hz, 2H), 0.81 (t, J=7.4 Hz, 3H); m/z (ESI) for (C10H13N5), 204.2 (M+H)+.

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Intermediate 17: 2-bromo-6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridine

This transformation was carried out in 5 parallel batches. Pyridine (20.0 ml) was cooled in an ice bath to 0°C. TFO (950 mg, 8.33 mmol), propan-1-amine (1.48 g, 25.0 mmol), and 2-bromo-6-(5-methyl1,3,4-oxadiazol-2-yl) pyridine (Intermediate 4) (2.00 g, 8.33 mmol) was added sequentially. The mixture was sealed and stirred at 100°C for 3.5 days with additional propan-1-amine (1.48 g, 25.0 mmol) added to the reaction mixture after 1.5 and 2.5 days, respectively. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. Parallel reactions were combined and concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , 0-100% EtOAc/petroleum ether). The desired fractions were re-purified by preparative HPLC with a YMC Triart C18 column (250x50 mm, 7 µm particle size), which was eluted with 30-70% MeCN/H ₂ O (+0.225% formic acid) at a flow rate of 25 ml/min. The desired fractions were made alkaline by adding saturated aqueous NaHCO ₃ to pH ~8. The solution was concentrated to remove MeCN and then extracted with DCM (3x50 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate 17 (6.11 g, 52% yield) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.31-8.24 (m, 1H), 7.70-7.63 (m, 1H), 7.51-7.47 (m, 1H), 4.40-4.32 (m, 2H), 2.53 (s, 3H), 1.86-1.74 (m, 2H), 1.00 (td, J=7.4, 2.9 Hz, 3H). m/z (ESI+) for (C ₁₁ H ₁₃ BrN ₄ ), 282.9 (M+H) ⁺ .

Intermediate 18: 2-bromo-6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridine vgXXl,

Step 1: 6-bromo-N'-propanoylpyridine-2-carbohydrazide

TEA (2.11 g, 20.8 mmol) and propanoyl chloride (1.35 g, 15.7 mmol). The mixture was stirred at 0°C for 20 minutes, and then at 20°C for 16 hours. TLC analysis (1:1 EtOAc/petroleum ether) showed the remaining starting material. The mixture was cooled to 0°C and additional TEA (2.11 g, 20.8 mmol) and propanoyl chloride (1.45 g, 15.7 mmol) were added. The mixture was stirred at 0°C for 20 minutes and then at 20°C for 16 hours. TLC analysis (1:1 EtOAc/petroleum ether) showed consumption of the starting material. The reaction was quenched by adding H2O (60 ml) and extracted with DCM (2x30 ml). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was suspended in EtOAc (10 ml) and petroleum ether (30 ml) for 10 min at 20°C. The solids were collected by filtration and dried under vacuum to give 6-bromo-Npropanoylpyridine-2-carbohydrazide (3.0 g, 79% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96 (b.d., J=5.4 Hz, 1H), 8.36 (b.d., J=5.4 Hz, 1H), 8 .10 (dd, J=7.5, 1.0 Hz, 1H), 7.47-7.70 (m, 1H), 7.65 (dd, J=7.9, 1.1 Hz, 1H ), 2.38 (sq., J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H).

Step 2: 2-bromo-6-(5-ethyl-1,3,4-oxadiazol-2-yl)pyridine

TEA (6.69 g, 66.2 mmol) and p-toluenesulfonyl chloride (2.31 g, 12.1 mmol). The mixture was stirred at ambient temperature for 60 hours. TLC analysis (EtOAc) showed consumption of the starting material. The mixture was concentrated to dryness. The residue was dissolved in H ₂ O (50 ml) and extracted with DCM (2x30 ml). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude material was suspended in EtOAc (3 ml) and petroleum ether (6 ml) at ambient temperature for 30 min. The solids were collected by filtration and dried under vacuum to give 2-bromo-6-(5-ethyl-1,3,4-oxadiazol-2-yl)pyridine (1.34 g, 48% yield) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (dd, J=7.6, 1.0 Hz, 1H), 7.80-7.68 (m, 1H), 7.64 (dd, J =8.0, 0.9 Hz, 1H),

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3.00 (sq., J=7.6 Hz, 2H), 1.46 (t, J=7.6 Hz, 3H). m/z (ESI+) for (ODVKzO), 256.0 (M+H)+. Step 3: 2-bromo-6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridine

Br

Intermediate 18

Pyridine (8.0 ml) was cooled in an ice bath to 0°C. TFO (301 mg, 2.64 mmol), 2-bromo-6-(5-ethyl1,3,4-oxadiazol-2-yl)pyridine (670 mg, 2.64 mmol) and ethylamine (476 mg, 10. 5 mmol) were added sequentially. The mixture was stirred at 95°C for 20 hours, and then at 100°C for 7 hours. The reaction mixture was concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , 1:10 MeOH/EtOAc) to give intermediate 18 (500 mg, 67% yield) as a yellow gum.

1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (dd, J=7.8, 0.9 Hz, 1H), 7.71-7.62 (m, 1H), 7.61-7.37 (m, 1H), 4.47 (sq., J=7.1 Hz, 2H), 2.84 (sq., J=7.6 Hz, 2H), 1.57-1.34 (m, 6H). m/z (ESI+) for (ScH^Br^), 280.7 (M+H)+.

Intermediate 19: tert-butyl methyl({6-[(2R)-2-methylpyridinyl-1-yl]-1-oxo-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl} methyl)carbamate

Step 1: tert-butyl ({3-formyl-6-[(2R)-2-methylpyrrolidinyl-1-yl]-4-(piperidin-1carbonyl)pyridin-2-yl}methyl)methylcarbamate

Solution

2-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1-carbonyl)pyridine-3 carbaldehyde (intermediate 10b) (600 mg, 1.79 mmol) and PdCl ₂ (dppf) (261 mg, 0.357 mmol) in 1,4-dioxane (25.0 ml) was bubbled with N2 for 5 min and then heated to 80°C. A solution of {[(tert-butoxycarbonyl)(methyl)amino]methyl}(chlorido)zinc (0.158 M in THF, 39.6 ml) was added at 80°C and the mixture was stirred for an additional 35 min at the same temperature. X-ray MS analysis showed consumption of the starting material to form the mass of the desired product. The mixture was cooled to 30°C and filtered through celite. The filter cake was washed with DCM (5x10 ml) and the filtrate was concentrated to dryness. The residue was combined with the crude material obtained from a parallel reaction in an identical manner with 100 mg of 2-chloro-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1carbonyl)pyridine-3-carbaldehyde. The mixture was purified using flash chromatography (SiO ₂ , 1:1 EtOAc/petroleum ether) to give tert-butyl ({3-formyl-6-[(2R)-2-methylpyrolidinyl-1-yl]-4(piperidin- 1-carbonyl)pyridin-2-yl}methyl)methylcarbamate (900 mg, 97% yield) as a yellow resin.

1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 6.40-6.06 (m, 1H), 4.91-4.45 (m, 2H), 4.52- 3.92 (m, 1H), 3.69-3.47 (m, 3H), 3.21-3.00 (m, 2H), 2.98-2.84 (m, 3H), 2. 22-1.82 (m, 3H), 1.83-1.66 (m, 1H), 1.59 (s, 4H), 1.41 (s, 7H), 1.19 (d, J= 18.2 Hz, 8H). m/z (ESI+) for (C ₂₄ H ₃₆ N ₄ O ₄ ), 445.4 (M+H)+.

Step 2: tert-butyl methyl{[3-{(E)-[(2-methylpropane-2-sulfinyl)imino]methyl}-6-[(2R)-2methylpyrrolidinyl-1 -yl]-4-(piperidin- 1 -carbonyl)pyridin-2-yl]methyl}carbamate

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Mixture of tert-butyl ({3-formyl-6-[(2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1carbonyl)pyridin-2-yl}methyl)methylcarbamate (1.40 g, 3 .15 mmol), titanium(IV) ethoxide (1.44 g, 6.30 mmol), and (S)-(-)-2-methyl-2-pronansulfinamideα (573 mg, 4.72 mmol) in THF ( 50.0 ml) was stirred at 50°C for 18 hours. Additional quantities of titanium(IV) ethoxide (359 mg, 1.57 mmol) and (S)-(-)-2-methyl-2-propanesulfinamide (115 mg, 0.945 mmol), and the mixture was stirred at 50°C for an additional 20 hours. RC-MS analysis showed consumption of the starting material to form the desired product mass. The reaction was quenched with saturated aqueous Na ₂ CO ₃ (150 ml) and diluted with DCM (100 ml). The mixture was filtered through celite and the layers were separated. The aqueous layer was extracted with DCM (100 ml). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to give tert-butyl methyl{[3-{(E)-[(2-methylpropane-2sulfinyl)imino]methyl}-6-[ (2R)-2-methylpyrolidinyl-1-yl]-4-(piperidin-1-carbonyl)pyridin-2yl]methyl}carbamate (1.7 g, >99% yield) as a yellow solid, m/z ( ESI+) for (C28H45N5O4S), 548.5 (M+H)+.

Step 3: tert-butyl methyl({6-[(2R)-2-methylpyrrolidinyl-1-yl]-1-oxo-2,3-dihydro-1Hpyrrolo[3,4-e]pyridin-4-yl}methyl )carbamate

To a solution of tert-butyl methyl{[3-{(E)-[(2-methylpropane-2-sulfinyl)imino]methyl}-6-[(2R)-2methylpyrrolidinyl-1-yl]-4-(piperidin-1 -carbonyl)pyridin-2-yl]methyl}carbamate (1.72 g, 3.41 mmol) in THF (20.0 ml) at 0°C was added LiBH ₄ (68.6 mg, 3.15 mmol). The reaction mixture was stirred at 0°C for 1 hour. TLC analysis showed consumption of the starting material. The mixture was warmed to ambient temperature and a solution of NaOMe (30% in MeOH, 6.24 g, 34.6 mmol) was added. The mixture was stirred for 16 hours. X-ray MS analysis showed the formation of the desired mass of product. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (40 ml) and washed with H ₂ O (40 ml). The aqueous layer was extracted with EtOAc (30 ml). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (SiO2, EtOAc) to give intermediate 19 (750 mg, 66% yield) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ 7.04-6.79 (m, 1H), 6.68 (s, 1H), 4.56-4.43 (m, 2H), 4.43-4 .33 (m, 2H), 4.274.16 (m, 1H), 3.58 (ddd, J=2.5, 7.3, 10.0 Hz, 1H), 3.45-3.30 (m , 1H), 3.01-2.91 (m, 3H), 2.17-1.96 (m, 3H), 1.801.72 (m, 1H), 1.53-1.37 (m, 9H ), 1.26-1.23 (m, 3H); m/z (ESI+) for (C19H28N4O3), 361.2 (M+H)+.

Intermediate 20: (4R)-3-(6-bromopyridin-2-yl)-4-(fluoromethyl)-1,3-oxazolidin-2-one

Step 1: Methyl (4R)-2-oxo-3-(triphenylmethyl)-1,3-oxazolidine-4-carboxylate

A solution of methyl N-(triphenylmethyl)-D-serinate (90.0 g, 249 mmol) and TEA (69.8 g, 690 mmol) in PhMe (1.8 L) was added dropwise to a solution of triphosgene (69.8 g , 41.5 mmol) in PhMe (300 ml) under N2, maintaining the temperature at -5 to 10°C (internal). The mixture was stirred at ambient temperature for 30 minutes. TLC analysis (1:2 EtOAc/petroleum ether) showed consumption of the starting material. The reaction was quenched by adding dropwise 1 N. HCl (600 ml) and the mixture was stirred for 10 minutes. The layers were separated. The aqueous layer was made alkaline to pH ~8-9 by adding 2N. NaOH and then extracted with DCM/PhMe (1:5, 1.5 L). The combined organic layers were washed with saturated aqueous NaHCO ₃ (500 ml) and brine (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The solids were suspended in EtOAc/petroleum ether (1:3, 400 ml) at room temperature for 30 minutes. The solids were collected by filtration and dried in vacuo to give methyl (4R)-2-oxo-3-(triphenylmethyl)-1,3-oxazolidine-4-carboxylate (71 g, 74% yield) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.27 (m, 15H), 4.61-4.50 (m, 1H), 4.50-4.38 (m, 1H), 4 .21 (dd, J=3.3,

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8.9 Hz, 1H), 3.49 (s, 3H).

Step 2: (4S)-4-(hydroxymethyl)-3-(triphenylmethyl)-1,3-oxazolidin-2-one

PhJ ^h o I ^Ph nA _q

G he

A solution of methyl (4R)-2-oxo-3-(triphenylmethyl)-1,3-oxazolidine-4-carboxylate (158 g, 409 mmol) in THF (2.4 L) was cooled to -65 °C (internal), and LiAlH ₄ (18.6 g, 490 mmol) was added in portions while maintaining the temperature below -60°C (internal). The mixture was stirred at -10°C (internal) for 1.5 hours. TLC analysis (1:2 EtOAc/petroleum ether) showed consumption of the starting material. The mixture was quenched by careful addition of Na ₂ SO ₄ -10H ₂ O until gas evolution was no longer observed. The suspension was filtered through a layer of celite. The filter cake was suspended in EtOAc (500 ml), stirred for 10 minutes, and then filtered. This process was repeated 3 times. The combined filtrate was concentrated to dryness. The residue was purified using flash chromatography (660 g SiO2, 0-80% EtOAc/petroleum ether) to give (4S)-4-(hydroxymethyl)-3-(triphenylmethyl)-1,3oxazolidin-2-one (29.9 g, 20% yield) as a white solid.

1H NMR (400 MHz, CDC13) δ 7.31-7.10 (m, 15H), 4.36-4.12 (m, 2H), 3.73-3.58 (m, 1H), 3, 22-2.94 (m,2H).

Step 3: (4R)-4-(fluoromethyl)-3-(triphenylmethyl)-1,3-oxazolidin-2-one

PhJ ^h o Ιρ^νΑ ( o Г' F

A solution of (4S)-4-(hydroxymethyl)-3-(triphenylmethyl)-1,3-oxazolidin-2-one (29.9 g, 83.3 mmol) and TEA (75.9 g, 750 mmol) in MeCN (400 ml) was cooled with an ice water bath to 0°C (internal), and nonafluorobutanesulfonyl fluoride (75.5 g, 250 mmol) was added slowly, maintaining the reaction temperature at 5-10°C (internal). The solution was stirred at 0°C (internal) for 5 min. TLC analysis (1:2 EtOAc/petroleum ether) showed consumption of the starting material. Triethylamine trihydrofluoride (40.3 g, 250 mmol) was added dropwise and the solution was stirred at 5-10°C (internal) for 2 hours. The mixture was partitioned between EtOAc (200 ml) and H2O (200 ml). The aqueous phase was extracted with EtOAc (200 ml). The combined organic layers were washed with saturated aqueous NaHCO ₃ (200 ml) and brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was suspended with petroleum ether (200 ml) and EtOAc (100 ml) for 2 hours at ambient temperature, and the solids were collected by filtration. The filtrate was concentrated to dryness and purified by flash chromatography (80 g SiO ₂ , 30-50% EtOAc/petroleum ether). The desired fractions were concentrated to dryness and combined with the pre-isolated filter cake to give (4R)-4-(fluoromethyl)-3-(triphenylmethyl)-1,3-oxazolidin-2-one (26.7 g, 89% yield) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.22 (m, 15H), 4.54-4.46 (m, 1H), 4.41-4.35 (m, 1H), 4 .08-3.82 (m, 3H); ^19F NMR (377 MHz, CDCI3) δ -231.64 (s, 1F).

Step 4: (4R)-4-(fluoromethyl)-1,3-oxazolidin-2-one

F

A suspension of (4R)-4-(fluoromethyl)-3-(triphenylmethyl)-1,3-oxazolidin-2-one (26.7 g, 74.0 mmol) in DCM (90.0 ml) was cooled to 0° C (internal) and treated dropwise with TFO (90.0 ml). The reaction mixture was stirred at room temperature for 1.5 hours. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness. The residue was dissolved in DCM (200 ml) and the solution was cooled to 0°C (internal) in an ice water bath. The mixture was basified with concentrated aqueous NH4OH to pH ~9, maintaining the internal temperature at 5-15°C (internal). The mixture was dried over Na2SO4, filtered and concentrated through a pad of celite. The filter cake was washed with DCM. The combined filtrate was concentrated to dryness. The residue was purified using flash chromatography (80 g SiO ₂ , EtOAc) to give (4R)-4-(fluoromethyl)-3-(triphenylmethyl)-1,3-oxazolidin2-one (3.86 g, 44% yield) as light yellow oil.

1H NMR (400 MHz, CDCl·,) δ 6.41 (b.s., 1H), 4.57-4.44 (m, 2H), 4.42-4.31 (m, 1H), 4 .29-4.23 (m, 1H), 4.22-4.10 (m, 1H); ^19F NMR (377 MHz, CDCI3) δ -229.49 (s, 1F).

Step 5: (4R)-3-(6-bromopyridin-2-yl)-4-(fluoromethyl)-1,3-oxazolidin-2-one

- 52 044841

F Intermediate connection 20

Mixture of (4R)-4-(fluoromethyl)-3-(triphenylmethyl)-1,3-oxazolidin-2-one (4.70 g, 39.5 mmol), 2,6dibromopyridine (14.5 g, 61. 2 mmol), and Cs ₂ CO ₃ (32.1 g, 98.7 mmol) in 1,4-dioxane (250.0 ml) was bubbled with N ₂ for 2 min. Pd(OAc) ₂ (886 mg, 3.95 mmol) and Xantphos (2.74 g, 4.74 mmol) were added and the mixture was bubbled with N ₂ . The mixture was stirred at 80°C for 3 hours, cooled to room temperature and filtered. The filter cake was washed with EtOAc (5x30 ml). The combined filtrate was concentrated to dryness. The residue was purified using flash chromatography (330 g SiO ₂ , 0-30% EtOAc/petroleum ether) to give intermediate 20 (3.72 g, 34% yield) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (dd, J=8.3, 0.7 Hz, 1H), 7.75-7.49 (m, 1H), 7.26 (dd, J =7.6, 0.7 Hz, 1H), 5.12-4.98 (m, 1H), 4.96 -4.61 (m, 2H), 4.60-4.48 (m, 2H ); ¹⁹ F NMR (377 MHz, CDCl3) δ -237.04; m/z (ESI+) for (C9H8BrFN2O2), 276.7 (M+H)+; [o]d ³⁰ =+97.3° (c=1.0, MeOH).

Examples.

General methods.

Unless otherwise noted, variables in the diagrams have the same meanings as defined herein. The amines mentioned herein may be protected amines that are deprotected under standard conditions known in the art.

Method A.

Method A refers to a single synthetic sequence for the preparation of compounds of formula I, as shown above. Regarding method A, the first step is bromination of a compound of formula A-1 (eg ethyl 2-chloro-3-methyl-isonicotinate) (J. Med. Chem., 47 (25), 6363-6372; 2004) using N-bromosuccinimide gives the compound of formula A-2. At this stage, the substituent R ³ must be represented by the same group as in the final product of formula I or a protected variant thereof. In the next step, the compound of formula A-2 undergoes ammonolysis with ammonia to form the compound 4-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, compound of formula A-3. The compound of formula A-3 then undergoes chloride carbonylation using carbon monoxide and methanol under palladium catalysis, followed by protection to give the ester of formula A4. In the next step, formation of the N-oxide of the compound of formula A-4 to form (hydrogen peroxide-urea) followed by chlorination of the compound of formula A-5 using phosphorus oxychloride produces the chloride of formula A-6. Deprotection of the carbamate of formula A-6 is then followed by reaction of the chloride with R ¹ (eg, amine) followed by reaction of the chloride with A-7 (eg, aminopyridine). During this step, the R ¹ substituent must be the same group as in the final Formula I product, or a protected variant thereof. In the next step, reduction of the ester functionality in formula A-7 gives the alcohol of formula A-8. Activation of the alcohol functional group of formula A-8, in the form of mesylate (A-9, Y=OSO ₂ CH ₃ ), followed by activation or:

i) azidation (A-9, Y=N3) and restoration of azide functionality under standard conditions to obtain primary amines (formula A-9, Y=NH ₂ ); or ii) direct replacement of the mesylate (Formula A-9, Y=OSO ₂ CH ₃ ) with primary amines to obtain the corresponding secondary amines (Formula A-9, Y=N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl) to obtain a compound of formula A-9.

Behind the protection of the amino functional group is the corresponding tert-butylcarbamate of the formula

- 53 044841

A-9 (Y=N(R ⁸ )Boc, R ⁸ =H or alkyl) follows coupling with bromopyridine of formula A-10 under palladium or copper catalysis to produce protected pyrrolo[3,4-c]pyridin-1-ones ( R ² =CH2N(R ⁸ )Boc, R ⁸ =H or alkyl). During this step, the R ⁴ and (R ⁵ )a substituents of Formula A-10 must be the same group as required in the final product of Formula I, or a protected variant thereof. Deprotection of the carbamate protecting group under standard conditions then gives pyrrolo[3,4c]pyridin-1-one of formula I (R ² =CH ₂ N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl).

Method B.

Method B refers to a single synthetic sequence for the preparation of compounds of formula II, as shown above. Regarding Method B, in the first benzyl bromination step of a compound of formula B-1 (e.g. ethyl 2-chloro-3-methylisonicotinate) (J. of Med. Chem., 47(25), 6363-6372; 2004) using N -bromosuccinimide gives the compound of formula B-2. In the next step, the compound of formula B-2 undergoes ammonolysis with ammonia to form the compound 4-chloro-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-1-oneα, compound of formula B-3. The compound of formula B-3 undergoes chloride carbonylation using carbon monoxide and methanol under palladium catalysis, followed by protection to give the ester of formula B-4. In the next step, formation of the N-oxide of the compound of formula B-4 under standard conditions (hydrogen peroxide-urea) followed by chlorination of the compound of formula B-5 using phosphorus oxychloride produces the chloride of formula B-6. Deprotection of the carbamate protecting group of the compound of Formula B-6 is then followed by reaction of the chloride with R ¹ (eg, an amine) to produce the compound of Formula B-7. At this stage, the substituent R ¹ must be represented by the same group as in the final product of formula II, or a protected variant thereof. In the next step, reduction of the ester functionality of Formula B-7 produces the alcohol compound of Formula B-8. Activation of the alcohol functionality of formula B-8, as the mesylate (B-9, Y=OSO ₂ CH ₃ ), followed by either:

i) azidation (B-9, Y=N ₃ ) and restoration of azide functionality under standard conditions to obtain primary amines (formula B-9, Y=NH2); or ii) direct replacement of the mesylate (formula B-9, Y=OSO ₂ CH ₃ ) with primary amines to obtain the corresponding secondary amines (formula B-9, Y=N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl) to obtain the compound of formula B-9.

Protection of the amino functional group as the corresponding tert-butyl carbamate of formula B-9 (Y=N(R ⁸ )Boc, R ⁸ =H or alkyl) is followed by coupling with bromopyridine of formula B-10 under palladium or copper catalysis to produce protected pyrrolo[3,4-c]pyridin-1-ones (R ² =CH ₂ N(R ⁸ )Boc, R ⁸ =H and/or alkyl). At this stage, the R ⁵ and R ¹² substituents of Formula B-10 must be the same group that is desired in the final product, Formula II, or must be represented by the same group that is desired in the final product.

Deprotection of the carbamate protecting group under standard conditions then gives pyrrolo[3,4c]pyridin-1-ones of formula II (R ² =CH ₂ N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl).

The preparation of the compound of formula B-10 can be accomplished by hydrazinolysis of the bromopyridine ester of formula B-11 (J. of Med. Chem., 60(2), 722-748; 2017) to form the compound of formula B-12. During this step, the R ⁵ substituent of Formula B-11 must be represented by the same moiety that is desired in the final product of Formula II or a protected variant thereof. The hydrazide of formula B-12 is then reacted with dimethylformamide dimethyl acetal to produce the compound of formula B-13. Condensation of the compound of formula B-13 with an amine (eg, R ¹² -NH ₂ ) gives the triazole of formula B-10. At this stage, the R ¹² amine substituent must be represented by the same group as in the final product of Formula II or a protected variant thereof.

Method C.

^S-3 Formula II

Method C refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. Referring to Method C, in the first step, reducing the ester functionality of the compound of formula B-6 gives the alcohol compound of formula C-1. Activation of the alcohol functionality of formula C-1 as the mesylate (C-2, Y=OSO ₂ CH ₃ ) was then followed by either:

i) azidation (C-2, Y=N ₃ ) and restoration of azide functionality under standard conditions to obtain primary amines (formula C-2, Y=NH ₂ ); or ii) direct replacement of the mesylate (formula C-2, Y=OSO ₂ CH ₃ ) with primary amines to obtain the corresponding secondary amines (formula C-2, Y=N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl) to obtain a compound of formula C-2.

Protection of the amino functional group, since the corresponding tert-butylcarbamate gives C-2 (Y=N(R ⁸ )Boc, R ⁸ =H or alkyl, followed by coupling with bromopyridine of formula B-10 under palladium or copper catalysis to provide protected pyrrolo[3,4-c]pyridin-1-ones of formula C-3 (R ² =CH2N(R ⁸ )Boc, R ⁸ =H or alkyl) At this stage, the substituents R ⁵ and R ¹² of formula B-10 should be represented by the same group that is desired in the final product, Formula II or a protected variant thereof.Then palladium or copper mediated cross-coupling of formula C3 with amines, protected amines or alkyl trifluoroborates/boronic acids/boronates/zincates or alkenylboronic esters followed by reduction or cyclopropanation and subsequent deprotection of the carbamate protecting group gives pyrrolo[3,4c]pyridin-1-ones of formula II (R ² =CH2N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl, substituent R ¹ must be presented in the same fragment as desired in the final product, Formula II, or a protected variant thereof).

Method D

Method D refers to the synthetic sequence for the preparation of compounds of formula III, as shown above. As for Method D, in the first step, the palladium-catalyzed combination of 2,6-dibromopyridine of formula D-1 with oxazolidinone of formula D-2 gives bromopyridine of formula D-3. At this stage, the R ⁵ substituent of formula D-1 and the R ¹² substituent of formula D-2 must be represented by the same moiety that is required in the final product of formula III or a protected variant thereof. Then coupling a compound of formula D-3 with a compound of formula B-9 (Y=N( ^R8 )Boc, ^R8 =H or alkyl) under palladium or copper catalysis gives protected pyrrolo[3,4-c]pyridin-1-ones (R ² =CH ₂ N(R ⁸ ) Boc, R ⁸ =H or alkyl, the substituent R ¹ must be the same moiety as desired in the final product, Formula III, or a protected variant thereof). In the next step, deprotection of the carbamate protecting group under standard conditions gives pyrrolo[3,4-c]pyridin-1-ones of Formula III (R ² =CH2N(R ⁸ )(R ⁹ )Boc, R ⁸ and R ⁹ =H and/or alkyl).

- 55 044841

Method E.

Method E refers to the synthetic sequence for the preparation of compounds of formula E-4 as shown above. As for Method E, in the first step, protection of a compound of formula E-1 (eg, 4bromo-5-isopropyl-III-pyrazole) with a tetrahydropyranyl (THP) group produces a pyrazole of formula E-2. During this step, the R ¹² substituent of formula E-1 must be the same group as is required in the final product of formula E-4 or a protected variant thereof. Formula E-2 is then combined with a 2,6-dibromopyridine of Formula D-1 (eg, R ⁵ =H or F) to produce bromopyridine of Formula E3. At this stage, the R ⁵ substituent of formula D-1 must be represented by the same group as in the final product of formula E-4 or a protected variant thereof. In the next step, the combination of formula E-3 with a compound of formula B-9 (Y=N(R ⁸ )Boc, R ⁸ =H or alkyl) under palladium or copper catalysis gives protected pyrrolo[3,4-c]pyridine-1- it has the formula E-4 (R ² =CH2N(R ⁸ )Boc, R ⁸ =H or alkyl). At this stage, the R ¹ substituent of formula B-9 and the R ⁵ substituent of formula E-3 must be represented by the same moiety that is required in the final product of formula E-4 or a protected variant thereof. Deprotection of the protected pyrrolo[3,4-c]pyridin-1-one under standard conditions then gives pyrrolo[3,4-c]pyridin-1-ones of formula E-4 (R ² =CH2N(R ⁸ )(R ⁹ ), R ⁸ and R9=H and/or alkyl).

Method F

Method F refers to the synthetic sequence for the preparation of compounds of formula F-3 as shown above. Referring to Method F, the first step involves binding a compound of formula B-3 under photooxidative catalysis conditions (Zuo, et al., Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp ³ -carbons with aryl halides, Science 2014,345, 437 -440) using sarcosine (F-1) as a source of aminoalkyl radical gives pyrrolo[3,4-c]pyridin-1-one of formula F-2. The combination of the compound of formula F-2 with the bromopyridine compound of formula B-10, under palladium or copper catalysis, then gives the protected pyrrolo[3,4-c]pyridin-1-one of formula F-3 (R ⁸ =Boc). At this stage, the R ⁵ and R ¹² substituents of Formula B-10 must be the same group as required in the final product, Formula F-3, or a protected variant thereof. In the next step, deprotection of the carbamate protecting group under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula F-3 with R ⁸ =H.

Method G.

Formula II

Method G refers to a different synthetic sequence for the preparation of compounds of formula II,

- 56 044841 as shown above. Referring to Method G, in the first step, a nucleophilic radical substitution reaction of a compound of Formula G-1 (e.g., methyl 3-methyl-isonicotinate) with a carboxylic acid (e.g., R1CO2H) under oxidative decarboxylation conditions with silver nitrate and an oxidizing agent (ammonium persulfate) provides an ester of formula G-2. During this step, the carboxylic acid substituent R ¹ must be the same group as is required in the final product of Formula II or a protected variant thereof. Bromination using Nbromosuccinimide then gives the bromide of formula G-3. In the next step, ammonolysis of the bromide of formula G-3 with ammonia gives 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one of formula G-4. Further, decarboxylate radical substitution with an N-Boc-protected amino acid under oxidative conditions gives the benzyl amine of formula B-9 (Y=N(R ⁸ )Boc, R ⁸ =H or alkyl). In the next step, combination with bromopyridine of formula B-10 under palladium or copper catalysis gives protected pyrrolo[3,4-c]pyridin-1-ones of formula II (R ² =CH2N(R ⁸ )Boc, R ⁸ =H or alkyl) . Deprotection of the carbamate protecting group under standard conditions then gives pyrrolo[3,4-c]pyridin-1-ones Formula II (R ² =CH2N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl).

Method H.

? /-Vr*

R ² Rl2''^

Formula III

Method H refers to the synthetic sequence for the preparation of compounds of formula III as shown above. As for Method H, in the first step, the oxazolidinone of formula H-2 is prepared by cyclization of methyltrityl-D-serinate of formula H-1 using triphosgene. Reduction of the ester of formula H-2 then produces the alcohol of formula H-3. In the next step either:

(i) deoxyfluorination of a compound of formula H-3 gives a compound of formula H-4 (W=fluoroalkyl, eg CH2F); or (ii) oxidation of the alcohol of formula H-3 to the aldehyde of formula H-4 (W=CHO) followed by difluoromethylation to give the compound of formula H-4 (W=CHF ₂ ).

Next, deprotection of the N-trityl group of formula H-4 followed by coupling of the corresponding oxazolidinone of formula H-5 with a 2,6-dibromopyridine of formula D-1 gives the bromopyridine of formula D-3. During this step, the R ⁵ substituent of formula D-1, in which the R ¹² substituent of formula H-5, must be present at the same moiety as desired in the final product of Formula III or a protected variant thereof. Then coupling the compound of Formula D-3 to the compound of Formula B-9 (substituent R1 must be the same moiety as desired in the final product of Formula III or a protected variant thereof, Y=N(R ⁸ )Boc, R ⁸ =H or alkyl) when catalyzed by palladium or copper provides the protected pyrrolo[3,4-c]pyridin-1-one of formula III (R ² =CH2N(R ⁸ )Boc, R8=H or alkyl, R ¹² =CH2F or CHF2). At the last stage, removal of the carbamate protecting group under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula III (R ² =CH2N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/ or alkyl).

Method I.

Method I refers to the synthetic sequence for the preparation of compounds of formula I-5, as

- 57 044841 shown above. Regarding Method I, in the first step, hydrazinolysis of 2-bromo-6-fluoropyridine of formula I-1 gives the compound of formula I-2. In the next step, diazotization of the hydrazine of formula I-2 gives the azide of formula I-3. Cycloaddition of an azide of formula I-3 to an alkyne then produces a 1,2,3-triazole of formula I4. During this step, the R ¹² alkyne substituent must be the same group as in the final product of Formula I-5 or a protected variant thereof. In the next step, the coupling of the compound of formula I-4 with B-9 (Y=N(R ⁸ )Boc, R ⁸ =H or alkyl, the substituent R1 must be the same moiety as desired in the final product, formula I-5 , or a protected variant thereof) under palladium catalysis provides the protected pyrrolo[3,4-e]pyridin-1-one of formula I-5. Deprotection of the carbamate protecting group under standard conditions then gives pyrrolo[3,4-e]pyridin-1-one of formula I-5 (R ² =CH ₂ N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ = H and/or alkyl).

Method J

Method J refers to a different synthetic sequence for the preparation of compounds of formula III, as shown above. Referring to Method J, in the first step, radical hydroxymethylation of the compound of formula G-4 using methanol and ammonium persulfate gives the compound of formula B-9 (Y=OH). During this step, the R ¹ substituent of formula G-4 must be represented by the same group that is required in the final product of formula III or a protected variant thereof.

Then activation of the alcohol functional group in the form of mesylate (B-9, Y=OSO ₂ CH ₃ ) is accompanied by azidation (B-9, Y=N ₃ ) and reduction of the azide functional group under standard conditions to obtain primary amines (B-9, Y =NH ₂ ). In the next step, protection of the amino functionality as the corresponding tert-butyl carbamate gives B-9 (Y=N(R ⁸ )Boc, R ⁸ =H). Next, the combination of a compound of formula D-3 with B-9 under palladium or copper catalysis gives the protected pyrrolo[3,4-e]pyridin-1-one of formula III (R ² =CH2N(R ⁸ )Boc, R ⁸ =H. Substituent R ¹² must be represented by the same fragment as in the final product of Formula III or a protected version thereof). In the last step, deprotection of the carbamate protecting group under standard conditions gives pyrrolo[3,4e]pyridin-1-one of formula III (R ² =CH2N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H).

Method K.

Method K refers to a different synthetic sequence for the preparation of compounds of formula III, as shown above. As for Method K, the first step is the condensation of 2-cyanoacetamide of formula K-1 with an oxalate ester of formula K-2 to produce hydroxypyridine of formula K-3 (Z=OH). During this step, the R ¹ substituent of Formula K-2 must be represented by the same group that is desired in the final product of Formula III or a protected variant thereof. In the next step, chlorination under standard conditions (POC13) gives chloropyridine of formula K-3 (Z=Cl). Then binding of chloropyridine of formula K-3 (Z=Cl) under conditions of photooxidative catalysis (Zuo, et al., Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp ³ -carbons with aryl halides, Science 2014,345, 437-440 ) using sarcosine as a source of aminoalkyl radical, gives benzylamine of formula K-4 Y=N(CH3)Boc)]. In the next step, reduction of the cyano group and concomitant cyclization gives 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one of formula B-9 (Y=N(CH3)Boc). Further, the communication of the compound of formula D-3 with B-9 (Y=N(CH3)Boc) when catalyzed by palladium or copper is provided by the protected pyrrolo[3,4-c]pyridin-1-one of formula III (R ² =CH2N(CH ₃ )Boc, the substituents R ⁵ and R ¹² must be present in the same moiety as desired in the final product, Formula III, or a protected variant thereof). At the final stage, removal of the carbamate protecting group under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula III (R ² =CH ₂ N(CH ₃ )H.

- 58 044841

Method L.

Method L refers to the synthetic sequence for the preparation of compounds of formula L-5 as shown above. Referring to Method L, the first step of protecting the lactam of formula F-2 with a carbamate protecting group using di-tert-butyl dicarbonate and 4-dimethylaminopyridine gives the compound of formula L-1. Trifluoromethylation of the compound of formula L-1 using zinc trifluoromethanesulfinate and tert-butyl hydroperoxide then gives a mixture of 6-(trifluoromethyl)-1,3-dihydro-2Hpyrrolo[3,4-c]pyridinα of formula L-2 and 7-(trifluoromethyl)- 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine of formula L-3. After separation by column chromatography, complete deprotection of the carbamate protecting groups of formula L-2 under acidic conditions (TFA) followed by selective protection of the benzylamine functionality with a carbamate protecting group using di-tert-butyl dicarbonate and trimethylamine gives the trifluoromethyl lactam of formula L-4. In the next step, palladium-catalyzed coupling of a compound of formula L-4 with a compound of formula B-10 gives the protected pyrrolo[3,4-c]pyridin-1-one of formula L-5 (R ⁸ =Boc). During this step, the R ⁵ and R ¹² substituents of Formula B-10 must be present at the same moiety as required in the final product, Formula L-5, or a protected variant thereof. In the final step, deprotection of the carbamate protecting group under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula L-5 (R ⁸ =H).

Method M.

Method M refers to a different synthetic sequence for the preparation of compounds of formula III, as shown above. Referring to Method M, in the first step, coupling of a compound of formula D-3 with a compound of formula C-2 (Y=N(R ⁸ )Boc, R ⁸ =H or alkyl) under palladium or copper catalysis provides protected pyrrolo[3,4- c]pyridin-1-one of formula M-1 (R ² =CH2N(R ⁸ )Boc, R ⁸ =H or alkyl). At this stage, the R ⁵ and R ¹² substituents of Formula D-3 must be represented by the same moiety as required in the final product, Formula III or a protected variant thereof. Palladium or copper mediated cross-coupling of formula M-1 or with amines, substituted amines or alkyl trifluoroborates/boronic acids/boronates/zincates or boronic acid esters, followed by reduction or cyclopropanation, and further carbamate deprotection then gives pyrrolo[3,4- c]pyridin-1-one of formula III, wherein R ¹ substituent must be the same moiety as desired in the final product, formula III, or a protected variant thereof (R ² =CH2N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl).

Method N.

Method N refers to a different synthetic sequence for the preparation of compounds of formula III, as shown above. As for Method N, in the first step, palladium or copper mediated cross-coupling between a compound of formula C-2 (Y=N(R ⁸ )Boc, R=H or alkyl) and or amines protected by amines or alkyl trifluoroborates/boronic acids/boronates/ zincates or alkenylboronic ethers followed by reduction or cyclopropanation give the compound of formula B-9. During this step, the R ¹ substituent of Formula B-9 must be represented by the same group that is desired in the final product of Formula III or a protected variant thereof. In the next step, the combination of formula D-3 with a compound of formula B-9 under palladium or copper catalysis

- 59 044841 followed by deprotection of the carbamate protecting group gives pyrrolo[3,4-c]pyridin-1-one of formula III (R ² =CH ₂ N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl). During this step, the substituents R ⁵ and R ¹² of the formula

D-3 must be the same moiety as required in the final product of Formula III or a protected variant thereof.

Method O.

0-6 in-9 in-th

Formula II

Method O refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. Referring to Method O, the first step is cross-coupling or nucleophilic aromatic substitution between the desired coupling partner or amine (or a protected version thereof) and a dichloropyridine of formula O-1 (V=N(CH ₃ ) ₂ or OH or piperidine or OMe ) gives O-2 (R1=NR ⁶ R ⁷ or alkyl). Formylation of O-2 then produces the aldehyde O-3. Subsequent condensation with Ellman's sulfinamide gives the compound of formula O-4. Subsequent reduction gave the compound of formula O-5. Carbonylation of the chloride of formula O-5 using carbon monoxide and methanol under palladium catalysis gives the ester of formula O-6. Reduction of the ester of formula O-6 gives benzyl alcohol B-9 (Y=OH). Activation of the alcohol functionality produces mesylate (B-9, Y=OSO ₂ CH ₃ ). At the next stage either:

i) azidation (B-9, Y=N ₃ ) and defunctionalization of the azide according to the standard condition for the production of primary amines (formula B-9, Y=NH ₂ ); or ii) direct replacement of the mesylate (formula B-9, Y=OSO ₂ CH ₃ ) with primary amines to give the corresponding secondary amines (formula B-9, Y=N(R ⁸ )(R ⁹ ), R ⁸ and R ⁹ =H and/or alkyl) to obtain a compound of formula B-9.

Protecting the amino functionality as the corresponding tert-butyl carbamate, B-9 (Y=N(R ⁸ )Boc), followed by coupling with bromopyridine triazole B-10 under palladium or copper catalysis yields protected pyrrolo[3,4-c]pyridine-1 -they are of formula II (R ² =CH2N(R ⁸ )Boc, R ⁸ =H or alkyl, R1=N(R ⁶ )(R ⁷ ) or alkyl). At this stage, the R ¹² substituent of Formula B-10 must be the same group that is desired in the final product of Formula II or a protected variant thereof. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-ones of formula II (R ² =CH2N(R ⁸ )(R ⁹ ), R1 = N(R ⁶ )( R ⁷ ) or alkyl).

Method P

ABOUT

R ¹²

Method P refers to another synthetic sequence for the preparation of compounds of formula II, as shown above. In the first stage, from a compound of formula O-3 (V=N(CH ₃ ) ₂ , or OH, or piperidine, or OMe, or OEt, or OiPr) either:

i. Iridium-mediated decarboxylated photoredox coupling with the desired carboxylic acid to give the compound of formula P-1 (Y=N(R ⁸ )Boc); or ii. Negishi coupling with the desired aminoalkyl zincate to obtain the compound of formula P-1 (Y=N(R ⁸ )Boc); or cross-coupling Suzuki with the desired trifluoroborate salt, boronic acid or boronic acid ester to produce a compound of formula P-1 (Y=N(R ⁸ )Boc).

Subsequent condensation with Ellman's sulfinamide and reduction gives the compound of formula B-9. Coupling with bromopyridine triazole B-10 catalyzed by palladium or copper gives the protected pyrrolo[3,4-c]pyridin-1-one of formula II (R ² =CH2N(R ⁸ )Boc). At this stage, the R ¹² substituent of formula B10 must be represented by the same group that is desired in the final product of formula II or a protected variant thereof. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula II (R ² =CH2N(R ⁸ )(R ⁹ )).

- 60 044841

Method Q.

Q-1 Formula II

Method Q refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. In the first step, reductive amination or alkylation of the amine of formula Q-1 gives pyrrolo[3,4-c]pyridin-1-one of formula II (R ² =CH ₂ N(R ⁸ )(R ⁹ )). At this stage, the substituents R ⁵ , R ¹² and R ¹ of formula Q-1 should be represented by the same group as in the final product, formula II.

Method R.

Method R refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. In the first step, reductive amination of the compound of formula O-3 with an equivalent of ammonia or, alternatively, Ellman's sulfinamide gives the compound of formula O-5. At this stage, the R ¹ substituent of formula O-3 must be represented by the same group as in the final product of formula II or a protected variant thereof. Combination with bromopyridine triazole B-10 under palladium or copper catalysis gives the compound of formula R-1. At this stage, the R ¹² substituent of Formula B-10 must be the same group that is desired in the final product of Formula II or a protected variant thereof. Suzuki cross-coupling with the appropriate trifluoroborate followed by deprotection of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1one of formula II (R ² =CH2N(R ⁸ )(R ⁹ )).

Method S.

Method S refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. In the first step, nickel-mediated reduction of the nitrile of the compound of formula K-3 (Z=Cl) gives the compound of formula O-5. At this stage, the R ¹ substituent of Formula K-3 must be the same moiety as required in the final product of Formula II or a protected variant thereof. The next step is either:

i) Nickel-mediated decarboxylated photooxidative cross-coupling of the compound of formula O-5 with the desired acid yields the compound of formula B-9 (Y=N(R ⁸ )Boc); or ii) Carbonylation of a chloride of formula O-5 using carbon monoxide and methanol under palladium catalysis produces an ester, which is then reduced (B-9, Y=OH) and activated as a mesylate (B-9, Y=OSO ₂ CH ₃ ). The next step is either:

a. Direct replacement of the mesylate with primary amines gives the corresponding secondary amines of formula B-9 (Y=N(R ⁸ )(R ⁹ )); or

b. Azidation (B-9, Y=N ₃ ) and reduction of azide functionality under standard conditions gives the primary amine of formula B-9 (Y=NH2).

Coupling of the compound of formula B-9 with bromopyridine triazole B-10 under palladium or copper catalysis followed by removal of the protecting group(s) under standard conditions gives the pyrrolo[3,4-c]pyridin-1-one of formula II.

- 61 044841

Method T.

Method T refers to a different synthetic sequence for the preparation of compounds of formula III, as shown above. In the first step, the compound of formula B-9 (Y=N(R ⁸ )Boc, R ¹ is as presented in the compound of formula III or a protected version thereof) undergoes copper-mediated palladium coupling with the compound of formula bromopyridine D-3 (obtained as described in Method H) to give pyrrolo[3,4-c]pyridin-1-one of formula III (R ² =CH ₂ N(R ⁸ )Boc). Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula III (R ² =CH2N(R ⁸ )(R ⁹ )).

Method U.

Method U refers to the synthetic sequence for the preparation of compounds of formula U-4 as shown above. In the first step, a compound of formula B-12 reacts with a suitable acyl chloride to form a compound of formula U-1. At this stage, the R ¹³ acyl chloride substituent is present in the final product of Formula U-4 or a protected version thereof. Cyclization of a compound of formula U-1 gives a compound of formula U-2. Bromopyridine of formula U-2 (eg, intermediate 4) is coupled with a compound of formula B-9 under palladium or copper catalysis to produce compound of formula U-3 (Y=N(R ⁸ )Boc). At this stage, the R ⁵ substituent on U-2 and the R ¹ substituent on B-9 must be represented by the same moiety that is required in the final product, formula U-4, or a protected variant thereof. The compound of formula U-3 reacts with the required amine to form the protected pyrrolo[3,4-c]pyridin-1-one compound from U-4. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U-4 (R ² =CH ₂ N(R ⁸ )(R ⁹ )).

Method V

Method V refers to the synthetic sequence for the preparation of compounds of formula V-5 as shown above. In the first step, alkylation of the imidazole of formula V-1 produces a compound of formula V2, in which the substituent R ¹² must be the same group as in the final product of formula V-5, or a protected variant thereof. The compound of formula B-9 is coupled with the compound of formula B-10 under palladium or copper catalysis, followed by removal of the protecting group(s) under standard conditions to give the pyrrolo[3,4-c]pyridin-1-one of formula II (R ² = CH ₂ N(R ⁸ )(R ⁹ )). At this stage, the R ⁵ and R ¹² substituents in B-10 should be the same group as in the final product, Formula II, or a substituted variant thereof.

- 62 044841

Method AA.

Method AA refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. In the first step, a compound of formula O-3 (Y=piperidine, dimethylamine, OH, OMe, OEt, OiPr) undergoes reductive amination with a pyridine amine of formula AA-1 to produce a compound of formula AA-2. At this stage, the R ¹ substituent in O-3 and the R ⁵ and R ¹² substituents in Formula AA-1 must be represented by the same group that is required in the final product of Formula II or a protected variant thereof. Palladium-mediated cross-coupling of Formula AA-2 with trifluoroborates or zincates of Formula AA-3, followed by removal of the protecting group(s) under standard conditions, then yields the pyrrolo[3,4-c]pyridin-1-one of Formula II. At this stage, the R ² substituent should be the same moiety as desired in the final product, Formula II, or a protected variant thereof.

The compound of formula B-10 is coupled with a tert-butyl carbamate under palladium catalysis followed by removal of the carbamate protecting group under standard conditions to yield the aminopyridine of formula AA-1.

Method AB.

Method AB refers to a different synthetic sequence for the preparation of compounds of formula U4 as shown above. In the first step, the combination of a compound of formula O-5 with a bromopyridine of formula U-2 under palladium or copper catalysis produces a compound of formula R-1. At this stage, the R ¹ substituent of Formula O-5 and the R ⁵ and R ¹³ substituents of Formula U-2 must be represented by the same group that is required in the final product of Formula U-4 or a protected variant thereof. Suzuki cross-coupling with the appropriate trifluoroborate or Negishi cross-coupling with the desired aminoalkyl zincate followed by deprotection of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U-4 (R ² =CH ₂ N(R ⁸ )(R ⁹ )).

AC method.

Method AC refers to a different synthesis sequence for the preparation of U-4 compounds as shown above. In the first step, a bromopyridine of formula U-2 (eg, intermediate 4) is coupled with a compound of formula C-2 under palladium or copper catalysis to produce a compound of formula AC-1 (Y=N(R ⁸ )Boc). At this stage, the R ⁵ and R ¹³ substituents in U-2 must be the same group as is required in the final product of Formula U-4 or a protected variant thereof. The compound of formula AC-1 undergoes palladium-mediated coupling with the desired amine or boronic acid ester, or a salt of boronic acid or tetrafluoroborate to produce the compound of formula U-3. At this stage, the R ¹ substituent in U-3 must be the same group as in the final product, formula U-4, or a protected variant thereof. Reaction of the compound of formula U-3 with the necessary amine produces the protected pyrrolo[3,4-c]pyridin1-one compound of formula U-4. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U-4 (R ² =CH ₂ N(R ⁸ )(R ⁹ )).

AD method.

Method AD refers to another synthetic sequence for the preparation of compounds of formula U-4, as shown above. In the first step, a bromopyridine of formula U-2 (eg, intermediate 4) is reacted with the desired amine to produce a compound of formula X-3. At this stage, the R ⁵ and R ¹² substituents in U-2 must be represented by the same group as in the final product of formula U-4 or a protected variant thereof. Coupling of a compound of formula X-3 with a compound of formula B-9 under palladium or copper catalysis to produce a compound of formula U-4 (Y=N(R ⁸ )Boc). At this stage, the R ¹ substituent in B-9 must be the same group as in the final product of Formula U-4 or a protected variant thereof. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U-4 (R ² =CH ₂ N(R ⁸ )(R ⁹ )).

Method AE.

Method AE refers to a different synthetic sequence for the preparation of compounds of formula U4 as shown above. In the first step, the reaction of a compound of formula AC-1 (Y=N(R ⁸ )Boc) with the desired amine produces a compound of formula AE-1. At this stage, the substituents R ⁵ and R ¹² must be the same group as required in the final product of Formula U-4 or a protected variant thereof. The compound of formula AE-1 undergoes palladium-mediated coupling with the desired amine or boronic acid ester, or boronic acid or tetrafluoroborate salt to form the protected pyrrolo[3,4-c]pyridin-1-one compound of formula U-4. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U4 (R ² =CH2N(R ⁸ )(R ⁹ )).

AF method.

Method AF refers to a different synthetic sequence for the preparation of compounds of formula U4 as shown above. In the first step, the combination of a compound of formula O-5 with bromopyridine X-3 under palladium or copper catalysis produces a compound of formula AF-1. At this stage, the R ¹ substituent of formula 0-5, and the R ⁵ , R ¹² and R ¹³ substituent(s) of formula X-3 must be represented by the same group that is desired in the final product of formula U-4 or a protected variant thereof. Suzuki cross-coupling with the corresponding trifluoroborate or Negishi cross-coupling with the corresponding aminoalkyl zincate followed by deprotection of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U-4 (R ² =CH ₂ N(R ⁸ )(R ⁹ )).

Method AG.

Method AG refers to the synthetic sequence for the preparation of compounds of formula AG-2,

- 64 044841 as shown above. In the first step, coupling of a compound of formula B-9 with a bromopyridine AG-1 (eg, Q=O, intermediate 5 or Q=S, intermediate 6) under palladium or copper catalysis produces a compound of formula AH-2. At this stage, the R ¹ substituent of formula B-9 must be represented by the same group as in the final product of formula AG-2 or a protected variant thereof. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1one of formula AG-2 (R ² =CH2N(R ⁸ )(R ⁹ )).

Method AH.

0-5 B-θ in-th Formula II

Method AH refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. In the first step, when the R ¹ substituent of formula O-5 must be the same group as required in the final product, formula II or a protected variant thereof, either:

i. Nickel-mediated decarboxylation cross-coupling of a compound of formula O5 with the desired acid yields a compound of formula B-9 (Y=N(R ⁸ )Boc); or ii. Cross-coupling Suzuki or Molander with the required boric acid, boronic acid ester or trifluoroborate salt gives the compound of formula B-9 (Y=N(R ⁸ )Boc); or iii. Cross-coupling Negishi with the required aminoalkyl zincate gives the compound of formula B-9 (Y=N(R ⁸ )Boc); or

Carbonylation of the chloride for formula O-5 using carbon monoxide and methanol under palladium catalysis produces the ester, which is then reduced (B-9, Y=OH) and activated as the mesylate (B-9, Y=OSO ₂ CH ₃ ). At the next stage either

a. Direct replacement of the mesylate with the desired primary amine to yield the corresponding secondary amine of formula B-9, (Y=N(R ⁸ )(R ⁹ )); or

b. Azidation (B-9, Y=N ₃ ) and reduction of azide functionality under standard conditions to give the primary amine of formula B-9 (Y=NH ₂ ).

c. Coupling of the compound of formula B-9 with bromopyridine triazole B-10 under palladium or copper catalysis followed by removal of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula II.

AI method.

Method AI refers to a different synthetic sequence for the preparation of compounds of formula U4, as shown above. In the first step, the bromopyridine of formula X-3 is coupled with a compound of formula C-2 (Y=N(R ⁸ )Boc) under palladium or copper catalysis. At this stage, the R ⁵ , R ¹² and R ¹³ substituents in X-3 must be the same group as required in the final product of Formula U-4 or a protected variant thereof. The compound of formula AI-1 undergoes palladium-mediated coupling with the desired amine, boronic acid ester or tetrafluoroborate salt to produce the compound of formula U-4. At this stage, the R ¹ substituent must be the same moiety as in the final product of Formula U-4 or a protected variant thereof. Cleavage of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U-4 (R ² =CH2N(R ⁸ )(R ⁹ )).

- 65 044841

Method AJ.

/ ^AJ-Z AJ-3 Formula II

Method AJ refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. In the first step, a compound of formula B-9 is coupled with a bromopyridine of formula B-11 under palladium or copper catalysis to produce a compound of formula AJ-1. At this stage, the R ¹ substituent in B-9 and the R ⁵ substituent in B-11 must be represented by the same moiety that is required in the final product of Formula II or a protected variant thereof. Hydrazinolysis of the compound of formula AJ-1 gives the compound of formula AJ-2. The hydrazine of formula AJ-2 then reacts with dimethylformamide dimethyl acetal to form the compound of formula AJ-3. Condensation of the compound of formula AJ-3 with a suitable amine (for example, R ¹² -NH2) followed by removal of the protecting group(s) under standard conditions gives pyrrolo[3,4-c]pyridin-1-one of formula U3 (R ² =CH2N( R ⁸ (R ⁹ )). During this step, the R ¹² amine substituent must be represented by the same group as in the final product of Formula II or a protected variant thereof.

Method AK.

r-1 AA-1 Formula II

Method AK refers to a different synthetic sequence for the preparation of compounds of formula II, as shown above. In Method AK, a compound of formula P-1 is subjected to reductive amination with a pyridine amine of formula AA-1 followed by deprotection to yield a compound of formula II. At this stage, the R ¹ substituent in P-1 and the R ⁵ and R ¹² substituents in Formula AA1 must be represented by the same group as in the final product of Formula II or a protected variant thereof.

Illustrative examples.

Example 1: 6-(dimethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2- yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl [(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2- yl}2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate

Tert-butyl [(6-chloro-1-oxo-2,3-dihydro-III-pyrrolo[3,4c]pyridin-4-yl)methyl]methylcarbamate (224 mg, 0.72 mmol) was charged into a microwave vessel. , 2-bromo-6-[4-(propan-2-yl)-4H-1,2,4-triazol3-yl]pyridine (192 mg, 0.72 mmol), potassium carbonate (218 mg, 1.6 mmol), 2-(dimethylamino)ethylamine (0.04

- 66 044841 ml, 0.36 mmol), copper iodide (34 mg, 0.18 mmol) and acetonitrile (3 ml, 0.2 M). The reaction mixture was sealed and heated in a microwave oven at 120°C for 90 min. The mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (0-10% methanol in 1:1 DCM/ethyl acetate) to give the title compound as an off-white solid (210 mg, 59%).

1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=8.44 Hz, 1H) 8.63-8.72 (m, 1H) 8.19 (s, 1H) 8.01 (t, J=8.01 Hz, 1H) 7.80 (s, 1H) 5.65-5.86 (m, 1H) 5.26 (b.s., 2H) 4.63 (b.s., 2H) 3.04 (s, 3H) 1.72 (d, J=5.26 Hz, 6H) 1.40 (w.s, 9H). m/z (APCI+) for (Cz^ClNjOj) 497.9 (M+H) ⁺ .

Step 2: tert-butyl {[6-(dimethylamino)-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2- yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl]methyl}methylcarbamate

Tert-butyl [(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} was loaded into the flask -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (50 mg, 0.10 mmol), cesium carbonate (98.1 mg, 0.30 mmol), 2M dimethylamine in THF (0.11 ml, 0.21 mmol), 1,4-dioxane ml) (3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2 '-amino-1,1' biphenyl)]palladium(II) methanesulfonate (8.4 mg, 0.01 mmol) The reaction mixture was heated to 100°C under nitrogen and allowed to stir for 16 hours. another crude batch of this reaction (210 mg scale).The combined material was filtered and washed with methanol/DCM (30 ml). The filtrate was concentrated to give a brown solid, which was purified by column chromatography (20:1 DCM/methanol) to give the above in the title compound as a yellow solid (160 mg, average yield 61%).

1H NMR (400 MHz, CDCl3) δ 8.72 (d, J=8.3 Hz, 1H), 8.40 (s, 1H), 8.09 (br.s., 1H), 7.98- 7.90 (m, 1H), 6.89 (s, 1H), 5.81-5.41 (m, 1H), 5.14-4.90 (m, 2H), 4.49 (s, 2H), 3.16 (s, 6H), 3.02 (s, 3H), 1.72-1.62 (m, 6H), 1.461.29 (m, 9H) m/z (APCI+) for ( C26H34N8O3) 507.3 (M+H) ⁺ .

Step 3: 6-(dimethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2- yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The flask was loaded with tert-butyl {[6-(dimethylamino)-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol3-yl]pyridin-2- yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl]methyl}methylcarbamate (43 mg, 0.09 mmol) and ethyl acetate (2 ml). The solution was cooled to 5°C and a 4M solution of HCl in ethyl acetate (5 ml) was added. The reaction mixture was allowed to warm to 20°C and stirred for 1 hour, after which the reaction mixture turned into a suspension. The suspension was filtered and the solids were collected to give the title compound as a yellow solid (35 mg, 93%).

1H NMR (400 MHz, DMSO-dg) δ 9.27 (b.s., 2H), 9.20 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 8, 15 (t, J=8.0 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 6.95 (s, 1H), 5.48 (quin., J=6, 8 Hz, 1H), 5.17 (s, 2H), 4.32 (bt, J=5.6 Hz, 2H), 3.18 (s, 6H), 2.73 (t, J =5.4 Hz, 3H), 1.61 (d, J=6.8 Hz, 6H). m/z (APCI+) for (C21H26N8O) 429.1 (M+Na) ⁺ .

Example 2: 6-(azetidin-1-yl)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl] pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl {[6-(azetidin-1-yl)-1-oxo-2-{6-[4-(npropan-2-yl)-4H-1,2,4-triazol-3yl] niridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]niridin-4-yl]methyl}methylcarbamate

- 67 044841

Tert-butyl [(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} was loaded into the flask -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (70.0 mg, 0.14 mmol), azetidine hydrochloride (39 mg, 0.42 mmol), cesium carbonate (210 mg, 0.65 mmol), (2dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II ) methanesulfonate (11.8 mg, 0.014 mmol) and 1,4-dioxane (2.8 ml, 0.05 M). The reaction mixture was heated at 100°C for 18 hours, after which more azetidine (39 mg, 0.42 mmol) and (2-dicyclohexylphosphino-2',6'diisopropoxy-1,1'-biphenyl)[2-( 2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11.8 mg, 0.014 mmol) and the reaction mixture was heated for 24 hours at 110°C. The reaction mixture was concentrated in vacuo and purified by column chromatography (0-10% methanol in 1:1 DCM/ethyl acetate) to give the title compound as an off-white solid (45 mg, 62%). m/z (APCI+) for (C27H34N8O3) 519.95 (M+H) ⁺ .

Step 2: 6-(azetidin-1-yl)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl] pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Tert-butyl {[6-(azetidin-1-yl)-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl] was loaded into the flask pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl]methyl}methylcarbamate (45 mg, 0.09 mmol) and DCM (3 ml, 0.03 M ). Trifluoroacetic acid (0.8 mL, 10 mmol) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was azeotroped with toluene (2x) and the resulting residue was purified using SFC (HA-Morpholine 60 A 5µm, 150x21.2mm column at 40°C, eluted with a gradient of 12-30% MeOH in CO2, ramped over 7 min Pressure maintained at 120 bar with a flow rate of 85 ml/min controlled by UV 224 nm) gave the title compound (17 mg, 48%).

1H NMR (400 MHz, DMSO) δ 8.83 - 8.93 (m, 1H) 8.50-8.62 (m, 1H) 7.97-8.08 (m, 1H) 7.83-7 .93 (m, 1H) 6.36-6.55 (m, 1H) 5.51 (dt, J=13.42, 6.68 Hz, 1H), 5.06-5.18 (m, 2H ) 3.87-3.98 (m, 4H) 3.66-3.81 (m, 2H) 2.24-2.32 (m, 5H) 1.51 (d, J=6.60 Hz, 6H). m/z (APCI+) for (C22H26N8O) 420.0 (M+H) ⁺ .

Example 3: 6-[(2R,4R)-2,4-dimethylazetidin-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H1, 2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one ⁰ P fR) N=/ \

HN \ Ave.-W

Step 1: tert-butyl [(6-[(2R,4R)-2,4-dimethylazetidin-1-yl]-1-oxo-2-{6-[4-(propan-2-yl)-4H- 1,2,4triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate

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Tert-butyl [(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} was loaded into the flask -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (100 mg, 0.20 mmol), (2R,4R)-2,4-dimethylazetidine hydrochloride (45 .6 mg, 0.40 mmol) and 1,4-dioxane (4 ml, 0.05 M). Cesium carbonate (196 mg, 0.60 mmol) was added followed by (2-dicyclohexylphosphino2',6'-diisopropoxy-1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium( P) methanesulfonate (16.8 mg, 0.02 mmol). The reaction mixture was heated for 16 hours at 100°C under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (50 ml) and washed with saturated saline (3x30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified by preparative TLC (silica gel, 1:4 petroleum ether/ethyl acetate, twice) to give the title compound as an off-white solid ( 40 mg, 36%). TLC Rf=0.3 (EtOAc UV imaging).

¹ H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.60 (d, J=8.31 Hz, 1H), 8.05-8.15 (m, 1H), 7.88-7.97 (m, 1H), 6.53 (s, 1H), 5.51 (b.s., 1H), 5.06 (b.d., J=19.32 Hz, 2H), 4.32-4.53 (m, 4H), 3.57 (s, 1H), 2.94 (s, 3H), 2.08 (bt, J=6.36 Hz, 2H), 1.56-1.70 (m, 6H), 1.37 (b.s., 11H), 1.09-1.28 (m, 6H). m/z for (C ₂₉ H ₃₈ N ₈ O ₃ ) 569.4 (M+Na)+.

Step 2: 6-[(2R,4R)-2,4-dimethylazetidin-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H1, 2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Tert-butyl [(6-[(2R,4R)-2,4-dimethylazetidin-1-yl]-1-oxo-2-{6-[4-(propan-2yl)-4H-1, 2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl)methyl]methylcarbamate (40 mg, 0.07 mmol) and DCM (3 ml, 0.02) and cooled to below 10°C. Trifluoroacetic acid (0.06 mL, 0.73 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 2 hours, the reaction mixture was added to ice water (20 ml). Solid sodium bicarbonate was added until the solution reached pH 9. The aqueous layer was extracted with DCM (3x20 ml). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by chromatography (0-10% methanol in DCM) to give the title compound as a yellow solid (20 mg, 61%).

1H NMR (400 MHz, DMSO-d6) δ 8.83-8.93 (m, 1H) 8.50-8.62 (m, 1H) 7.97-8.08 (m, 1H) 7.83 -7.93 (m, 1H) 6.36-6.55 (m, 1H) 5.51 (dt, J=13.42, 6.68 Hz, 1H) 5.06-5.18 (m, 2H) 3.87-3.98 (m, 4H) 3.66-3.81 (m, 2H) 2.242.32 (m, 6H) 1.51 (d, J=6.60 Hz, 6H). m/z (APCI+) for (C ₂₄ H ₃₀ N ₈ O) 447.2 (M+H)+.

Example 4: 6-(diethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2- yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; ⁿ⁼ $\HN\Ex.-4

Step 1: tert-butyl {[6-(diethylamino)-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2- yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl]methyl}methylcarbamate

Tert-butyl [(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} was loaded into the flask -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (100 mg, 0.20 mmol), diethylamine (0.04 ml, 0.40 mmol), cesium carbonate (229 mg, 0.70 mmol) and 1,4-dioxane (4 ml,

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0.05M). Add (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium(11) methanesulfonate (16.8 mg, 0. 02 mmol). The reaction mixture was degassed with nitrogen gas (three times) and heated for 16 hours at 100°C, upon completion of which diethylamine (0.04 ml, 0.40 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1'-biphenyl)[2-(2'-amino1,G-biphenyl)]palladium(P) methanesulfonate (16.8 mg, 0.02 mmol). The reaction mixture was degassed with nitrogen gas (three times) and heated for 16 hours at 100°C. The mixture was added to water (15 ml) and extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude compound as a yellow gum (100 mg). The crude material was purified by preparative TLC (20:1 ethyl acetate/methanol, Rf=0.5 in ethyl acetate, UV imaging) to give a yellow solid (60 mg). The compound was further purified by preparative HPLC using water (0.04% NH3H2O+10 mM NH ₄ HCO ₃ ) as the mobile phase on a Waters Xbridge Prep PBD C18 150x30 10 μm column. this gave the title compound as a yellow solid (40 mg, 37%).

1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 8.15-8.06 (m, 1H), 7.98 -7.93 (m, 1H), 6.85 (s, 1H), 5.78-5.45 (m, 1H), 5.09 (b.s., 2H), 4.48 (s, 2H), 3.60 (sq., J=7.1 Hz, 4H), 3.08-3.02 (m, 3H), 1.741.66 (m, 6H), 1.46-1.30 ( m, 9H), 1.23 (t, J=7.0 Hz, 6H). m/z (APCI+) for (C ₂₈ H ₃₈ N ₈ O ₃ ) 535.4 (M+H) ⁺ .

Step 2: 6-(diethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2- yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The flask was loaded with tert-butyl {[6-(diethylamino)-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]πpyridin-2- yl}-2,3-dihydro-1H-πpyrrolo[3,4-c]πpyridin-4-yl]methyl}methylcarbamate (40 mg, 0.075 mmol) and ethyl acetate (5 ml, 0.02 M) and cooled to 0° C. A solution of 4 M hydrochloric acid in ethyl acetate (5 ml, 20 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 1 hour. Methanol (3 ml) was added and the reaction mixture was stirred for 1 hour and the mixture was concentrated in vacuo. The resulting residue was lyophilized for 16 hours to obtain the title compound as a yellow solid (28 mg, 79%).

1H NMR (400 MHz, DMSOC) δ 9.76 (b.s., 1H), 9.60 (b.s., 2H), 8.69 (b.s., J=8.2 Hz, 1H ), 8.18 (bt, J=7.6 Hz, 1H), 7.98 (td, J=7.2 Hz, 1H), 6.85 (s, 1H), 5 .65-5.48 (m, 1H), 5.22 (b.s., 2H), 4.25 (b.s., 2H), 3.63 (b.d., J=6.6 Hz, 4H), 2.77-2.58 (m, 3H), 1.65 (b.d., J=6.1 Hz, 6H), 1.15 (b.t., J=6, 5 Hz, 6H)]. m/z (APCI+) for (C23H3oN ₈ 0) 435.3 (M+H) ⁺ .

Example 5: 6-cyclopropyl-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl [(6-cyclopropyl-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]niridin-2-yl} -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate

Tert-butyl [(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} was loaded into the flask -2,3-dihydro-1H-πurrolo[3,4-c]πpyridin-4-yl)methyl]methylcarbamate (100 mg, 0.20 mmol), potassium cyclopropyl trifluoroborate (59.4 mg, 0.40 mmol), palladium acetate (9.0 mg, 0.04 mmol),

- 70 044841 di(1-adamantyl)-n-butylphosphine (21.6 mg, 0.06 mmol), cesium carbonate (196 mg, 0.60 mmol), water (0.25 ml) and toluene (2.5 ml, 0.08M). The reaction mixture was heated for 20 hours at 110°C, after which the reaction mixture was diluted with ethyl acetate (50 ml). The solution was washed with saturated saline 3x30 ml), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (0-5% methanol in DCM) to give the title compound as an off-white solid (80 mg, 79%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.62 (d, J=7.95 Hz, 1H), 8.12 (t, J=8.07 Hz, 1H), 7.95 (d, J=7.46 Hz, 1H), 7.67 (s, 1H), 5.50 (br.s., 1H), 5.20 (b.s., 2H ), 4.55 (s, 2H), 2.90 (s, 3H), 2.26-2.35 (m, 1H), 1.58 (b.s., 6H), 1.18-1 .45 (m, 9H), 0.93-1.05 (m, 4H)). m/z (APCI+) for (C27H33N7O3) 404.2 (M+H) ⁺ .

Step 2: 6-cyclopronyl-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Tert-butyl [(6-cyclopropyl-1-oxo-2-{6-[4-(nponan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} was loaded into the flask -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (80 mg, 0.16 mmol) and DCM (3 ml, 0.5 M). The solution was cooled to below 10°C and TFO (0.12 ml, 1.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was diluted with ice water (20 ml) and solid sodium bicarbonate was added until the aqueous layer reached ~pH 9. The layers were separated and the aqueous layer was extracted with DCM/DCM (3x20 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This material was purified by column chromatography (0-10% methanol in DCM) to give the title compound as an off-white solid (30 mg, 47%).

1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.63 (d, J=8.31 Hz, 1H), 8.11 (t, J=8.01 Hz, 1H ), 7.94-8.00 (m, 1H), 7.60 (s, 1H), 5.58 (quin., J=6.76 Hz, 1H), 5.28 (s, 2H), 3.93 (s, 2H), 2.35 (s, 3H), 2.25-2.32 (m, 1H), 1.59 (d, J=6.72 Hz, 6H), 0.97 -1.04 (m, 4H). m/z (APCI+) for (C22H25N7O) 404.2 (M+H) ⁺ .

Example 6: 4-[(methylamino)methyl]-6-[methyl(nponan-2-yl)amino]-2-{6-[4-(propan-2-yl)-4H-1,2,4triazol- 3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl methyl[(6-[methyl(propan-2-yl)amino]-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4triazole -3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate

Tert-butyl was loaded into the flask

[(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3 yl]pyridin-2-yl}-2,3- Dihydro-1H-nurrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (96 mg, 0.19 mmol), N-methylisopropylamine (0.1 ml, 0.96 mmol), cesium carbonate (188 mg, 0.58 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (16 mg, 0.019 mmol), and 1,4-dioxane (3.9 ml). The reaction mixture was heated for 18 hours at 100°C. The mixture was cooled to room temperature and filtered through a pad of Celite® and washed with 10% methanol in DCM. The filtrate was concentrated in vacuo and the resulting material was purified using column chromatography (0-10% methanol in 1:1 DCM/ethyl acetate) to give the title compound as a white solid (60 mg, 58%). m/z (APCI+) for (C28H38N8O3) 535.3 (M+H) ⁺ .

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Step 2: 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-{6-[4-(propan-2-yl)-4H-1,2,4triazol- 3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The flask was loaded with tert-butyl methyl[(6-[methyl(propan-2-yl)amino]-1-oxo-2-{6-[4-(propan-2-yl)4H-1,2,4- triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate (60 mg, 0.11 mmol) and DCM ( 6 ml). Added 4 N. a solution of the hydrochloride in 1,4-dioxane (2 mL, 8.0 mmol) and the solution was allowed to stir at room temperature for 1 hour. The solution was partially concentrated in vacuo and then azeotroped with toluene (2x). The resulting material was purified using SFC (DCPak SFC-B 150x21.2 mm, 5 µm column at 40°C, eluted with a gradient of 15-35% methanol in carbon dioxide with a gradual increase over 7 min, the pressure was maintained at 120 bar with flow rate 85 ml/min) to obtain the title compound as a solid (28.9 mg, 59%).

1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H) 8.63 (d, J=7.95 Hz, 1H) 8.10 (t, J=8.01 Hz, 1H) 7 .95 (d,

J=7.21 Hz, 1H) 6.81 (s, 1H) 5.54 (dt, J=13.36, 6.71 Hz, 1H) 5.15 (s, 2H) 4.89-5, 05 (m, 1H) 3.98 (s, 2H) 2.89 (s, 3H) 2.48 (s, 3H) 1.59 (d, J=6.72 Hz, 6H) 1.16 (d , J=6.72 Hz, 6H). m/z (APCI+) for (C23H30N8O) 435.0 (M+H)+.

Example 7: 4-[(methylamino)methyl]-6-(1-methylcyclonropyl)-2-{6-[4-(pronan-2-yl)-4H-1,2,4-triazol3 -yl]pyridin- 2-yl}-2,3-dihydro-1H-pyrrolo[3,4ω]pyridin-1-one

Step 1: 4-[(methylamino)methyl]-6-(1-methylcyclopropyl)-2-{6-[4-(pronan-2-yl)-4H-1,2,4-triazol3 -yl]pyridin- 2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Tert-butyl [(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl} was loaded into the flask -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (88 mg, 0.18 mmol), 4,4,5,5-tetramethyl-2-(1 -methylcyclopropyl)-1,3,2-dioxaborolane (43 mg, 0.26 mmol), palladium acetate (7.9 mg, 0.035 mmol), di(1-adamantyl)-n-butylphosphine (19 mg, 0.053 mmol) , cesium carbonate (172 mg, 0.53 mmol), toluene (4 ml) and water (0.4 ml). The mixture was degassed with nitrogen for 8 min and then heated for 4 h at 110°C. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo. The resulting material was purified using column chromatography (080% ethyl acetate in heptane) to give a light yellow solid (96 mg), which was used directly in the next step. The flask was charged with the isolated solid, DCM (2 ml), and trifluoroacetic acid (0.4 ml). The reaction mixture was allowed to stir at room temperature for 2 hours. The mixture was concentrated and purified using reverse phase HPLC (5-100% mobile phase B in mobile phase A, mobile phase A: 0.05% TPO in water (v/v .), mobile phase B: 0.05% TFO in acetonitrile (v/v), Waters Sunfire C18 19x100.5 µm column, flow rate: 25 mL/min) to obtain the title compound as a solid ( 94 mg, 90% in 2 stages).

1H NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H) 8.63 (d, J=8.44 Hz, 1H) 8.14 (t, J=7.98 Hz, 1H) 7 .95 (d, J=7.70 Hz, 1H) 7.71 (s, 1H) 5.43 (quin., J=6.60 Hz, 1H) 5.23 (s, 2H) 4.48 ( s, 2H) 2.77 (s, 3H) 1.57-1.62 (m, 9H) 1.42-1.47 (m, 2H) 0.92-0.97 (m, 2H). m/z (APCI+) for (C23H2?N ₇ O) 418.2 (M+H)+.

Example 8: 6-[(2R,5R)-2,5-dimethylpyrolidinyl-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)4H-1 ,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

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Step 1: tert-butyl [(6-[(2R,5R)-2,5-dimethylpyrrolidinyl-1-yl]-1-oxo-2-{6-[4-(propan-2-yl)-4H1, 2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate

Tert-butyl was loaded into the flask

[(6-chloro-1-oxo-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3 yl]pyridin-2-yl}-2,3- Dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]methylcarbamate (100 mg, 0.20 mmol), (2R,5R)-2,5-dimethylpyrrolidine HCl salt (55 mg, 0. 40 mmol), cesium carbonate (196 mg, 0.60 mmol), 1,4-dioxane (3 ml) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-( 2'-amino1,1'-biphenyl)]palladium(P) methanesulfonate (17 mg, 0.02 mmol). The atmosphere was replaced with nitrogen gas and the reaction mixture was heated for 40 hours at 100°C. The mixture was cooled to room temperature and diluted with DCM (50 ml). The solution was washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow gum. The crude material was purified by preparative TLC (1:4 petroleum ether/ethyl acetate) to give the title compound as a light green solid (10 mg, 9 1H NMR (400 MHz, CDCI3) δ 8.73 (d, J =8.2 Hz, 1H), 8.43 (s, 1H), 8.11 (sh.s., 1H), 8.00-7.90 (m, 1H), 6.76 (s, 1H ), 5.825.47 (m, 1H), 5.15 -4.93 (m, 2H), 4.63-4.40 (m, 2H), 3.05 (b.s., 3H), 2 .30 (b.s., 2H), 1.73-1.66 (m, 8H), 1.451.30 (m, 11H), 1.21 (d, J=6.1 Hz, 6H).m /z (APCI+) for (C30H40N8O3) 561.4 (M+H)+.

Step 2: 6-[(2R,5R)-2,5-dimethylpyrolidinyl-1-yl]-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)4H-1 ,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Tert-butyl [(6-[(2R,5R)-2,5-dimethylpyrrolidinyl-1-yl]-1-oxo-2-{6-[4-(propan2-yl)-4H-1, 2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl)methyl]methylcarbamate (10 mg, 0.018 mmol) and DCM ( 3 ml) and cooled to 0°C. Trifluoroacetic acid (0.2 ml) was added dropwise. The solution was allowed to warm to 25°C and stirred for 3 hours. The mixture was diluted with ice water (10 ml) and the pH was adjusted to pH 9 by adding solid sodium carbonate. The layers were separated, the aqueous layer was extracted with DCM (3x20 ml). The combined organic layer was washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (8 mg, 97%).

1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.62 (d, J=7.9 Hz, 1H), 8.14-8.06 (m, 1H), 7 .95 (d, J=7.1 Hz, 1H), 6.64 (s, 1H), 5.55 (td, J=6.7, 13.3 Hz, 1H), 5.21 - 5, 08 (m, 2H), 4.27 (b.s., 1H), 3.95-3.85 (m, 2H), 2.43 (s., 3H), 2.23 (b.s., 2H), 1.65 (b.d., J=5.5 Hz, 2H), 1.58 (d., J=6.7 Hz, 6H), 1.36-1.28 (m, 2I) , 1.17-1.07 (m, 6H). m/z (APCI+) for (C25H32N8O) 483.3 (M+Na)+.

Example 9: 6-(diethylamino)-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

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Step 1: 2-bromo-6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridine

The flask was charged with N'-[(6-bromopyridin-2-yl)carbonyl]-N,N-dimethylhydrazonoformamide (2.0 g, 7.4 mmol), ethylamine (0.5 ml, 333 mg, 7.4 mmol ), acetic acid (3 ml) and acetonitrile (15 ml, 0.5 M). The solution was heated for 16 hours at 95°C. The reaction mixture was diluted with ethyl acetate (10 ml) and water (10 ml). Solid potassium carbonate was added until the pH of the aqueous layer reached ~pH 8. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x30 ml). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the crude product (1.8 g) as a yellow solid. The crude material was diluted with ethyl acetate (0.3 ml) and petroleum ether (3 ml), stirred for 5 minutes and filtered. This gave the title compound as a pale yellow solid (1.5 g, 80%).

1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=7.8 Hz, 1H), 8.24 (s, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 4.59 (q, J=7.3 Hz, 2H), 1.52 (t, J=7.2 Hz, 3H). m/z (APCI+) for (C^BrN), 252.7 (M+H)+.

Step 2: tert-butyl ({6-chloro-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-1-oxo-2,3dihydro -1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate ϊ Λ ^N

CI— ^Ν 4 \ —Ν

The flask was loaded with tert-butyl ((6-chloro-1-oxo-2,3-dihydro-III-pyrrolo[3,4-e]pyridin-4yl)methyl)(methyl)carbamate (100 mg, 0.32 mmol ), 2-bromo-6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridine (97.4 mg, 0.39 mmol), copper iodide (15.3 mg, 0. 08 mmol), potassium carbonate (97.5 mg, 0.71 mmol) and acetonitrile (5 ml, 0.06 M). The solution was bubbled with nitrogen gas for 5 min, sealed and heated for 1.5 h at 120°C. The reaction mixture was cooled to room temperature and diluted with DCM (100 ml). The solution was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow gum (200 mg). The crude material was purified by column chromatography to obtain the title compound as a white solid (120 mg, 77%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.69 (d, J=8.5 Hz, 1H), 8.28 (s, 1H), 8.17 (b.d., J=6.8 Hz , 1H), 7.97 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 5.24 (br.s., 2H), 4.72 (b.s., 2H), 4.68-4.63 (m, 2H), 2.98 (s, 3H), 1.47-1.28 (m, 12H). m/z (APCI+) for (C ₂₃ H ₂₆ ClN ₇ O) 484.1 (M+H)+.

Step 3: tert-butyl ({6-(diethylamino)-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-1-oxo2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate

The flask was loaded with tert-butyl ({6-chloro-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-1-oxo2,3-dihydro -1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (120 mg, 0.25 mmol), cesium carbonate

- 74 044841 (242 mg, 0.74 mmol), diethylamine (0.05 ml, 0.52 mmol) and 1,4-dioxane (4 ml, 0.06 M). (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,G-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(I) methanesulfonate (20.7 mg, 0.025 mmol) was added. and the reaction mixture was heated for 16 hours at 100°C under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated saline (3x30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude residue. The crude material was purified by column chromatography (10:1 DCM/methanol) to give the title compound (60 mg, 46%).

1H NMR (400 MHz, CDCl3) δ 8.78 - 8.69 (m, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 1H), 7.93 (t, J=7.9 Hz, 1H), 6.83 (s, 1H), 5.10-4.92 (m, 2H), 4.72 (br.s., 2H), 4.50 (br. s., 2H), 3.59 (sq., J=7.3 Hz, 4H), 2.99 (sh.s., 3H), 1.461.31 (m, 11H), 1.21 (t, J=7.0 Hz, 6H). m/z (APCI+) for (C27H36N8O3) 521.3 (M+H) ⁺ .

Step 4: 6-(diethylamino)-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

HN\

The flask was loaded with tert-butyl ({6-(diethylamino)-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2yl]-1-oxo-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (60 mg, 0.12 mmol) and ethyl acetate (2 ml, 0.06 M), and the reaction mixture was cooled to below 5° C. A solution of 4M hydrochloric acid in ethyl acetate (5 mL, 20 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated to give a yellow solid. The crude material was purified by preparative HPLC using water (0.05% HCl)/acetonitrile on a PhenomenexSynergi C18 150 x 0 mm x 4 µm column to obtain the title compound as a yellow solid (30 mg, 57%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (b.d., J=5.8 Hz, 2H), 9.10 (s, 1H), 8.66 (d, J=8, 3 Hz, 1H), 8.15 (t, J=8.0 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 6.87 (s, 1H), 5.17 (s, 2H), 4.67 (sq., J=7.0 Hz, 2H), 4.32 (t, J=5.8 Hz, 2H), 3.65 (sq., J=6, 8 Hz, 4H), 2.73 (t, J=5.3 Hz, 3H), 1.52 (t, J=7.2 Hz, 3H), 1.16 (t, J=6.9 Hz , 6H). m/z (APCI+) for (C22H28N8O) 442.9 (M+Na)+.

Additional compounds of the present invention were prepared by modifications of the methods exemplified herein. Unless otherwise stated, all compounds having chiral centers were prepared and/or isolated as a single enantiomer having a known relative configuration. Compounds labeled absolute stereochemistry unknown were typically prepared from racemic intermediates and separated into individual enantiomers using a suitable chiral SFC preparative method before being characterized and tested. If the absolute stereochemistry of a pair of enantiomers is unknown, the stereochemistry presented in Table 1 is assigned based on the optical rotation value ([α]D20) and relative biological activity, similar to compounds having known absolute stereochemical configurations.

The selected compounds and their corresponding characterization data are presented in Table. 1 below, where the method used to obtain the compound is indicated in parentheses under the example number:

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Table 1

Etc.

No.

RX-MS stereochemical notes

absolute stereochemistry is known

4-(aminomethyl)-6-(dimethylamino)-2{6-[5-(propan-2-yl)-1/7-pyrazol-4yl]pyridin-2-yl}-2,3-dihydro-1/ 7pyrrolo[3,4-c]pyridin-1-one

6-(dimethylamino)-4[(methylamino)methyl]-2-{6-[(48)-4methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro -1/7pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (M.P.); ¹⁹ F NMR (m.p.);

[M+H]’ rotation of the plane of polarization of light;

Ή NMR (400 MHz, DMSO-sub) δ 9.23 (b.s., 2H), 8.23 (d, >8.0 Hz, 1H), 7.96 (t, >8.2 Hz, 1H), 7.82 (d, >8.0 Hz, 1H), 6.91 (s, 1H), 5.15 4.99 (m, 2H), 4.98 - 4.90 (m, 1H ), 4.61 (t, >8.3 Hz, 1H), 4.40 - 4.30 (m, 2H), 4.17 (dd, >3.8, 8.5 Hz, 1H), 3 .17 (s, 6H), 2.72 (t, >5.4 Hz,

ZN), 1.49 (d, >6.3 Hz, ZN) ¹ H NMR (400 MHz, DMSO-sub) δ 8.48 (b.s., ZN), 8.32 (d, >8, 0 Hz, 1H), 8.16 (s, 1H), 7.89 (t, >7.9 Hz, 1H), 7.49 (d, >7.5 Hz, 1H), 6.89 (s , 1H), 5.14 (s, 2H), 4.24 (b.d., >5.5 Hz, 2H), 3.96 - 3.95 (m, 1H), 3.17 (s, 6H), 1.38 (d, >7.0 Hz, 6H)

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12 (IN) 1 L \ 1 ^N G > / \=L H ₂ N 4-(aminomethyl)-6-(dimethylamino)-2{6-[4-(propan-2-yl)-4/7-1,2,4 -triazol3-yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 13 (IN) 1 Λ / Ν \ \ Ζ-----K / , Ν \—/ ^z^ / \=/ -4' _F h ₂ n ' _f 4-(aminomethyl)-6-(dimethylamino)-2(6 -{4-[(28)-4,4,4-trifluorobutan-2-yl]4/7-1,2,4-triazol-3-yl}pyridin-2-yl)2,3-dihyde rho- 1/7-pyrrolo[3,4c]pyridin-1-one 14 (IN) 1 Λ /Ν\ \ G, A / 1 ,N \—/ ^z^ /Ν=/ ΗΝ\ 2-(6-{4-[(28)-butan-2-yl]-4H-1,2,4triazol-3-yl}pyridin-2-yl)-6(dimethylamino)-4- [(methylamino)methyl]-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 15 (IN) 1 Λ \=/ Λζ ΗΝ 1 \ 4-[(methylamino)methyl]-6- (pyrolidinil-1-yl)-2-(6-{4-[(28)4,4,4-trifluorobutan-2-yl]-4H-1,2,4triazol-3-yl}pyridin-2-yl )-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-1one

393.3 ^1H NMR (400 MHz, DMSO-de) δ 9.07 (s, 1H), 8.65 (d, 4=7.8 Hz, 1H), 8.38 (br.s., ZN), 8 .14 (t, 4=8.0 Hz, 1H), 7.95 (dd, 4=0.6, 7.6 Hz, 1H), 6.91 (s, 1H), 5.54-5, 41 [M+Na] ⁺ 429 ^1H NMR (400 MHz, DMSO-sub) δ 9.27 (b.s., 2H), 9.20 (s, 1H), 8.66 (d, 4=8.3 Hz, 1H), 8 .15 (t, 4=8.0 Hz, 1H), 7.96 (d, 4=7.5 Hz, 1H), 6.95 (s, 1H), 5.48 (quin., 4=6 .8 Hz, 1H), 5.17 (s, 2H), 4.32 (wt„ 4=5.6 Hz, 2H), 3.18 (s, 6H), 2.73 (t, 4 =5.4 Hz, ZN), 1.61 (d, 4=6.8 Hz, 6H) absolute stereochemistry is known [M+Na] ⁺ 443 ^1H NMR (400 MHz, DMSO-sub) δ 9.33 (b.s., 2H), 9.22 (s, 1H), 8.67 (b.d., 4=8.5 Hz, 1H ), 8.15 (b.d. 4=8.2 Hz, 1H), 7.96 (b.d., 4=7.5 Hz, 1H), 6.94 (s, 1H), 5, 34 (b.s., 4=6.3 Hz, 1H), 5.16 (s, 2H), 4.29 (b.s., 2H), 3.18 (s, 6H), 2.78 - 2.68 (m, ZN), 2.06 - 1.86 (m, 2N), 1.60 (b.d., 4 = 6.5 Hz, ZN), 0.83 (b. t„ 4=7.2 Hz, ZN) absolute stereochemistry is known 500.2 ¹ H NMR (400 MHz, DMSO-sub) δ 9.10 (s, 1 H) 8.65 (d, 4=8.31 Hz, 1 H) 8.12 (t, 4=8.01 Hz, 1 N) 7.96 (d, 4=7.46 Hz, 1 N) 6.65 (s, 1 N) 5.87 6.12 (m, 1 N) 5.13 (d, 4=11, 13 Hz, 2 N) 3.92 (s, 2 N) 3.48 (sh. s., 4 N) 2.44 (s, 3 N) 1.94 - 2.07 (m, 4 N) 1 .91 (s, 2 H) 1.68 (d, 4=6.72 Hz, 3 H) absolute stereochemistry known

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405.2

4-(aminomethyl)-2-{6-[4(cyclopropylmethyl)-4/7-1,2,4triazol-3-yl]pyridin-2-yl}-6(dimethylamino)-2,3-dihyde rho- 1 Npyrrolo[3,4-c]pyridin-1-one

475.2

6-(dimethylamino)-4[(methylamino)methyl]-2-(6-{4-[(28)4,4,4-trifluorobutan-2-yl]-4/7-1,2,4triazol-3 -yl}pyridin-2-yl)-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin-1one ¹ H NMR (400 MHz, DMSO-sub) δ 9.04 (s, 1H), 8 .65 (d, 7=7.5 Hz, 1H), 8.55 (sh.s., ZN), 8.18-8.11 (m, 1H), 8.08 - 8.03 (m, 1H), 6.91 (s, 1H), 5.21 (s, 2H), 4.50 (d, 7=7.0 Hz, 2H), 4.23 (b.d., 7=5, 8 Hz, 2H), 3.18 (s, 6H), 1.49 (b.d., 7 = 7.5 Hz, 1H), 0.66 - 0.59 (m, 2H), 0.56 - 0.50 (m, 2H) ^1H NMR (400 MHz, DMSO-sub) δ 9.37 (b.s., 2H), 9.22 (s, 1H), 8.65 (d, 7= 8.5 Hz, 1H), 8.15 (t, 7=8.0 Hz, 1H), 7.95 (d, 7=7.5 Hz, 1H), 6.95 (s, 1H), 6 .01 -5.91 (m, 1H), 5.24 5.11 (m, 2H), 4.27 (wt„ 7 = 5.9 Hz, 2H), 3.35 - 3.23 ( m, 1H), 3.18 (s, 6H), 3.14 - 3.01 (m, 1H), 2.71 (t, 7 = 5.4 Hz, ZN), 1.71 (d, 7 =6.8 Hz,ZN) absolute stereochemistry is known

- 78 044841

18 (IN) 1 jQ /N N\ \G,-----Ъ 1, N \-/ \-1 R 6-(dimethylamino)-4- [(methylamino)methyl]-2-(6-{4-[^)1,1,1-trifluoropentan-3-yl]-4/7-1,2,4triazol-3-yl}pyridin-2-yl )-2,3dihydro-1/7-pyrrolo[3,4-c]pyridine-1- He 489.2 ^1H NMR (400 MHz, DMSO-s( ₆ ) δ 9.33 (b.s., 2H), 9.14 (s, 1H), 8.65 (d, 4=8.3 Hz, 1H) , 8.14 (t, 4=8.0 Hz, 1H), 7.95 (d, 4=7.5 Hz, 1H), 6.95 (s, 1H), 5.99 - 5.87 ( m, 1H), 5.21 5.08 (m, 2H), 4.25 (wt„ 4 = 5.8 Hz, 2H), 3.31 - 3.20 (m, 1H), 3, 18 (s, 6H), 3.13 - 2.98 (m, 1H), 2.72 (t, 4=5.4 Hz, ZN), 2.15 - 1.91 (m, 2H), 0 .82 (t, 4=7.4 Hz, ZN) [a]20D =3.8° (0.02 M, MeOH), >99% une absolute stereochemistry unknown* 19 (IN) 1 P XXV Lx HNp 6-(dimethylamino)-4[(Μβτππ3ΜΗΗθ)Μβτππ]-2-(6-{4-[(3ξ)1,1,1-trifluoropentan-3-yl]-4/7-1,2,4triazol-3 -yl}pyridin-2-yl)-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin-1one [M+Na] ⁺ 489.2 ^1H NMR (400 MHz, DMSO-s( ₆ ) δ 9.32 (b.s., 2H), 9.13 (s, 1H), 8.65 (d, 4=8.5 Hz, 1H) , 8.14 (t, 4=8.0 Hz, 1H), 7.95 (d, 4=7.8 Hz, 1H), 6.95 (s, 1H), 5.98 - 5.87 ( m, 1H), 5.21 5.08 (m, 2H), 4.26 (wt„ 4 = 5.8 Hz, 2H), 3.30 - 3.20 (m, 1H), 3, 18 (s, 6H), 3.12 - 2.99 (m, 1H), 2.72 (t, 4=5.3 Hz, ZN), 2.14 - 1.93 (m, 2H), 0 .82 (t, 4=7.4 Hz, ZN) [a]20D = -20.2° (0.02 M, MeOH), 99% eu absolute stereochemistry unknown*

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392.9

6-(dimethylamino)-2-[6-(4-ethyl-4/71,2,4-triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-2,3-dihydro -1/7pyrrolo[3,4-c]pyridin-1-one

2-{6-[4-(cyclopropylmethyl)-4/7-1,2,4triazol-3-yl]pyridin-2-yl}-6(dimethylamino)-4[(methylamino)methyl]-2,3- Dihydro-1Hpyrrolo[3,4-c]pyridin-1-one ^1H NMR (400 MHz, DMSO-cO δ 9.33 (b.d., 7=5.5 Hz, 2H), 9.08 (s , 1H), 8.66 (d, 7=8.3 Hz, 1H), 8.14 (t, 7=8.0 Hz, 1H), 8.01 (d, 7=7.5 Hz, 1H ), 6.93 (s, 1H), 5.17 (s, 2H), 4.67 (sq., 7 = 7.0 Hz, 2H), 4.34 (w. t„ 7 = 5.6 Hz, 2H), 3.17 (s, 6H), 2.72 (t, 7=5.3 Hz, ZN), 1.51 (t, 7=7.2 Hz,

ZH) ^1H NMR (400 MHz, DMSO-s/b) δ 9.33 (b.s., 2H), 9.01 (s, 1H), 8.65 (d, 7=8.3 Hz, 1H), 8.17 - 8.11 (m, 1H), 8.05 (d, 7 = 7.3 Hz, 1H), 6.94 _[M + _Na] ^{+ (C} ' ^{1 H)} ' ⁵ ' ² ° ^(C ' ^2H) ' ⁴ ' ^{49 (D} ' ^{J = 7} ' ³ 441 Hz, 2H), 4.32 (sh. t., 7 = 5.8 Hz, 2H), 3.18 (s, 6H), 2.73 (t, 7=5.4 Hz, ZN), 1.46 (b.d., 7=7.3 Hz, 1H), 0.65 0.58 (m, 2H), 0.55-0.48 (m, 2H)

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6-(dimethylamino)-2-{5-fluoro-6-[5(propan-2-yl)-1 /7-pyrazol-4yl]pyridin-2-yl}-4[(methylamino)methyl]-2, 3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one

4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro -1/7pyrrolo[3,4-c]pyridin-1-one

4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro -1/7pyrrolo[3,4-c]pyridin-1-one ^1H NMR (400 MHz, DMSO-sub) δ 9.12 (b.d., 7=3.8 Hz, 2H), 8.38 (dd, 7=3.3, 9.0 Hz, 1H), 8.02 - 7.96 (m, 1H), 7.89 (t, 7=9.7 Hz, 1H), 6.92 ( s, 1H), 5.10 (s, 2H), 4.32 (wt„ 7 = 5.6 Hz, 2H), 3.87 - 3.77 (m, 1H), 3.17 (s , 6H), 2.79 - 2.70 (m, ZN), 1.37 (d, 7=7.0 Hz, 6H) ¹ H NMR (400 MHz, Methanol-^) δ 1.79 - 1, 86 (d, J=Q,7 Hz, 6H), 2.93 2.98 (s, ZN), 4.65 - 4.70 (s, 2H), 5.38 - 5.43 (s, 2H ), 5.77 - 5.91 (p, J=Q.7 Hz, 1H), 7.89 - 7.95 (d, 7=5.0 Hz, 1H), 8.03 - 8.10 ( dd, J=7.6, 0.8 Hz, 1H), 8.19 - 8.28 (dd, J=8.6, 7.6 Hz, 1H), 8.83-8.98 (m, 2H), 10.11 10.17 (s, 1H).

¹ H NMR (600 MHz, DMSO-sub) δ 8.93 (s, 1 H) 8.61 (dd, 7=8.25, 2.38 Hz, 1 H) 8.07 (td, 7=7 .84, 2.48 Hz, 1 N) 7.95 (d, 7=7.52 Hz, 1 N) 6.72 (b.s., 1 N) 6.64 (b.s., 1 N ) 5.555.62 (m, 1 N) 5.14 (sh.s., 2 N) 3.79 (s, 2 N) 2.83 (d, 7=3.67 Hz, 3 N) 2.35 (s, 3 N) 1.59 (d, 7 = 6.60 Hz, 6 N)

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known

4-(aminomethyl)-6-cyclopropyl-2-{6[(48)-4-methyl-2-oxo-1,3-oxazolidin3-yl]pyridin-2-yl}-2,3-dihydro-1/ 7pyrrolo[3,4-c]pyridin-1-one

6-[(15,43)-7-azabicyclo[2,2,1 ]hept-7yl]-4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/ 7-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one

¹ H NMR (600 MHz, DMSO-sub) δ 8.86 (d, 4=1.47 Hz, 1 H) 8.53 (d, 4=8.25 Hz, 1 H) 8.02 (t, 4=7.98 Hz, 1 N) 7.88 (dd, 4=7.52, 0.73 Hz, 1 N) 7.01 (s, 1 N) 5.46 (dq, 4=12.75 , 6.45 Hz, 1 N) 5.10 (s, 2 N) 4.56 (sh. s., 2 N) 3.85 (sh. s., 2 N) 2.36 (sh. s. , 3 N) 1.60 (d, 4=7.70 Hz, 4 N) 1.51 (d, 4=6.60 Hz, 6 N) 1.37-1.40

H) ¹ H NMR (400 MHz, DMSO-sub) δ 8.23 (d, 4=7.83 Hz, 1 H) 7.96 (t, 4=8.07 Hz, 1 H) 7.83 ( d, 4=7.83 Hz, 1 N) 7.71 (s, 1 N) 6.58 (sh. s., 1 N) 5.19 - 5.27 (m, 1 N) 5.07 - 5.15 (m, 1 N) 4.91 - 4.98 (m, 1 N) 4.60 (t, 4=8.19 Hz, 1 N) 4.29 - 4.39 (m, 2 N )

4.16 (dd, 4=8.44, 3.79 Hz, 1 N) 3.51 (s, 1 N) 2.28 - 2.37 (m, 1 N) 1.49 (d, 4= 6.36 Hz, 3 N) 1.11 - 1.22 (m, 2 N) 1.03 (dd, 4 = 7.83, 3.18 Hz, 2 N) absolute stereochemistry

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27 (C) - ί L Q^QJ HN\ 6-[(2/?,55)-2,5-dimethylpyrolidinyl1-yl]-4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1, 2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 28 (WITH) to Λ XX-TxJ Yj pH? n^=Z\ n\ 6-[(2/?,4/?)-2,4-dimethylazetidin-1yl]-4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7- 1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 29 (G) 1 Λ \ ^Ν Γ > -\ ^Ν= \ \ ΗΝ \ 6-tert-butyl-4-[(methylamino)methyl]2-{6-[4-(propan-2-yl)-4H-1,2, 4triazol-3-yl]pyridin-2-yl}-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin-1one

461.2 ¹ H NMR (400 MHz, DMSO-sub) δ 8.94 (s, 1 H) 8.64 (d, 4=8.31 Hz, 1 H) 8.10 (t, 4=8.01 Hz, 1 N) 7.96 (d, 4=7.58 Hz, 1 N) 6.61 (s, 1 N) 5.59 (s1quin., 4=13.31, 6.76, 6.76, 6 .76, 6.76 Hz, 1 N) 5.17 (s, 2 N) 4.01 4.19 (m, 2 N) 3.83 (s, 2 N) 2.37 (s, 3 N) 2.02 - 2.14 (m, 2 N) 1.67-1.84 (m, 2 N) 1.59 (d, 4=6.60 Hz, 6 N) 1.31 (d, 4= 5.99 Hz, 6 N) 447.2 ^1H NMR (400 MHz, DMSO-sub) δ 8.95 (s, 1H), 8.62 (d, 4=8.44 Hz, 1H), 8.06-8.15 (m, 1H), 7.95 (d, 4=7.58 Hz, 1H), 6.56 (s, 1H), 5.53 (td, 4=6.51, 13.39 Hz, 1H), 5.095.22 (m , 2H), 4.43-4.55 (m, 2H), 3.96 (s, 2H), 2.47 (s, ZN), 2.10 (wt„ 4 = 6.48 Hz, 2H), 1.58 (d, 4=6.60 Hz, 6H), 1.39 (d, 4=6.11 Hz, 6H) absolute stereochemistry known 420.0 ¹ H NMR (600 MHz, DMSO-cO δ 8.95 (s, 1 H) 8.62 (d, 4 = 8.44 Hz, 1 H) 8.06 - 8.19 (m, 1 H) 7 .97 (d, 4=7.52 Hz, 1 N) 7.63 (s, 1 N) 5.59 (dt, 4=13.34, 6.63 Hz, 1 N) 5.30 (s, 2 N) 3.99 (s, 2 N) 2.38 (s, 3 N) 1.60 (d, 4=6.79 Hz, 6 N) 1.39 (s, 9 N)

- 83 044841

30 (C) ΐ Λ \ Wi ^Ν Г > \ / ^/ ^Ν ~^ ^Ν= \ \ ΗΝ \ 4-[(methylamino)methyl]-6-(propan-2yl)-2-{6-[4-(propan-2- yl)-4/7-1,2,4triazol-3-yl]pyridin-2-yl}-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin-1one 31 (C) ι Λ IX__/ A η ₂ ν 4-(aminomethyl)-6-cyclopropyl-2-{6[4-(propan-2-yl)-4/7-1,2,4-triazol-Zyl]pyridine-2 -yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 32 (D) o fl Ί o k Λ A l ^1\Г Х'\ \ X / \ 7 / ^N= \ h ₂ n 4-(aminomethyl)-6-(dimethylamino)-2{6-[(48)-4- methyl-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin-1-one

406.0 ¹ H NMR (600 MHz, DMSO-s( ₆ ) δ 8.94 (s, 1 H) 8.61 (d, 4=8.25 Hz, 1 H) 8.09 (t, 4=7.98 Hz, 1 N) 7.97 (d, 4=7.52 Hz, 1 N) 7.54 (s, 1 N) 5.59 (dt, 4=13.20, 6.60 Hz, 1 N) 5.30 (s, 2 N) 3.98 (s, 2 N) 3.17 (dt, 4=13.62, 6.85 Hz, 2 N) 2.37 (s, 3 N) 1.60 (d, 4=6.60 Hz, 6 N) 1.30 (d, 4=6.79 Hz, 6 N) 390.1 ¹ H NMR (600 MHz, DMSO-<4 ₆ ) δ wt. 8.89 - 8.97 (m, 1 N) 8.56 - 8.64 (m, 1 N) 8.05 - 8.14 (m, 1 N) 7.90 7.97 (m, 1 N ) 7.52 - 7.62 (m, 1 N) 5.52 (dt, 4=13.34, 6.63 Hz, 1 N) 5.28 (sh.s., 2 N) 4.08 ( w.s., 2 N) 3.17 (s., 2 N) 2.30 (w.s., 1 N) 1.521.61 (m, 6 N) 1.03 - 1.09 (m, 2 N ) 0.94-1.03 (m, 2 N) 382.9 ¹ H NMR (400 MHz, DMSO-<4 ₆ ) δ 8.43 (b.s., ZN), 8.23 (d, 4=8.0 Hz, 1H), 7.96 (t, 4=8 ,2 Hz, 1H), 7.82 (d, 4=8.0 Hz, 1H), 6.89 (s, 1H), 5.17 4.99 (m, 2H), 4.99 - 4, 90 (m, 1H), 4.60 (t, 4=8.3 Hz, 1H), 4.30 - 4.20 (m, 2H), 4.16 (dd, 4=3.6, 8, 4 Hz, 1H), 3.17 (s, 6H), 1.49 (d, 4=6.3 Hz, ZN) absolute stereochemistry known

- 84 044841

33 (Μ) kad Ν--—--- \/ \ / Ν ( ΗΝ \ 6-(azetidin-1-yl)-4- [(methylamino)methyl]-2-{6-[(45)-4methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3, 4-c]pyridin-1-one 34 (WITH) 1 P 1 / Ν X A^/Aj .^-7 η ₂ ν 4-(aminomethyl)-6-[(2R,48)-2,4dimethylazetidin-1-yl]-2-{6-[4(propan- 2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 35 (1) ΐ Jd / Ν Ν N^ D \ W / \=l a h ₂ n 4-(aminomethyl)-6-(dimethylamino)-2{6-[5-(propan-2-yl)-1 /7-1 ,2,3-triazol1-yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

[M+Na]+ 431.2 ^1H NMR (400 MHz, DMSO-de) δ 8.20 (d, 7=8.03 Hz, 1H), 7.92 (t, 7=8.03 Hz, 1H), 7.79 (d, 7=8.28 Hz, 1H), 6.52 (s, 1H), 4.96-5.16 (m, 2H), 4.82-4.92 (m, 1H), 4.59 (t , 7=8.28 Hz, 1H), 4.15 (dd, 7=3.76, 8.53 Hz, 1H), 4.00 (t, 7=7.40 Hz, 4H), 3.86 (d, 7=1.25 Hz, 2H), 2.40 (s, ZN), 2.29-2.37 (m, 2H), 1.49 (d, 7=6.27 Hz, ZN) absolute stereochemistry is known 433.2 ¹ H NMR (700 MHz, DMSO-de) δ 8.90 - 8.96 (m, 1 H) 8.60 (d, 7=7.96 Hz, 1 H) 8.08 (t, 7=7 .53 Hz, 1 N) 7.91 - 7.97 (m, 1 N) 6.49 (s, 1 N) 5.54 (quin., 7 = 6.67 Hz, 1 N) 5.19 ( w.s., 2 N) 4.06 - 4.14 (m, 2 N) 3.86 (w.s., 2 N) 1.57 (d, 7=6.45 Hz, 6 N) 1 .49 (d, 7=6.24 Hz, 6 N) 1.33 (s, 4 N) 393.2 ¹ H NMR (400 MHz, DMSO-de) δ 8.67 (d, 7=8.59 Hz, 1 H) 8.32 (b.s., 3 H) 8.23 (t, 7=8, 00 Hz, 1 N) 7.84 (s, 1 N) 7.72 (d, 7=7.41 Hz, 1 N) 6.90 (s, 1 N) 5.07 (s, 2 N) 4 .27 (s, 2 N) 3.66-3.78 (m, 1 N) 3.16 (s, 6 N) 2.54 (s, 1 N) 1.30 (d, 7 = 6.63 GC, 6 N)

- 85 044841

36(J) kOu \ Hj e/ / \ τ' / n=< h ₂ n 4-(aminomethyl)-6-tert-butyl-2-{6[(48)-4-methyl-2-oxo-1,3-oxazolidine3 -yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 37 (Η) U-r /\/ ΗΝ\ 2-{6-[(4R)-4-(difluoromethyl)-2-oxo- 1,3-oxazolidin-3-yl]pyridin-2-yl}- 6-(dimethylamino)-4- [(methylamino)methyl]-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 38 (C) 1 Λ / / g ^Ν > η ₂ ν 4-(aminomethyl)-6-(diethylamino)-2-{6[4-(propan-2-yl)-4/7-1,2,4-triazol-3yl ]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

396.4 ¹ H NMR (400 MHz, DMSO-s/ ₆ ) δ 8.16 (d, 4=7.95 Hz, 1 H) 7.88 (t, 4=8.13 Hz, 1 H) 7.74 ( d, 4=8.07 Hz, 1 N) 7.53 (s, 1 N) 5.69 (s, 1 N) 5.05 - 5.34 (m, 2 N) 4.75 - 5.00 (m, 1 N) 4.52 (t, 4=8.31 Hz, 1 N) 4.07 (dd, 4=8.38, 3.85 Hz, 1 N) 3.95 (sh.s. , 2 H) 1.42 (d, 4=6.11 Hz, 3 H) 1.32 (s, 9 H) absolute stereochemistry known 433.5 ^1H NMR (600 MHz, DMSO-sub) δ 8.96 (s, 1H), 8.28 (d, 4=8.0 Hz, 1H), 8.01 (t, 4=8.1 Hz, 1H), 7.87 (d, 4=8.1 Hz, 1H), 6.92 (s, 1H), 6.78 (t, 4=54 Hz, 1H), 5.36 - 5.25 ( m, 1H), 5.07 (sq., 4=17.0 Hz, 2H), 4.70 4.60 (m, 2H), 4.36 (s, 2H), 3.17 (s, 6H ), 2.55 (s, ZN) absolute stereochemistry is known [M+Na] ⁺ 442.9 ¹ H NMR (400 MHz, DMSO-cO δ 9.28 (b.d., 4=5.8 Hz, 2H), 9.10 (s, 1H), 8.66 (d, 4=8.3 Hz, 1H), 8.15 (t, 4=8.0 Hz, 1H), 8.02 (d, 4=7.5 Hz, 1H), 6.87 (s, 1H), 5.17 ( s, 2H), 4.67 (sq., 4=7.0 Hz, 2H), 4.32 (t, 4=5.8 Hz, 2H), 3.65 (sq., 4=6.8 Hz, 4H), 2.73 (t, 4=5.3 Hz, ZN), 1.52 (t, 4=7.2 Hz, ZN), 1.16 (t, 4=6.9 Hz, 6H)

- 86 044841

He

6-tert-butyl-4-[(methylamino)methyl]2-{6-[(45)-4-methyl-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}-2,3dihydro -1/7-pyrrolo[3,4-c]pyridine-1-

6-cyclopropyl-4[(methylamino)methyl]-2-{6-[(48)-4methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro-1 /7pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (600 MHz, DMSO-c/ ₆ ) δ wt. 8.14 (d, 4=8.07 Hz, 1 N) 7.86 (t, 4=8.07 Hz, 1 N) 7.74 (d, 4=8.25 Hz, 1 N) 7, 54 (s, 1 N) 5.03 - 5.27 (m, 2 N) 4.73 - 4.93 (m, 1 N) 4.53 (t, 4=8.25 Hz, 1 N) 4 .08 (dd, 4=8.44, 3.85 Hz, 1 N) 3.90 (s, 2 N) 2.32 (s, 3 N) 1.44 (d, 4=6.24 Hz, 3 H)1.31 (s, 9 H) absolute stereochemistry known ¹ H NMR (400 MHz, DMSO-s/ ₆ ) δ 8.22 (d, 4=7.95 Hz, 1H), 7.94 (t , 4=8.13 Hz, 1H), 7.81 (d, 4=8.07 Hz, 1H), 7.56 (s, 1H), 5.07-5.28 (m, 2H), 4 ,84-4.97 (m,1H), 4.59 (t, 4=8.31 Hz, 1H), 4.15 (dd, 4=3.79, 8.44 Hz, 1H), 3, 85-3.95 (m, 2H), 2.35 (s, ZN), 2.25-2.31 (m, 1H), 1.50 (d, 4=6.24 Hz, ZN), 0 .95-1.05 (m, 4H) absolute stereochemistry known

- 87 044841 (Ν)

382.1

4-(aminomethyl)-2-{6-[(48)-4-methyl-2oxo-1,3-oxazolidin-3-yl]pyridin-2yl}-6-(propan-2-yl)-2,3 -dihydro-1/7pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-sub) δ 8.66 (b.s., 3N), 8.23 (d, 7= 7.9 Hz, 1H), 7.96 (wt„ 7=8.1 Hz, 1H), 7.83 (d, 7=8.1 Hz, 1H), 7.68 (s, 1H) , 5.30 (b.d., 7=18.3 Hz, 1H), 5.19 (b.d., 7=18.3 Hz, 1H), 4.98 (b.s., 1H) , 4.60 (w. t„ 7 = 8.1 Hz, 1H), 4.45 - 4.31 (m, 2H), 4.16 (W.D.S1, 7 = 3.2, 7, 9 Hz, 1H), 3.30 3.14 (m, 1H), 1.49 (b.d., 7=6.0 Hz, ZN), 1.34 (d., 7=6.8 Hz, 6H) absolute stereochemistry is known (M)

394.4

4-(aminomethyl)-6-(1 methylcyclopropyl)-2-{6-[(48)-4methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro- 1/7pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (600 MHz, DMSO-sub) δ 8.31 (s., 2H), 8.23 (d, 7=8.1 Hz, 1H), 7.97 (t, 7=8.1 Hz, 1H), 7.83 (d, 7=8.3 Hz, 1H), 7.66 (s, 1H), 5.28 5.09 (m, 2H), 5.00 - 4.92 (m, 1H), 4.60 (t, 7 = 8.3 Hz, 1H), 4.44 - 4.34 (m, 2H), 4, 17 (dd, 7=3.9, 8.4 Hz, 1H), 1.59 (s, ZN), 1.50 (d, 7=6.2 Hz, ZN), 1.48 - 1.43 (m, 2H), 0.91 (d, 7=2.9 Hz, 2H) absolute stereochemistry known

-88044841

43 (Μ) ι. ATX/ ^Ν ^\ Η ₂ Ν 4-(aminomethyl)-6-[(2R,4R)-2,4dimethylazetidin-1-yl]-2-{6-[(48)-4methyl-2-oxo-1, 3-oxazolidin-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 44 (Μ) o Ιι η o ι 11 ι X'\ _o ΟΆ/- ⁷ g-X ^N= \ h ₂ n 4-(aminomethyl)-6-(azetidin-1-yl)-2{6-[(48)-4 -methyl-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-1one

[M+Na] ⁺ 444.8 ^1H NMR (400 MHz, DMSO-sub) δ 8.21 (d, 7=8.1 Hz, 1H), 7.93 (t, 7=8.1 Hz, 1H), 7.80 (d, 7=8.1 Hz, 1H), 6.48 (s, 1H), 5.16 - 5.01 (m, 2H), 4.98 - 4.88 (m, 1H), 4.59 (t , 7=8.3 Hz, 1H), 4.52 - 4.42 (m, 2H), 4.14 (dd, 7=3.8, 8.4 Hz, 1H), 3.84 (s, 2H), 2.09 (t, 7=6.5 Hz, 2H), 1.48 (d, 7=6.2 Hz, ZN), 1.38 (d, 7=6.1 Hz, 6H) absolute stereochemistry is known 394.9 ^1H NMR (400 MHz, DMSO-sub) δ 8.22 (d, 7=7.7 Hz, 1H), 7.93 (t, 7=8.1 Hz, 1H), 7.80 (d, 7=7.7 Hz, 1H), 6.54 (s, 1H), 5.20 - 5.02 (m, 2H), 4.93 (ddd, 7=3.8, 6.2, 8, 1 Hz, 1H), 4.59 (t, 7=8.3 Hz, 1H), 4.14 (dd, 7=3.8, 8.4 Hz, 1H), 4.02 (t, 7= 7.3 Hz, 4H), 3.90 (s, 2H), 2.40 2.34 (m, 2H), 1.48 (d, 7=6.1 Hz, ZH) absolute stereochemistry known

- 89 044841

45 (Η) kХХА \ Ly° / \ ' ^Ν ^\ ΗΝ 6-(dimethylamino)-2-{6-[(4R)-4(fluoromethyl)-2-oxo-1,3-oxazolidin3-yl]pyridin-2-yl} -4-[(methylamino)methyl]-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one 415.3 ^1H NMR (400 MHz, DMSO-sub) δ 8.25 (d, 7=8.0 Hz, 1H), 7.98 (t, 7=8.1 Hz, 1H), 7.89 (d, 7=8.2 Hz, 1H), 6.85 (s, 1H), 5.06 (dt, 7=25.4, 13.9 Hz, 4H), 4.80 (dd, 7=45.7 , 10.1 Hz, 1H), 4.65 (t, 7=8.9 Hz, 1H), 4.53 (s, 1H), 4.12 (s, 2H), 3.14 (s, 6H ), 2.58 (s, ZN). absolute stereochemistry is known 46 (WITH) ΐ Λ / Ν Ν \ \ L---< I 1 ,Ν A/ ^λ \ ί ΗΝ \ 6-(dimethylamino)-4-[(methylamino)methyl]-2-[6-(4-propyl4/7- 1,2,4-triazol-3-yl)pyridin-2-yl]2,3-dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one 406.9 ^1H NMR (400 MHz, DMSO-sub) δ 8.75 (s, 1H), 8.63 (d, 7=8.3 Hz, 1H), 8.12 - 8.06 (m, 1H), 8.03 - 7.99 (m, 1H), 6.81 (s, 1H), 5.15 (s, 2H), 4.58 (t, 7=7.2 Hz, 2H), 3.89 (s, 2H), 3.12 (s, 6H), 2.41 (s, ZN), 1.94 1.83 (m, 2H), 0.94 (t, 7=7.4 Hz, ZN )

- 90 044841

6-methyl-4-[(methylamino)methyl]-2-{6[4-(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-2 ,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

[M+Na]'

400.2

6-[ethyl(methyl)amino]-4[(methylamino)methyl]-2-{6-[4-(propan2-yl)-4H-1,2,4-triazol-3-yl]pyridin2-yl} -2,3-dihydro-1/7-pyrrolo[3,4c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-de) δ 9.56 (b.s., 2H), 9.41 ( s, 1H), 8.68 (d, 4=7.82 Hz, 1H), 8.18 (t, 4=8.07 Hz, 1H), 7.99 (d, 4=7.09 Hz, 1H), 7.79 (s, 1H), 5.51 (td, 4=6.71, 13.36 Hz, 1H), 5.39 (s, 2H), 4.43 (b.s., 2H), 2.63-2.76 (m, 6H), 1.64 (d, 4=6.72 Hz, 6H) ¹ H NMR (400 MHz, DMSO-de) δ 8.95 (s, 1 N) 8.63 (d, 4=8.31 Hz, 1 N) 8.09 (t, 4=8.01 Hz, 1 N) 7.96 (d, 4=7.34 Hz, 1 N) 6.75 (s, 1 N) 5.59 (quin., 4 = 6.76 Hz, 1 N) 5.17 (s, 2 N) 3.82 (s, 2 N) 3.55 - 3, 70 (m, 2 N) 3.05 (s, 3 N) 2.36 (s, 3 N) 1.59 (d, 4=6.72 Hz, 6 N) 1.10 (t, 4=6 .97 Hz, 3 N)

h ₂ n

6-amino-4-[(methylamino)methyl]-2-{6[4-(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-2 ,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

4-[(methylamino)methyl]-6-(1 methylcyclopropyl)-2-{6-[(48)-4methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-2,3 -dihydro-1Hpyrrolo[3,4-c]pyridin-1-one

^1H NMR (600 MHz, DMSO-de) δ 8.89 (s, 1H), 8.24 (d, 4=8.1 Hz, 1H), 7.98 (t, 4=8.1 Hz, 1H), 7.84 (d, 4=8.1 Hz, 1H), 7.69 (s, 1H), 5.25 5.07 (m, 2H), 4.99 - 4.89 (m, 1H), 4.61 (t, 4=8.3 Hz, 1H), 4.51 (sh.s., 2H), 4.17 (dd, 4=3.9, 8.3 Hz, 1H) , 2.57 (s, ZN), 1.59 (s, ZN), 1.50 (d, 4=6.2 Hz, ZN), 1.43 (d, 4=3.9 Hz, 2N) , 0.93 (d, 4=2.8 Hz, 2H) absolute stereochemistry known ¹ H NMR (600 MHz, DMSO-de) δ 8.40 - 8.49 (m, 1 H) 8.05 - 8, 16 (m, 1 N) 7.57 - 7.67 (m, 1 N) 7.42 - 7.49 (m, 1 N) 6.79 (w.s., 1 N) 6.71 (w s., 1 N) 6.62 (sh. s., 1 N) 6.40 (s, 1 N) 4.89 - 4.99 (m, 1 N) 4.51 - 4.67 (m , 2 N) 3.77 (s, 2 N) 2.24 (s, 3 N) 1.04-1.15 (m, 6 N)

- 91 044841 (θ)

502.3

6-tert-butyl-4-[(methylamino)methyl]2-(6-{4-[(3ξ)-1,1,1-trifluoropentane-Zyl]-4/-/-1,2,4-triazole -3-yl}pyridin-2yl)-2,3-dihyde rho-1 /7-pyrrolo[3,4c]pyridin-1-one

4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-6-(trifluoromethyl) 2,3-dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one ^1H NMR (400 MHz, Methanol-^) δ 8.89 (s, 1H), 8.70 (dd, 2 =0.67, 8.50 Hz, 1H), 8.00 (dd, 2=7.70, 8.44 Hz, 1H), 7.85 (dd, 2=0.79, 7.64 Hz, 1H), 7.69 (s, 1H), 5.84-6.03 (m, 1H), 5.07-5.29 (m, 2H), 3.95 (s, 2H), 2.95 -3.11 (m, 1H), 2.71-2.93 (m, 1H), 2.47 (s, ZN), 1.86-2.17 (m, 2H), 1.36 (s , 9N), 0.80-0.90 (m, ZN)

[a]D22 = -6.6°, (0.2 M, MeOH), >99% e.n.

absolute stereochemistry unknown* ¹ H NMR (400 MHz, DMSO-s/b) δ 9.22 (b.s., 2 H) 8.96 (s, 1 H) 8.63 (dd, 2=8.31 , 0.73 Hz, 1 N) 8.36 (s, 1 N) 8.18 (dd, 2=8.31, 7.58 Hz, 1 N) (S)

447

6-[(2R,48)-2,4-dimethylazetidin-1yl]-4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1,2, 4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/-/pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-s/b) δ 8.95 (s, 1 N) 8.56 - 8.70 (m, 1 N) 8.06 - 8.15 (m, 1 N) 7.92 - 8.00 (m, 1 N) 6, 53 (s, 1 N) 5.49 - 5.70 (m, 1 N) 5.19 (s, 2 N) 4.01 -4.18 (m, 2 N) 3.82 (s, 2 N ) 2.61-2.68 (m, 1 N) 2.35 (s, 3 N) 1.61 - 1.70 (m, 1 N) 1.59 (d, 2=6.72 Hz, 6 H) 1.50 (d, 2=6.11 Hz, 6H) * The use of or 1 in the structure and ξ in the name indicates a chiral center that has been separated into two separate enantiomers, but the specific enantiomer has not been confirmed; the structure shows a solid or dotted wedge, but the real enantiomer may be a different enantiomer.

Example 46: 6-(dimethylamino)-4-[(methylamino)methyl]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2-yl]-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

-92044841

Step 1: tert-butyl ({6-(dimethylamino)-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2yl]-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate

Mixture of Intermediate 3 (1.33 g, 4.15 mmol), Intermediate 13 (1.16 g, 4.36 mmol), Pd ₂ (dba) ₃ (380 mg, 0.415 mmol), Xantphos (480 g , 0.830 mmol), and K3PO4 (2.64 g, 12.5 mmol) in 1,4-dioxane (46 ml) were degassed with N2 for 5 min and stirred at 85°C for 16 h. The reaction mixture was analyzed using X-ray MS analysis, which shows the consumption of the output substance. The mixture was cooled to room temperature, filtered through a pad of Celite® and concentrated in vacuo. The residue was suspended in EtOAc (15 ml) for 10 min and the solids were collected by filtration. The filter cake was washed with EtOAc (4x) and then dried in a vacuum. The residue was purified using flash chromatography (40 g SiO ₂ , 0-100% EtOAc/heptane then 10% MeOH/EtOAc) to give a light yellow solid. The material was dissolved in 1:9 EtOH/DCM and treated with Ultra-pure Si-Thio SiO ₂ (1.59 g). The mixture was stirred for 2 hours and filtered. The filter cake was washed with 1:9 EtOH/DCM and the combined filtrate was concentrated in vacuo. The residue was dissolved in 1:9 EtOH/DCM and treated with Ultra-pure Si-Thio SiO ₂ (1.32 g). The mixture was stirred for 3 hours and then filtered. The filter cake was washed with 1:9 EtOH/DCM and the combined filtrate was concentrated. The residue was dissolved in 1:9 EtOH and treated with Ultra-pure Si-Thio SiO ₂ (1.22 g). The mixture was stirred for 16 hours and then filtered. The filter cake was washed with 1:9 EtOH/DCM. The combined filtrate was concentrated to dryness by removing tert-butyl ({6(dimethylamino)-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl] -2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (2.08 g, 95% yield) as a light yellow solid.

1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.09 (t, J=8.0 Hz, 1H ), 7.97 (d, J=7.6 Hz, 1H), 6.82 (s, 1H), 5.05 (d, J=11.7 Hz, 2H), 4.56 (s, 2H ), 4.52-4.46 (m, 2H), 3.09 (s, 6H), 2.92 (s, 3H), 1.88-1.76 (m, 2H), 1.40- 1.19 (m, 9H), 0.87 (t, J=7.4 Hz, 3H); X-ray MS m/z (ESI+) for (C ₂₆ H ₃₄ N ₈ O ₃ ), 507.4 (M+H) ⁺ .

Alternative step 1: tert-butyl ({6-(dimethylamino)-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol3-yl)pyridin-2-yl]-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate.

To a solution of tert-butyl {[6-(dimethylamino)-4-(dimethylcarbamoyl)-3-formylpyridin-2yl]methyl}methylcarbamate (Ze) (500 mg, 1.37 mmol) and 6-(4-propyl-4H- 1,2,4-triazol-3-yl)pyridin-2amine (Intermediate 16) (293 mg, 1.44 mmol) in MeOH (9.1 mL) was added with decaborane (62.0 mg, 0.508 mmol). The mixture was stirred at room temperature for 16 hours and then a solution of NaOMe (25% in MeOH, 5.02 mL, 22.0 mmol) was added. The mixture was stirred at 65°C for 2 hours, obtaining a yellow suspension. Additional NaOMe (0.5M in MeOH, 13.7 mL, 6.86 mmol) was added and the mixture was stirred at 65°C for 3 hours. The reaction mixture was cooled to room temperature and the yellow solids were collected by filtration. The filtered cake was washed with H2O (2x3 ml) and dried in vacuum to obtain tert-butyl ({6-(dimethylamino)-1-oxo-2-[6-(4-propyl4H-1,2,4-triazol-3-yl )pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]niridin-4yl}methyl)methylcarbamate (518 mg, 75% yield) as a light yellow solid. RX-MS m/z (ESI+) for (C ₂₆ H ₃₄ N ₈ O ₃ ), 507.5 (M+H)+.

Step 2: 6-(dimethylamino)-4-[(methylamino)methyl]-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin2-yl]-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

To a suspension of tert-butyl ({6-(dimethylamino)-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2-yl]-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (1.96 g, 3.87 mmol) in MeOH (20 ml) slowly added a solution of HCl (4.0 M in 1. 4-dioxane, 19.3 ml, 77.4 mmol) at 0°C. The mixture was stirred for 3 hours at 0°C and then allowed to warm slowly to room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness. The solids were dissolved in 1:9 MeOH/DCM (80 ml), cooled to 0°C, and

- 93 044841 was then stirred with saturated aqueous Na2CO ₃ (25 ml) for 20 minutes. The mixture was separated. The aqueous layer was extracted with 1:19 MeOH/DCM (3x50 ml). The combined organic layers were washed with H2O (2x30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The solids were suspended in EtOAc at 40°C for 40 minutes. Solids were collected by filtration. The filter cake was washed with EtOAc, and then dried for 16 hours in a vacuum oven at 30°C to obtain 6-(dimethylamino)-4-[(methylamino)methyl]-2-[6-(4-propyl-4H-1, 2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (1.42 g, 90% yield) as a yellow solid substances.

1H NMR (400 MHz, DMSO-b6) δ 8.73 (s, 1H), 8.62 (dd, J=8.4, 1.0 Hz, 1H), 8.11-8.04 (m, 1H), 8.00 (dd, J=7.7, 1.0 Hz, 1H), 6.78 (s, 1H), 5.14 (s, 2H), 4.57 (dd, J=7 ,9, 6.5 Hz, 2H), 3.80 (s, 2H), 3.09 (s, 6H), 2.35 (s, 3H), 1.88 (d, J=7.4 Hz , 2H), 0.93 (t, J=7.4 Hz, 3H); X-ray MS m/z (ESI+) for (C21H26N8O), 407.3 (M+H) ⁺ .

Example 55: 4-[(methylamino)methyl]-6-[(2R)-2-methylpyrrolidinyl-1-yl]-2-[6-(4-propyl-4H-1,2,4triazol-3-yl) pyridin-2-yl]-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro -1 H-pyrrolo[3,4-c]pyridin-4-yl} methyl)methylcarbamate o

I gb o^o

To a solution of intermediate 2 (430 mg, 1.38 mmol), intermediate 13 (368 mg, 1.38 mmol), K ₂ CO ₃ (419 mg, 3.03 mmol), and N,N-dimethylethylenediamine (60 .7 mg, 0.690 mmol) to MeCN (10.0 ml) was added CuI (65.7 mg, 0.345 mmol). The mixture was bubbled with N2 for 5 min and then stirred at 120°C for 1.5 h under microwave atmosphere. X-ray MS analysis showed consumption of the starting material. The reaction mixture was cooled to room temperature and H ₂ O (10 ml) was added. The mixture was stirred for 15 minutes and then filtered. The filtered cake was washed with H2O (3x3 ml) and dried in a vacuum. The residue was purified using flash chromatography (12 g SiO ₂ , EtOAc) to give tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H1,2,4-triazol-3- yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (430 mg, 63% yield) as a yellow glassy substance.

^1H NMR (400 MHz, chloroform-d) δ 8.68 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 8.02- 7.92 (m, 1H), 7.78 (s, 1H), 5.14 (s, 2H), 4.76-4.50 (m, 4H), 2.97 (s, 3H), 1 .97-1.80 (m, 2H), 1.37 (s, 9H), 0.94 (s, 3H); m/z (ESI+) for (C24H28QN7O3), 498.2 (M+H) ⁺ .

Step 2: tert-butyl methyl({6-[(2R)-2-methylpyrolidinyl-1-yl]-1-oxo-2-[6-(4-nropyl-4H-1,2,4triazol-3-yl )pyridin-2-yl]-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate

A solution of tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro-1H -pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (200 mg, 0.402 mmol) and Cs ₂ CO ₃ (720 mg, 2.21 mmol) in 1,4-dioxane (5.0 ml ) were bubbled with argon for 3 min, and RuPhos Pd G3 (33.6 mg, 0.0402 mmol) was added. The mixture was bubbled with argon for 3 min and (2R)-2methylpyrrolidinyl (171 mg, 2.01 mmol) was added. The mixture was stirred at 100°C for 18 hours. X-ray MS analysis showed consumption of the starting material. The mixture was filtered and the filter cake was washed with DCM (2x10 ml). The combined filtrate was concentrated to dryness. The residue was purified using flash chromatography (8 g SiO ₂ , EtOAc) to give tert-butyl methyl({6-[(2R)-2-methylpyrrolidinyl-1yl]-1-oxo-2-[6-(4-propyl -4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin4-yl}methyl)carbamate (210 mg, 96 % yield) as a yellow solid.

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1H NMR (400 MHz, CDCI3) δ 8.82-8.62 (m, 1H), 8.25 (s, 1H), 8.17-8.09 (m, 1H), 7.97-7, 89 (m, 1H), 6.74 (s, 1H), 5.13-4.85 (m, 2H), 4.76-4.58 (m, 2H), 4.64-4.42 ( m, 2H), 4.35-4.19 (m, 1H), 3.84-3.73 (m, 2H), 3.67-3.57 (m, 1H), 3.46-3. 31 (m, 1H), 3.01 (b.s., 3H), 2.19-2.08 (m, 2H), 1.99-1.90 (m, 1H), 1.81-1 .74 (m, 1H), 1.48-1.31 (m, 9H), 1.27 (d, J=6.1 Hz, 3H), 0.98 (t, J=6.3 Hz, 3H); m/z (ESI+) for (C29H38N8O3), 547.4 (M+H) ⁺ .

Step 3: 4-[(methylamino)methyl]-6-[(2R)-2-methylpyrrolidinyl-1-yl]-2-[6-(4-propyl-4H-1,2,4triazol-3-yl) pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride salt

To a solution of tert-butyl methyl({6-[(2R)-2-methylpyrolidinyl-1-yl]-1-oxo-2-[6-(4-propyl-4H-1,2,4triazol-3-yl) pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate (210 mg, 0.384 mmol) in DCM (5.0 ml) at 0° C HCl solution (1.0 M in EtOAc, 5.0 ml) was added. The mixture was stirred at 20°C for 4 hours to obtain a suspension. X-ray MS analysis showed consumption of the starting material. The suspension was filtered. The filter cake was washed with DCM (5 ml) and dried under vacuum. The material was dissolved in H2O (30 ml), and dried by lyophilization to give 4-[(methylamino)methyl]-6-[(2R)2-methylpyrolidinyl-1-yl]-2-[6-(4-propyl-4H -1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one, isolated as hydrochloride (170 mg, 92% yield ) as a yellow solid.

1H NMR (600 MHz, DMSO) δ 8.68 (s, 1H), 8.53 (dt, J=6.2, 2.9 Hz, 1H), 8.04-7.98 (m, 1H) , 7.94 (dd, J=8.0, 2.8 Hz, 1H), 6.53 (s, 1H), 5.06-4.98 (m, 2H), 4.56-4.48 (m, 2H), 3.84 (2H obscured by solvent peak), 3.28 (d, J=9.3 Hz, 1H), 2.46-2.34 (m, 3H), 2.09- 1.96 (m, 2H), 1.96-1.89 (m, 1H), 1.88-1.74 (m, 4H), 1.74-1.63 (m, 1H), 1. 15 (d, J=6.1 Hz, 3H), 0.90 (t, J=7.4 Hz, 3H); m/z (ESI+) for (C24H30N8O), 447.1 (M+H) ⁺ .

Example 56: 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2yl]-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride

Step 1: tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro -1 H-pyrrolo[3,4-c]pyridin-4-yl} methyl)carbamate

To a solution of intermediate 7 (300 mg, 1.01 mmol), intermediate 13 (306 mg, 2.22 mmol), N,N-dimethylethylenediamine (44.4 mg, 0.504 mmol) and K ₂ CO ₃ (306 mg , 2.22 mmol) to MeCN (10.0 mL) was added CuI (48.0 mg, 0.252 mmol) and the mixture was bubbled with argon for 5 min. The mixture was stirred at 120°C for 1.5 hours under microwave irradiation. TLC analysis showed consumption of the starting material. The reaction mixture was cooled to room temperature and H2O (80 ml) was added. The mixture was filtered and the filter cake was washed with H2O (3x5 ml) and dried in vacuo to give tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazole -3-yl)pyridin-2yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate (290 mg, 60% yield) as a brown solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 8.59 (d, J=8.3 Hz, 1H), 8.18-8.07 (m, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.84 (s, 1H), 7.55 (t, J=5.9 Hz, 1H), 5.26 (s, 2H), 4.58 (t, J=7.1 Hz, 2H), 4.39 (d, J=5.9 Hz, 2H), 1.83 (sq., J=7.4 Hz, 2H), 1 .35 (s, 9H), 0.86 (t, J=7.3 Hz, 3H); m/z (ESI+) for (C ₂₃ H ₂₆ ClN ₇ O ₃ ), 484.2 (M+H) ⁺ .

Step 2: tert-butyl ({6-[ethyl(methyl)amino]-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin2-yl] -2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-4-yl } methyl)carbamate

- 95 044841

A solution of tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro-1H -pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate (290 mg, 0.599 mmol) and Cs ₂ CO ₃ (586 mg, 1.8 mmol) in 1,4-dioxane (10.0 ml ) were bubbled with argon for 3 min, and RuPhos Pd G3 (50.1, 0.0599 mmol) was added. The mixture was bubbled with argon for 3 min and N-methylethaneamine (70.8 mg, 1.2 mmol) was added. The mixture was stirred at 100°C for 18 hours under Ar atmosphere. PX-MS analysis showed consumption of the starting material. The reaction mixture was concentrated to dryness and the residue was purified using preparative TLC (SiO ₂ , 1:20 MeOH/EtOAc) to give tert-butyl ({6[ethyl(methyl)amino]-1-oxo-2-[6-(4 -propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate (90 mg , 30% yield) as a yellow solid, m/z (ESI+) for (C26H34N8O3), 507.3 (M+H) ⁺ .

Step 3: 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2yl]-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride

To a solution of tert-butyl ({6-[ethyl(methyl)amino]-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2-yl]- A solution of HCl (4.0 M in EtOAc, 3.0 ml) at 0°C. The mixture was stirred at 15°C for 20 hours. X-ray MS analysis showed consumption of the starting material. The reaction mixture was concentrated to dryness. The residue was purified using preparative HPLC with a YMC-Actus Triart C-18 column (150x30 mm, 5 μm particle size), which was eluted with 11-51% MeCN/H ₂ O (+0.05% HCl) at a flow rate of 30 ml/ min to give 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-[6-(4-propyl-4H-1,2,4triazol-3-yl)pyridin-2-yl]-2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, isolated as the hydrochloride (37 mg, 47% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.48 (s, 3H), 8.16 -8.09 (m, 1H), 8.02 (d, J=7.6 Hz, 1H), 6.88 (s, 1H), 5.14 (s, 2H), 4.59 (t, J=7.3 Hz, 2H), 4.22 (d, J=6.1 Hz, 2H), 3.71 (sq, J=7.1 Hz, 2H), 3.11 (s, 3H ), 1.89 (sq., J=7.3 Hz, 2H), 1.11 (t, J=6.9 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H) ; m/z (ESI+) for (C ₂₁ H ₂₆ N ₈ O), 407.3 (M+H) ⁺ .

Example 57: 4-[(methylamino)methyl]-6-(1-methylcyclopropyl)-2-{6-[4-(pentan-3-yl)-4H-1,2,4triazol-3-yl]pyridin- 2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl methyl{[6-(1-methylcyclopropyl)-1-oxo-2-{6-[4-(pentan-3-yl)-4H-1,2,4triazol-3-yl]pyridine -2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl]methyl}carbamate

To a mixture _of intermediate 8 (100 mg, 0.302 mmol), intermediate 14 (89.1 mg, 0.302 mmol) and _K3PO4 (192 mg, 0.905 mmol) in 1,4-dioxane (5.0 ml) Pd ₂ (dba) ₃ (27.6 mg, 0.0302 mmol) and Xantphos (34.9 mg, 0.0603 mmol) were added under N ₂ atmosphere. The mixture was bubbled with N2 for two minutes. The mixture was stirred at 85°C for 18 hours. X-ray MS analysis showed consumption of the starting material. The reaction mixture was diluted with H2O (1.5 ml) and extracted with EtOAc (2x10 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified using preparative TLC (SiO2, 1:30 MeOH/EtOAc) to give tert-butyl methyl{[6-(1methylcyclopropyl)-1-oxo-2-{6-[4-(pentan-3-yl)- 4H-1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-4-yl]methyl}carbamate (100 mg, 61% yield) as a light yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.14-8.06 (m, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.58 (s, 1H), 5.17 (d, J=23.7 Hz, 2H), 4.53 (s, 2H), 2.92 (s, 3H), 1.99-1.83 (m, 1H), 1.54 (s, 3H), 1.38 (s, 5H), 1.23 (s, 4H), 1 .18 (s, 4H), 0.91-0.82 (m, 4H), 0.78 (t, J=7.4 Hz, 6H); m/z (ESI+) for (C ₃₀ H3 ₉ N ₇ O ₃ ), 546.5 (M+H) ⁺ .

Step 2: 4-[(methylamino)methyl]-6-(1-methylcyclopropyl)-2-{6-[4-(pentan-3-yl)-4H-1,2,4-triazol3 -yl]pyridin- 2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

V ⁰ .J __ _{_} /=N

H

A solution of tert-butyl methyl {[6-( 1 -methylcyclopropyl)-1-oxo-2-{6-[4-(pentan-3-yl)-4H-1,2,4-triazol3-yl]pyridin-2 -yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl]methyl}carbamate (100 mg, 0.183 mmol) in DCM (3.0 ml) was cooled to 0°C, and TFO (1.0 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated. The residue was dissolved in DCM (50 ml) and washed with saturated aqueous NaHCO ₃ (20 ml) and brine (20 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The solids were dried by lyophilization to give 4-[(methylamino)methyl]-6(1-methylcyclopropyl)-2-{6-[4-(pentan-3-yl)-4H-1,2,4-triazol-3 -yl]pyridin-2-yl}-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one (33 mg, 40% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-b ₆ ) δ 8.93 (s, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.14-8.06 (m, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 5.43 (td, J=8.7, 4.3 Hz, 1H), 5.26 (s , 2H), 3.91 (s, 2H), 2.34 (s, 4H), 1.99-1.86 (m, J=6.7 Hz, 4H), 1.56 (s, 3H) , 1.25 (p, J=3.5 Hz, 2H), 0.87 (sq, J=3.6 Hz, 2H), 0.83 (s, 6H); m/z (ESI+) for (C ₂₅ H ₃₁ N ₇ O), 446.5 (M+H)+.

Example 58: 2-(6-{4-[(2S)-butan-2-yl]-4H-1,2,4-triazol-3-yl}pyridin-2-yl)-4-[(methylamino) methyl]6-(1-methylcyclopropyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

V ⁰ \ J _h / = ^N N

Ave.-58

A mixture of intermediate 8 (68.4 mg, 0.206 mmol), intermediate 15 (58.0 mg, 0.210 mmol), K ₂ CO ₃ (71.3 mg, 0.516 mmol), N,N-dimethylethylenediamine (8, 61 mg, 0.0977 mmol), and CuI (9.3 mg, 0.0488 mmol) were stirred at 120°C for 90 min under microwave irradiation. X-ray MS analysis showed consumption of the starting material. The mixture was cooled to room temperature and filtered through Celite®. The filter cake was washed with 10% MeOH/DCM and the combined filtrate was concentrated to dryness. The residue was dissolved in DCM (2.0 ml) and TFO (1.0 ml) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness. The residue was purified using preparative SFC with a ZymorSPHERE HADP column (4.6x150 mm, 5 μm particle size) which was eluted with 5-50% MeOH/CO ₂ at a flow rate of 4.0 ml/min to obtain (57.6 mg, 65 % yield) as a solid.

1H NMR (600 MHz, DMSO-Y6) δ 8.92 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.15-8.07 (m, 1H), 7 .93 (d, J=7.2 Hz, 1H), 7.66 (s, 1H), 5.31 (p, J=7.2 Hz, 1H), 5.25-5.17 (m, 2H), 4.35 (s, 2H), 2.68 (s, 3H), 1.92 (ddp, J=36.2, 14.6, 7.4 Hz, 2H), 1.57 (d , J=8.2 Hz, 6H), 1.42-1.37 (m, 2H), 0.91 (d, J=5.4 Hz, 2H), 0.82 (t, J=7, 3 Hz, 3H); m/z (ESI+) for (C24H29N7O), 432.2 (M+H) ⁺ .

Example 59: 6-[ethyl(methyl)amino]-4-[(methylamino)methyl]-2-[6-(4-πpropyl-4H-1,2,4-triazol-3yl)pyridin-2-yl] -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

- 97 044841

Step 1: tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro -1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate

To a solution of intermediate 2 (200 mg, 0.642 mmol), intermediate 13 (180 mg, 0.674 mmol), K ₂ CO ₃ (195 mg, 1.41 mmol), and N,N-dimethylethylenediamine (28.3 mg, 0.321 mmol) to MeCN (7.0 ml) was added CuI (30.5 mg, 0.160 mmol). The mixture was bubbled with argon for 5 min and then stirred at 120°C for 1.5 h under microwave atmosphere. X-ray MS analysis showed consumption of the starting material. The mixture was diluted with H2O (30 ml). The resulting precipitate was collected by filtration. The filter cake was stirred in EtOAc (100 ml) and filtered to remove undissolved solids. The filtrate was concentrated to dryness to give tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (270 mg, 85% yield) as a gray solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 8.60 (d, J=8.3 Hz, 1H), 8.17 - 8.10 (m, 1H) , 8.00 (d, J=7.6 Hz, 1H), 7.87 (s, 1H), 5.21 (s, 2H), 4.66 (s, 2H), 4.60-4, 54 (m, 2H), 2.93 (s, 3H), 1.81 (s, 2H), 1.37 (s, 5H), 1.24 (s, 4H), 0.86 (t, J =7.3 Hz, 3H); m/z (ESI+) for (C ₂₄ H ₂₈ ClN ₇ O ₃ ), 498.2 (M+H) ⁺ .

Step 2: tert-butyl ({6-[ethyl(methyl)amino]-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin2-yl] -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate

A mixture of tert-butyl ({6-chloro-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro- 1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (270 mg, 0.542 mmol), Nmethylethanamine (64.1 mg, 1.08 mmol), and Cs ₂ CO ₃ (530 mg, 1.63 mmol) in 1,4-dioxane (8.0 ml) was bubbled with argon for 3 min and RuPhos Pd G3 (45.4 mg, 0.542 mmol). The mixture was bubbled with argon for an additional 3 minutes and then stirred at 100°C for 18 hours. X-ray MS analysis showed consumption of the starting material. The mixture was diluted with H ₂ O (50 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using preparative TLC (1:20 MeOH/EtOAc) to give tert-butyl ({6-[ethyl(methyl)amino]-1-oxo-2-[6-(4-propyl-4H-1,2 ,4-triazol3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (99 mg, 35% yield) as brown solid matter.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.76 (s, 1H), 8.62 (d, J=8.4 Hz, 1H), 8.12-8.06 (m, 1H) , 7.98 (d, J=7.6 Hz, 1H), 6.78 (s, 1H), 5.09-5.00 (m, 2H), 4.57 (s, 2H), 4, 49 (s, 2H), 3.68-3.60 (m, 2H), 3.05 (s, 3H), 2.94 (s, 3H), 1.90-1.77 (m, 2H) , 1.38 (s, 4H), 1.23 (s, 5H), 1.07 (d, J=7.9 Hz, 3H), 0.89 (t, J=7.5 Hz, 3H) .; m/z (ESI+) for (C27H ₃ 6N8O ₃ ), 521.4 (M+H) ⁺ .

Step 3: 6-[ethyl(methyl)amino]-4-[(methylamino)methyl]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2-yl] -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride

A solution of tert-butyl ({6-[ethyl(methyl)amino]-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin2-yl]-2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (99 mg, 0.19 mmol) in DCM (20 ml) was cooled to 0°C and treated dropwise with HCl solution (4.0M in EtOAc, 5.0 ml). The reaction mixture was stirred at room temperature for 2 days. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness. The residue was purified using preparative HPLC with a YMC-Actus Triart C18 column (150x30 mm, 5 µm particle size), which was eluted with 12-98 044841

52% MeCN/H ₂ O (+0.05% HCl) at a flow rate of 30 ml/min to give 6-[ethyl(methyl)amino]-4[(methylamino)methyl]-2-[6-(4- propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-1-one, isolated as hydrochloride (62.2 mg, 72% yield) as a yellow solid.

^1H NMR (400 MHz, DMSOL6) δ 9.15 (d, J=8.2 Hz, 2H), 8.85 (s, 1H), 8.65 (d, J=8.2 Hz, 1H) , 8.16-8.10 (m, 1H), 8.04-7.98 (m, 1H), 6.92 (s, 1H), 5.13 (s, 2H), 4.58 (t , J=7.2 Hz, 2H), 4.33 (t, J=5.9 Hz, 2H), 3.72 (sq., J=7.0 Hz, 2H), 3.12 (s, 3H), 2.73 (t, J=5.4 Hz, 3H), 1.87 (g, J=7.4 Hz, 2H), 1.12 (t, J=7.0 Hz, 3H) , 0.93 (t, J=7.4 Hz, 3H); m/z (ESI+) for (C ₂₂ H ₂₈ N ₈ O), 421.2 (M+H) ⁺ .

Example 60: 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2yl]-2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

ABOUT

N?

_{Ν_Ζ}

J /^N ^H 2 ^N Λ ^Ν Χ^ / Pr.-60

Step 1: 4-chloro-6-[ethyl(methyl)amino]-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2, 3dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

And o x a

Mixture of 4-chloro-6-[ethyl(methyl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (intermediate 9) (123 mg, 0.487 mmol), intermediate 12 (110 mg, 0.487 mmol), K ₂ CO ₃ (196 mg, 1.42 mmol), N,N-dimethylethylenediamine (28.4 mg, 0.322 mmol) and CuI (30.7 mg, 0.161 mmol) in MeCN (4.0 ml) was stirred at 120°C for 90 min under microwave irradiation. X-ray MS analysis showed consumption of the starting material. The mixture was filtered through Celite®. The filter cake was washed with 10% MeOH/DCM and the combined filtrate was concentrated to dryness. The residue was purified using flash chromatography (12 g SiO ₂ , 0-10% MeOH/DCM) to give 4-chloro-6[ethyl(methyl)amino]-2-[6-(4-ethyl-4H-1, 2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-1-one (173 mg, 89% yield) as a yellow solid, m/z (APCI+) for (C ₁₉ H ₂₀ ClN ₇ O), 398.2 (M+H) ⁺ .

Step 2: 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

A mixture of 4-chloro-6-[ethyl(methyl)amino]-2-[6-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3dihydro -1H-pyrrolo[3,4-c]pyridin-1-one (172 mg, 0.432 mmol), potassium N-Boc-aminomethyltrifluoroborate (205 mg, 0.865 mmol), K2CO3 (299 mg, 2.16 mmol), cataCXium A (31.0 mg, 0.0865 mmol), Pd(OAc) ₂ (19.4 mg, 0.0865 mmol) and tetraethylammonium tetrafluoroborate (93.8 mg, 0.432 mmol) in tert-AmOH (4.0 ml ) and H ₂ O (0.4 ml) were stirred at 110°C for 20 hours under N ₂ atmosphere. PX-MS analysis showed consumption of the starting material. The mixture was cooled to room temperature, diluted with H2O (10 ml) and extracted with DCM (2x10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was taken into DCM (2.0 ml) and treated with TFO (1.0 ml). The mixture was stirred for 2 hours and then concentrated to dryness. The residue was purified using preparative SFC with a Princeton SFC HA-Morpholine column (150x4.6 mm, 5 μm particle size) which was eluted with 5-50% MeOH/CO ₂ at a flow rate of 4.0 ml/min to give 4-(aminomethyl )-6-[ethyl(methyl)amino]-2-[6-(4ethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo [3,4-c]pyridin-1-one (114.4 mg, 67% yield) as a solid.

1H NMR (600 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.32 (s, 3H), 8.12-8 .06 (m, 1H), 7.98 (d, J=7.6 Hz, 1H), 6.87 (s, 1H), 5.11 (s, 2H), 4.61 (sq, J =7.2 Hz, 2H), 4.26 (s, 2H), 3.70 (sq., J=7.0 Hz, 2H), 3.11 (s, 3H), 1.47 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H); m/z (APCI+) for (C ₂₀ H ₂₄ N ₈ O), 393.0 (M+H) ⁺ .

Example 61: 4-(aminomethyl)-2-[6-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2R) -2methylpyrrolidinyl-1 -yl]-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-1 -one

- 99 044841

Step 1: 4-chloro-2-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-6-[(2R)-2-methylpyrrolidinyl1 -yl]- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

A mixture of intermediate 10 (142 mg, 0.593 mmol), intermediate 4 (120 mg, 0.477 mmol), K2CO3 (145 mg, 1.05 mmol), CuI (22.7 mg, 0.119 mmol) and N,N- dimethylethylenediamine (21.0 mg, 0.238 mmol) in MeCN (3.0 ml) was stirred at 120°C for 90 min under microwave irradiation. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness and the residue was purified using flash chromatography (SiO ₂ , 1:1 EtOAc/DCM) to give 4-chloro-2-[6-(5-methyl-1,3,4-oxadiazol-2-yl )pyridin-2-yl]-6-[(2R)-2-methylpyrrolidinyl-1-yl]-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (162 mg, 83% yield ) in the form of a pale yellow foam.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.79 (d, J=8.07 Hz, 1H), 7.91-8.08 (m, 2H), 6.76 (s, 1H), 5 .13 (s, 2H), 4.23 (quin., J=5.84 Hz, 1H), 3.59-3.70 (m, 1H), 3.36-3.50 (m, 1H) , 2.73 (s, 3H), 2.10-2.29 (m, 2H) 1.97-2.09 (m, 1H), 1.74-1.86 (m, 1H) 1.28 (d, J=6.36 Hz, 3H); m/z (APCI+) for (C ₂₀ H ₁₉ ClN ₆ O ₂ ), 411.0 (M+H) ⁺ .

Step 2: tert-butyl ({2-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-6-[(2R)-2methylpyrolidinyl-1 -yl] -1-oxo-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-4-yl } methyl)carbamate

A mixture of 4-chloro-2-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-6-[(2R)-2-methylpyrrolidinyl-1 yl]- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (160 mg, 0.389 mmol), potassium N-Bocaminomethyltrifluoroborate (369 mg, 1.56 mmol), cataCXium (27.9 mg, 0.0779 mmol), Pd(OAc) ₂ (17.5 mg, 0.0779 mmol) and tetraethylammonium tetrafluoroborate (84.5 mg, 0.389 mmol) in t-BuOH (6.0 ml) and H ₂ O (0 .6 ml) was stirred at 110°C for 18 hours. X-ray MS analysis showed consumption of the starting material. The reaction mixture was cooled to room temperature, diluted with H2O (10 ml) and extracted with DCM (2x10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (12 g SiO ₂ , 30-100% EtOAc/heptane) to give tert-butyl ({2-[6-(5-methyl-1,3,4-oxadiazol-2-yl) pyridin-2-yl]-6-[(2R)-2-methylnyrolidinyl-1-yl]1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl) carbamate (182 mg, 92% yield) as a white solid. m/z (APCI+) for (C ₂₆ H ₃₁ N ₇ O ₄ ), 506.2 (M+H) ⁺ .

Step 3: 4-(aminomethyl)-2-[6-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2R) -2methylpyrrolidinyl-1 -yl]-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-1 -one

A mixture of tert-butyl ({2-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-6-[(2R)-2methylpyrrolidinyl-1 -yl]- 1-oxo-2,3-dihydro-1H-pyrrolo[3,4-e]pyridin-4-yl} methyl)carbamate (84 mg, 0.17 mmol), ethylamine hydrochloride (279 mg, 3.42 mmol) , and TEA (353 mg, 3.49 mmol) in NMP (1.0 ml) were stirred at 140°C for 18 hours. RC-MS analysis showed consumption of the starting material. The reaction mixture was cooled to room temperature, diluted with H2O (20 ml) and extracted with EtOAc (20 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (0-10% MeOH/DCM). The desired fractions were concentrated to dryness. The residue was dissolved in DCM (5.0 ml) and treated with HCl solution (4.0 N in 1,4-dioxane, 1.0 ml). The mixture was stirred for 4 hours and then concentrated to dryness. The residue was purified using preparative HPLC with a Phenemonex Gemini NX C18 column (150x21.2 mm, 5 µm particle size), which was eluted with 30-100% MeCN/H ₂ O (+10 mM NH ₄ OAc) at a flow rate of 40 ml/min to obtain tert-butyl ({2-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-6-[(2R)-2-methylpyrolidinyl1-yl]- 1-oxo-2,3-dihydro-1H-nirrolo[3,4-c]pyridin-4-yl}methyl)carbamate (24.0 mg, 33% yield) as a solid.

^1H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J=8.3, 0.9 Hz, 1H), 8.08-8.01 (m, 1H), 7.96 (dd , J=7.7, 1.0 Hz, 1H), 6.60 (s, 1H), 5.19 (s, 2H), 4.56 (sq., J=7.1 Hz, 2H), 4.31-4.20 (m, 1H), 3.91 (s, 2H), 3.53-3.43 (4H obscured by solvent peak), 3.21 (s, 3H), 2.15- 2.03 (m, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.24 (d, J=6.2 Hz, 3H); m/z (APCI+) for (C23H28N8O), 433.3 (M+H) ⁺ .

Example 62: 4-[(methylamino)methyl]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6[( 2R)-2-methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

— I Project-62

Step 1: tert-butyl ({6-chloro-2-[6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1-oxo-2,3dihydro-1H -pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate O

A mixture of intermediate 2 (200 mg, 0.642 mmol), intermediate 4 (154 mg, 0.642 mmol), K2CO3 (195 mg, 1.41 mmol), CuI (30.5 mg, 0.160 mmol) and N,N- dimethylethylenediamine (28.3 mg, 0.321 mmol) in MeCN (2.0 ml) was bubbled with N2 for 5 min and then stirred at 120°C for 100 min under microwave irradiation. X-ray MS analysis showed consumption of the starting material. The mixture was filtered through a pad of Celite® and the filtrate was concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , 0-70% [8:1:1

EtOAc/MeOH/DCM]/heptane) to give tert-butyl ({6-chloro-2-[6-(5-methyl-1,3,4-oxadiazol-2yl)pyridin-2-yl]-1-oxo -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (217 mg, 72% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (d, J=8.5 Hz, 1H), 8.22-8.14 (m, 1H), 8.00 (d, J=7 .6 Hz, 1H), 7.87 (s, 1H), 5.21 (s, 2H), 4.71 (s, 2H), 3.29 (s, 3H), 2.64 (s, 3H ), 1.43 (s, 4H), 1.36 (s, 5H); m/z (ESI+) for (C ₂₂ H ₂₃ ClN ₆ O ₄ ), 471.3 (M+H) ⁺ .

Step 2: tert-butyl ({6-chloro-2-[6-(5-methyl-4-pronyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-1-oxo2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate

ABOUT

This reaction was carried out in two parallel batches. To a mixture of tert-butyl ({6-chloro-2-[6(5 -methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl]-1-oxo-2,3-dihydro- 1 H-pyrrolo[3,4-c]pyridin-4yl}methyl)methylcarbamate (100 mg, 0.212 mmol) and acetic acid (31.9 mg, 0.531 mmol) in MeCN (2.5 ml) added N-propylamine hydrochloride (203 mg, 2.12 mmol) and TEA (215 mg, 2.12 mmol). The reaction mixture was stirred at 100°C for 16 hours. The mixture was concentrated to dryness. The combined reaction crude residues were purified using flash chromatography (12 g SiO2, 40-100% EtOAc/heptane then 10% MeOH/EtOAc) to give tert-butyl ({6-chloro-2-[6-(5-methyl- 4-propyl-4H

- 101 044841

1,2,4-triazol-3-yl)pyridin-2-yl]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl}methyl)methylcarbamate (68.4 mg, 31% yield) in the form of an almost white foam.

1H NMR (600 MHz, DMSO-d ₆ ) δ 8.59 (d, J=8.4 Hz, 1H), 8.15-8.09 (m, 1H), 7.96 (d, J=7 .6 Hz, 1H), 7.87 (s, 1H), 5.26-5.15 (m, 2H), 4.65 (s, 2H), 4.53-4.45 (m, 2H) , 2.93 (s, 3H), 2.49 (s, 3H), 1.77-1.68 (m, 2H), 1.37 (s, 5H), 1.23 (s, 4H), 0.86 (t, J=7.4 Hz, 3H); m/z (ESI+) for ^HzoC^O3), 512.3 (M+H)+.

Step 3: 4-[(methylamino)methyl]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6[( 2R)-2-methylpyrrolidinil-1 -yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, trifluoroacetate

A mixture of tert-butyl ({6-chloro-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-1-oxo2, 3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (50.0 mg, 0.098 mmol), (2R)-2methylpyrrolidinyl (41.6 mg, 0.488 mmol), Cs ₂ CO ₃ (95.5 mg, 0.293 mmol), and RuPhos-Pd G3 (12.3 mg, 0.0146 mmol) were bubbled with N2 for 5 min and then stirred at 100°C for 18 h. The mixture was cooled to room temperature temperature and filtered through Celite®. The filter cake was washed with 10% MeOH/EtOAc. The combined filtrate was concentrated to dryness. The residue was dissolved in DCM (1.5 ml) and TFO (0.6 ml) was added. The mixture was stirred for 30 minutes and then concentrated to dryness. The residue was purified using preparative HPLC with a Waters Sunfire C-18 column (19x100 mm, 5 µm particle size), which was eluted with 5-100% MeCN/H ₂ O (+0.05% TFO) at a flow rate of 25 ml/min with producing 4-[(methylamino)methyl]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2yl]-6-[(2R)- 2-methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one was isolated as a trifluoroacetate salt (38 mg, 68% yield) as a solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 3H), 8.63 (d, J=8.4 Hz, 1H), 8.16-8.06 (m, 1H), 7.96 (d, J=7.6 Hz, 1H), 6.75 (s, 1H), 5.10 (s, 2H), 4.44 (dd, J=8.6, 6.6 Hz , 2H), 4.38-4.31 (m, 3H), 3.65 (t, J=9.0 Hz, 1H), 2.812.73 (m, 3H), 2.54 (s, 3H) , 2.16-1.96 (m, 4H), 1.85-1.71 (m, 3H), 1.20 (d, J=6.2 Hz, 3H), 0.93 (t, J =7.4 Hz, 3H); m/z (ESI+) for (C25H32N8O), 461.7 (M+H) ⁺ . [ / Г22 -53.3° (c=0.5, MeOH).

Example 63: 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol3-yl)pyridin- 2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: Methyl 6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4carboxylate

A mixture of intermediate 11 (11.3 g, 47.1 mmol), PdCl ₂ (dppf) (2.16 g, 2.95 mmol), and TEA (14.3 g, 141 mmol) in MeOH (200 ml ) was stirred at 80°C for 40 hours under a CO atmosphere at 50 psi. TLC analysis (1:1 EtOAc/petroleum ether) showed consumption of the starting material. The reaction mixture was concentrated to dryness. The residue was dissolved in H2O (200 ml) and extracted with DCM (2x150 ml). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was suspended in DCM (50 ml) for 30 min. Solids were collected by filtration. The filtered cake was washed with petroleum ether (3x5 ml) and dried in vacuum. The filtrate was purified using flash chromatography (SiO ₂ , 40-70% EtOAc/DCM). The desired fractions were concentrated to dryness and combined with the above filter cake to give methyl 6-[methyl(propan-2-yl)amino]-1-oxo2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- carboxylate (12.3 g, 99% yield) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ 7.12 (s, 1H), 6.79 (s, 1H), 4.89 (p, J=6.6 Hz, 1H), 4.68 (d, J =1.1 Hz, 2H), 3.97 (s, 3H), 2.96 (s, 3H), 1.21 (d, J=6.7 Hz, 6H); m/z (ESI+) for (C13H17N3O3), 263.9 (M+H) ⁺ .

Step 2: 4-(hydroxymethyl)-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 102 044841

1-he

To a mixture of methyl 6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4carboxylate (1.0 g, 3.80 mmol) in THF (60 ml) a solution of LiAlH ₄ (2.5 M in THF, 1.67 ml, 4.18 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour and then at 20°C for 16 hours. TLC analysis (1:1 EtOAc/petroleum ether) showed consumption of the starting material. The mixture was quenched by adding 20% aqueous NaOH (0.5 ml). Na ₂ SO ₄ (4 g) was added to the mixture. The mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated to dryness to give 4(hydroxymethyl)-6-[methyl(propan-2-yl)αmino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (890 mg, > 99% yield) as a yellow solid.

^1H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 6.82 (s, 1H), 4.85 (p, J=6.6 Hz, 1H), 4.67 (d, J=4.7 Hz, 2H), 4.33 (s, 2H), 4.09 (t, J=4.6 Hz, 1H), 2.92 (s, 3H), 1.20 (d, J=6.7 Hz, 6H); m/z (ESI+) for (C ₁₂ H ₁₇ N ₃ O ₂ ), 236.0 (M+H) ⁺ .

Step 3: {6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl} methylmethanesulfonate

To a mixture of 4-(hydroxymethyl)-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-1-one (890 mg, 3.78 mmol ) and TEA (957 mg, 9.46 mmol) in THF (20.0 ml), MsCl (953 mg, 8.23 mmol) was added dropwise at 0°C under N ₂ atmosphere. The mixture was stirred at 0°C. X-ray MS analysis showed consumption of the starting material. The reaction mixture was diluted with saturated aqueous Na ₂ CO ₃ (30 ml) and extracted with EtOAc (2x20 ml). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give {6-[methyl(propan2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c]pyridin-4-yl}methyl methanesulfonate (1.2 g, >99% yield) as a yellow solid, which was used without further purification, m/z (ESI+) for (C13H19N3O4S), 314.0 (M+H) ⁺ .

Step 4: 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-1-one

To a mixture of {6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4yl}methylmethanesulfonate (1.18 g, 3 .78 mmol) in THF (20.0 ml) was added a solution of methylamine (2.0 M in THF, 37.8 ml, 75.6 mmol). The mixture was stirred for 1 hour. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness to give 4-[(methylamino)methyl]-6[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (940 mg, >99% yield) as a brown solid, which was used without further purification, m/z (ESI+) for (C13H20N4O), 249.0 (M+H) ⁺ .

Step 5: tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4e]pyridin-4-yl} methyl)carbamate

To a solution of 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-1-one (940 mg, 11. 4 mmol) and TEA (1.15 g, 11.4 mmol) in DCM (20.0 ml) was added Boc ₂ O (1.65

- 103 044841 mg, 7.57 mmol). The mixture was stirred for 30 minutes. X-ray MS analysis showed consumption of the starting material. The reaction mixture was concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , EtOAc) to give tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2,3dihydro-1H-pyrrolo[3,4-c ]pyridin-4-yl}methyl)carbamate (600 mg, 46% yield) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 6.81 (s, 1H), 6.57-6.42 (m, 1H), 4.91 (p, J=6.6 Hz, 1H), 4, 48 (s, 2H), 4.35 (d, J=12.4 Hz, 2H), 2.92 (s, 3H), 2.88 (s, 3H), 1.48 (s, 5H), 1.41 (s, 4H), 1.17 (d, J=6.7 Hz, 6H); m/z (ESI+) for (C18H28N4O3), 349.2 (M+H) ⁺ .

Step 6: tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2-[6-(4-propyl-4H-1,2,4-triazol3-yl)pyridine -2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate

To a mixture of tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-4-yl}methyl)carbamate (80 mg, 0.23 mmol), intermediate 13 (64.4 mg, 0.24 mmol), and K ₃ PO ₄ (146 mg, 0.69 mmol) in 1,4-dioxane (3.0 ml ) Pd ₂ (dba) ₃ (21.0 mg, 0.023 mmol) and Xantphos (26.6 mg, 0.046 mmol) were added. The mixture was bubbled with N2 for 2 minutes and then stirred at 85°C for 18 hours. X-ray MS analysis showed consumption of the starting material. The reaction mixture was concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , 1:10 MeOH/EtOAc) to give tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2-[6-( 4-propyl-4H1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate (90 mg, 73% yield) as a brown solid.

^1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 8.14-8.06 (m, 1H), 7, 96-7.87 (m, 1H), 6.86 (s, 1H), 5.04 (s, 1H), 5.00-4.90 (m, 2H), 4.68-4.57 ( m, 2H), 4.51 (s, 2H), 3.03-2.93 (m, 3H), 2.92 (s, 3H), 1.90 (s, 2H), 1.41 (s , 5H), 1.33 (s, 4H), 1.20 (d, J=6.7 Hz, 6H), 0.98-0.91 (m, 3H); m/z (ESI+) for (C28H ₃ 8N8O3), 535.4 (M+H)+.

Step 7: 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin- 2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride

To a solution of tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2-[6-(4-propyl-4H-1,2,4triazol-3-yl)pyridin- 2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate (90 mg, 0.17 mmol) in EtOAc (5.0 ml) added HCl solution (4.0M in EtOAc, 2.0 ml) at 0°C. The mixture was stirred at room temperature for 4 hours. X-ray MS analysis showed consumption of the starting material. The reaction mixture was concentrated in vacuo and then dried by lyophilization to give 4[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2, 4-triazol-3-yl)pyridin-2-yl]2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, isolated as hydrochloride (62.9 mg, 79% yield) in as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.65 (dd, J=8.4, 0.9 Hz, 1H), 8.17-8.10 (m , 1H), 7.99 (dd, J=7.6, 0.9 Hz, 1H), 6.88 (s, 1H), 5.10 (s, 2H), 5.05-4.92 ( m, 1H), 4.60 (dd, J=8.1, 6.4 Hz, 2H), 4.31 (s, 2H), 2.90 (s, 3H), 2.71 (s, 3H ), 1.88 (g, J=7.3 Hz, 2H), 1.14 (d, J=6.6 Hz, 6H), 0.92 (t, J=7.4 Hz, 3H); m/z (ESI+) for (C ₂₃ H ₃₀ N ₈ O), 435.3 (M+H) ⁺ .

Example 64: 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4triazol-3 - yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl methyl({6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4triazol-3-yl)pyridine -2-yl]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate

- 104 044841

To a mixture of tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-4-yl}methyl)carbamate (see synthesis in Example 63) (200 mg, 0.574 mmol), intermediate 17 (169 mg, 0.603 mmol) and K3PO4 (366 mg, 1.72 mmol) in 1,4-dioxane (10.0 ml) in atmosphere N ₂ Pd ₂ (dba) ₃ (52.6 mg, 0.0574 mmol) and Xantphos (66.4 mg, 0.115 mmol) were added. The mixture was sealed and stirred at 85°C for 18 hours. TLC analysis (EtOAc) showed consumption of the starting material. The reaction mixture was concentrated to dryness and the residue was purified using flash chromatography (SiO ₂ , 1:20 MeOH/EtOAc). The following steps were carried out five times in succession: The residue was dissolved in 1:10 MeOH/EtOAc (30 ml) and Ultra-pure Si-Thio SiO ₂ (1 g) was added. The mixture was stirred at 50°C for 30 minutes. The mixture was filtered and the filter cake was washed with 1:10 MeOH/EtOAc (3x30 ml). The filtrate was concentrated to dryness. The resulting residue was purified using flash chromatography (SiO ₂ , 1:10 MeOH/EtOAc) to give tert-butyl methyl({6-[methyl(propan2-yl)amino]-2-[6-(5-methyl -4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-1-oxo-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-4-yl} methyl)carbamate (250 mg, 79% yield) as a yellow solid.

Ή NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J=9.4 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.94-7.85 ( m, 1H), 6.86 (s, 1H), 5.02 (s, 1H), 4.94 (d, J=9.4 Hz, 2H), 4.53 (s, 3H), 3, 01-2.94 (m, 4H), 2.92 (s, 3H), 2.55 (s, 3H), 1.75 (s, 2H), 1.47-1.27 (m, 9H) , 1.20 (d, J=6.7 Hz, 6H), 0.90 (t, J=7.3 Hz, 3H); X-ray MS m/z (ESI+) for (C29H40N8O3), 549.6 (M+H) ⁺ .

Step 2: 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4triazol-3 - yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, hydrochloride

I R

I - on ) /=N ⁿ 7

Solution of tert-butyl methyl({6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol3-yl)pyridin-2 -yl]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)carbamate (250 mg, 0.456 mmol) in EtOAc (5.0 ml) was cooled to 0°C and treated with HCl solution (4.0 N in EtOAc, 3.0 ml). The mixture was stirred at 25°C for 1 hour. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness. The residue was purified using preparative HPLC with a Phenomenex Gemini-NX column (150x30 mm, 5 μm particle size) which was eluted with 19-39% MeCN/H ₂ O (+0.05% HCl) at a flow rate of 30 ml/min to obtain 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl) pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1one was isolated as hydrochloric acid salt (140 mg, 63% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 2H), 8.71 (d, J=8.5 Hz, 1H), 8.21-8.14 (m, 1H) , 7.98 (d, J=7.6 Hz, 1H), 6.92 (s, 1H), 5.15 (s, 2H), 5.11-4.98 (m, 1H), 4, 58-4.48 (m, 2H), 4.30 (t, J=5.8 Hz, 2H), 2.93 (s, 3H), 2.71 (t, J=5.4 Hz, 3H ), 2.67 (s, 3H), 1.87 (p, J=7.5 Hz, 2H), 1.17 (d, J=6.6 Hz, 6H), 0.97 (t, J =7.4 Hz, 3H); RXMS m/z (ESI+) for (C24H32N8O), 449.2 (M+H) ⁺ .

Alternatively, Example 64 was also prepared as follows.

Step 1: tert-butyl methyl({6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4triazol-3-yl)pyridine -2-yl]-1-oxo-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-4-yl} methyl)carbamate.

To a mixture of tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4c]pyridin-4-yl}methyl)carbamate (see synthesis in example 63) (7000 mg, 20.09 mmol), intermediate 17 (5650, 20.1 mmol) and K3PO4 (12800 mg, 60.3 mmol) in 1,4-dioxane (70 ml) in Pd2(dba)3 (1840 mg, 2.01 mmol) and Xantphos (2320 mg, 4.02 mmol) were added under N2 atmosphere. The mixture was sealed and stirred at 85°C for 18 hours. TLC analysis (EtOAc) showed consumption of the starting material. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with EtOAc (250 ml). The filtrate was concentrated to a residue which was triturated with 35 ml of a 60:40 mixture of EtOAc:H ₂ O. The suspension was then filtered and the filter cake dried in vacuo to give tert-butyl methyl({6-[methyl(propan-2-yl) amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin2-yl]-1-oxo-2,3-dihydro-1H-pyrrolo[ 3,4-c]pyridin-4-yl}methyl)carbamate (10400 mg, 94% yield) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J=9.4 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.94-7.85 ( m, 1H), 6.86 (s,

- 105 044841

1H), 5.02 (s, 1H), 4.94 (d, J=9.4 Hz, 2H), 4.53 (s, 3H), 3.01-2.94 (m, 4H), 2.92 (s, 3H), 2.55 (s, 3H), 1.75 (s,

2H), 1.47-1.27 (m, 9H), 1.20 (d, J=6.7 Hz, 6H), 0.90 (t, J=7.3 Hz, 3H); RX-MS m/z (ESI+) for (C ₂₉ H ₄₀ N ₈ O ₃ ),

549.3 (M+H) ⁺ .

Step 2: 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4triazol-3- yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one.

A solution of tert-butyl methyl({6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol3-yl)pyridin-2 -yl]-1-oxo-2,3-dihydro-1 H-pyrrolo[3,4-e]pyridin-4-yl}methyl)carbamate (10400 mg, 18.95 mmol) in EtOAc (15.0 ml ) and MeOH (5 ml) were cooled to 0°C and treated with HCl solution (4.0N in EtOAc, 100 ml). The mixture was stirred at 25°C for 4 hours. TLC analysis (EtOAc, 254 nm, UV) showed consumption of the starting material. The reaction mixture was filtered and concentrated to a residue, which was dissolved in water (200 ml) and extracted with EtOAc (150 ml). DCM (250 ml) was added to the aqueous layer, and then solid NaHCO ₃ was added until the pH of the mixture reached ~8. The layers were separated and the aqueous layer was extracted with DCM (2x100 ml). The combined organic layers were washed with brine (150 ml), dried over sodium sulfate, filtered and concentrated to a residue. The residue was triturated with 22 ml of a 10:1 mixture of EtOAc:MeCN and the suspension was filtered and the cake dried in vacuo to give 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2[ 6-(5-methyl-4-propyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-e]niridin- 1-one (5.59 g, 66% yield) as a yellow solid.

1H NMR (400 MHz, CDC13) δ 8.73 (d, J=8.5 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.92 (t, J=8 .0 Hz, 1H), 6.88 (s, 1H), 5.05 (s, 2H), 4.98-4.92 (m, 1H), 4.53-4.45 (m, 2H) , 3.88 (s, 2H), 2.95 (s, 3H), 2.58 (s, 3H), 2.55 (s, 3H), 1.91-1.85 (m, 2H), 1.23 (d, J=6.8 Hz, 6H), 1.04 (t, J=7.4 Hz, 3H); RX-MS m/z (ESI+) for ^H^O), 449.2 (M+H) ⁺ .

Example 65: 2-[6-(4-cyclobutyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4-[(methylamino)methyl]-6-(1methylcyclopropyl)-2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: methyl 6-[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-6-(1-methylcyclopropyl)-1oxo-1,3-dihydro-2H-pyrrolo[3,4-c] pyridin-2-yl]pyridin-2-carboxylate

To a mixture of intermediate 8 (1.50 g, 4.53 mmol), methyl 6-bromopyridine-2carboxylate (1.17 g, 5.43 mmol) and K ₃ PO ₄ (2.88 g, 13.6 mmol ) in 1,4-dioxane (50.0 ml) under N ₂ atmosphere, Pd ₂ (dba) ₃ (414 mg, 0.453 mmol) and Xantphos (524 mg, 0.905 mmol) were added. The mixture was bubbled with N2 for 2 min and then sealed and stirred at 85°C for 5 h. X-ray MS analysis showed consumption of the starting material. The reaction mixture was diluted with H2O (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified using flash chromatography (SiO ₂ , 1:3 EtOAc/petroleum ether) to give methyl 6-[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-6-(1-methylcyclopropyl)-1-oxo- 1,3-dihydro-2H-pyrrolo[3,4c]pyridin-2-yl]pyridin-2-carboxylate (1.89 g, 89% yield) as a brown solid.

^1H NMR (400 MHz, _CDC13 ) δ 8.95-8.61 (m, 1H), 7.96-7.83 (m, 2H), 7.78-7.62 (m, 1H), 5.18 (s, 2H), 4.64 (d, J=10.3 Hz, 2H), 3.99 (s, 3H), 2.96 (s, 3H), 1.58 (s, 3H ), 1.53-1.41 (m, 9H), 1.33 (sq., J=3.7 Hz, 2H), 0.950.77 (m, 2H); X-ray MS m/z (ESI+) for (C25H30N4O5), 467.4 (M+H) ⁺ .

Step 2: tert-butyl ({2-[6-(hydrazinecarbonyl)pyridin-2-yl]-6-(1-methylcyclopropyl)-1-oxo-2,3dihydro-1H-pyrrolo[3,4-c]pyridine -4-yl}methyl)methylcarbamate

- 106 044841

To a suspension of methyl 6-[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-6-(1-methylcyclopropyl)1-OkCO-1,3-dihydro-2H-pyrrolo[3,4-c ]pyridin-2-yl]pyridin-2-carboxylate (1.89 g, 4.05 mmol) in MeOH (50.0 ml) was added hydrazine monohydrate (715 mg, 12.1 mmol). The mixture was stirred for 3 hours. TLC analysis (1:3 EtOAc/petroleum ether) showed consumption of the starting material. The reaction mixture was concentrated to dryness to give tert-butyl ({2-[6-(hydrazinecarbonyl)pyridin-2-yl]-6-(1methylcyclopropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl}methyl)methylcarbamate (1.74 g, 92% yield) as a yellow solid, which was used without further purification.

^1H NMR (400 MHz, DMSO-d6) δ 10.09-9.54 (m, 1H), 8.73-8.52 (m, 1H), 8.17-7.98 (m, 1H) , 7.82 (d, J=7.4 Hz, 1H), 7.56 (s, 1H), 5.29 (d, J=8.3 Hz, 2H), 4.81-4.07 ( m, 4H), 2.93 (s, 3H), 1.55 (s, 3H), 1.44 (b.s., 4H), 1.28-1.15 (m, 7H), 0. 94-0.70 (m, 2H); X-ray MS m/z (ESI+) for (C ₂₄ H ₃₀ N ₆ O ₄ ), 467.3 (M+H) ⁺ .

Step 3: tert-butyl {[2-(6-{(2E)-2-[(dimethylamino)methylidene]hydrazinecarbonyl}-pyridin-2-yl)6-(1-methylcyclopropyl)-1-oxo-2,3 -dihydro-1 H-pyrrolo[3,4-c]pyridin-4-yl]methyl} methylcarbamate g GU ⁿ .

sl — ¹ o 'Ν=<

—Ν Vos

A solution of tert-butyl ({2-[6-(hydrazinecarbonyl)pyridin-2-yl]-6-(1-methylcyclopropyl)-1-oxo-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-4 -yl}methyl)methylcarbamate (1.74 g, 3.84 mmol) in N,Ndimethyldimethoxymethylamine (40.0 ml) was stirred at 80°C for 6 hours. TLC analysis (1:10 MeOH/EtOAc) showed consumption of the starting material substances. The mixture was concentrated to dryness. The residue was suspended in TBME (40 ml) for 20 min. The solids were collected by filtration and dried in vacuo to give tert-butyl {[2-(6-{(2E)-2[(dimethylamino)methylidene]hydrazinecarbonyl}pyridin-2-yl)-6-(1-methylcyclopropyl) -1-oxo-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl]methyl}methylcarbamate (1.76 g, 88% yield) as a white solid.

1H NMR (400 MHz, DMSO- _d6 ) δ 10.77-10.44 (m, 1H), 8.82-8.34 (m, 1H), 8.25-7.98 (m, 2H) , 7.82 (d, J=7.5 Hz, 1H), 7.58 (s, 1H), 5.30 (bd, J=11.0 Hz, 2H), 4.66 (s , 2H), 2.92 (s, 3H), 2.91 (s, 6H), 1.56 (s, 3H), 1.43 (s, 4H), 1.25 (d, J=6, 9 Hz, 5H), 1.11 (s, 2H), 0.93-0.73 (m, 2H); X-ray MS m/z (ESI+) for (C ₂₇ H ₃₅ N ₇ O ₄ ), 522.4 (M+H) ⁺ .

Step 4: tert-butyl ({2-[6-(4-cyclobutyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-(1methylcyclopropyl)-1-oxo-2 ,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate

To a suspension of tert-butyl {[2-(6-{(2E)-2-[(dimethylamino)methylidene]hydrazinecarbonyl}pyridin2-yl)-6-(1-methylcyclopropyl)-1-oxo-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-4yl]methyl}methylcarbamate (180 mg, 0.345 mmol) in MeCN (2.0 ml) was added cyclobutanamine (61.4 mg, 0.863 mmol) and acetic acid ( 0.4 ml). The mixture was stirred at 95°C for 3 hours. TLC analysis (1:10 MeOH/EtOAc) showed consumption of the starting material. The solution was concentrated to dryness. The residue was dissolved in H2O (20 ml) and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using flash chromatography (SiO ₂ , 1:10 MeOH/EtOAc) to give tert-butyl ({2-[6-(4-cyclo6util-4H-1,2,4-triazol-3-yl)pyridin-2 -yl]-6-(1-methylcyclopropyl)-1-oxo-2,3dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (104 mg, 57% yield) as white glass la.

- 107 044841

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (b.s., 1H), 8.62 (b.d., J=8.3 Hz, 1H), 8.19-8.01 (m, 1H), 7.91 (b.s., J=7.5 Hz, 1H), 7.61 (s, 1H), 5.74-5.55 (m, 1H), 5.25 (s, 2H), 4.61 (s, 2H), 2.97-2.88 (m, 3H), 1.93-1.75 (m,

2H), 1.57 (s, 3H), 1.47-1.10 (m, 15H), 0.94-0.73 (m, 2H); RX-MS m/z (ESI+) for (C ₂₉ H ₃₅ N ₇ O ₃ )), 530.3 (M+H) ⁺ .

Step 5: 2-[6-(4-cyclobutyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4-[(methylamino)methyl]-6-(1 methylcyclopropyl)- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

HN\

A solution of tert-butyl ({2-[6-(4-cyclobutyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-(1methylcyclopropyl)-1-oxo-2,3 -dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (104 mg, 0.196 mmol) in DCM (5.0 ml) was cooled to 0°C and treated with TFO (3.0 ml). The mixture was stirred at 15°C for 2 hours. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness. The residue was dissolved in H2O (20 ml) and made alkaline with saturated aqueous Na ₂ CO ₃ (~3 ml) to pH~9. The mixture was extracted with DCM (2x20 ml). The combined organic layers were washed with brine (2x15 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using preparative HPLC with an Agela DuraShell C18 column (150x25 mm, 5 µm particle size) eluted with 33-63% MeCN/H ₂ O (+0.04% NH4OH, +10 mM NH4HCO3) at a flow rate of 2 ml /min. The required fractions were re-purified using preparative HPLC with a Phenomenex Gemini NX column (150x30 mm, 5 µm particle size), which was eluted with 36-76% MeCN/H ₂ O (+0.05% NH4OH) at a flow rate of 30 ml/min s yielding Example 65 (15.4 mg, 18% yield) as a white solid.

1H NMR (400 MHz, DMSO-66) δ 9.09 (s, 1H), 8.64 (d, J=8.3 Hz, 1H), 8.24-8.01 (m, 1H), 7 .94 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 5.74 (p, J=8.6 Hz, 1H), 5.35 (s, 2H), 3 .94 (s, 2H), 2.61-2.54 (m, 2H), 2.48-2.42 (m, 2H), 2.35 (s, 3H), 1.98-1.78 (m, 2H), 1.56 (s, 3H), 1.38-1.09 (m, 2H), 1.06-0.66 (m, 2H); RX-MS m/z (ESI+) for (C ₂₄ H ₂₇ N ₇ O), 430.2 (M+H) ⁺ .

Example 66: 2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4-[(methylamino)methyl]-6-[(2R )-2methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

HN\Pr.-bb

Step 1: tert-butyl ({2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2R)-2methylpyrolidinyl- 1 -yl] -1 -oxo-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-4-yl } methyl)methylcarbamate

To a solution of intermediate 19 (80.0 mg, 0.222 mmol), intermediate 18 (93.6 mg, 0.333 mmol), and K3PO4 (141 mg, 0.666 mmol) in 1,4-dioxane (5.0 mL) in Pd ₂ (dba) ₃ (20.3 mg, 0.0223 mmol) and Xantphos (25.7 mg, 0.0444 mmol) were added under N2 atmosphere. The mixture was bubbled with N2 for 2 minutes and then sealed and stirred at 85°C for 18 hours. TLC analysis (EtOAc) showed consumption of the starting material. The mixture was concentrated to dryness. The residue was purified using flash chromatography (SiO ₂ , 1:10 MeOH/EtOAc) to give tert-butyl ({2-[6-(4,5-diethyl-4H1,2,4-triazol-3-yl)pyridine -2-yl]-6-[(2R)-2-methylpyridinyl-1-yl]-1-oxo-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate ( 120 mg, >99% yield) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.69 (b.d., J=8.3 Hz, 1H), 8.09 (b.d., J=7.5 Hz, 1H), 7, 97-7.73 (m, 1H), 6.72 (s, 1H), 5.14-4.90 (m, 2H), 4.73-4.43 (m, 5H), 4.31- 4.16 (m, 1H), 3.70-3.52 (m, 2H), 3.44-3.29 (m, 2H), 2.99 (b.s., 3H), 2.92 -2.77 (m, 2H), 2.20-1.96 (m, 3H), 1.80-1.70 (m, 1H), 1.62 (s, 9H), 1.43-1 .38 (m, 3H), 1.32-1.11 (m, 3H). X-ray MS m/z (ESI+) for (C ₃₀ H ₄₀ N ₈ O ₃ ), 561.4 (M+H) ⁺ .

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Step 2: 2-[6-(4,5-diethyl-4H-1,2,4-triαzol-3-yl)pyridin-2-yl]-4-[(methylamino)methyl]-6-[(2R )-2methylpyrrolidinil-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride

Suspension of tert-butyl ({2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(2R)-2methylpyrolidinyl-1 -yl]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (120 mg, 0.222 mmol) in EtOAc (10.0 ml) cooled to 0°C and treated with HCl solution (4.0 N in EtOAc, 5.0 ml). The mixture was stirred for 2 hours. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness. The residue was purified using preparative HPLC with a Phenomenex Gemini-NX column (150x30 mm, 5 μm particle size) which was eluted with 12-42% MeCN/H ₂ O (+0.05% HCl) at a flow rate of 30 ml/min to obtain 2-[6-(4,5-diethyl-4H-1,2,4triazol-3-yl)pyridin-2-yl]-4-[(methylamino)methyl]-6-[(2R)-2-methylpyrolidinyl -1-yl]-2,3-dihydro-1Hpyrrolo[3,4-e]pyridin-1-one, isolated as hydrochloric acid salt (72.0 mg, 66% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.65-9.29 (m, 2H), 8.73 (d, J=8.4 Hz, 1H), 8.33-8.13 (m , 1H), 8.02 (d, J=7.6 Hz, 1H), 6.75 (s, 1H), 5.21 (s, 2H), 4.66 (sq., J=7.1 Hz, 2H), 4.42-4.28 (m, 3H), 3.65 (t, J=8.7 Hz, 1H), 3.50 - 3.30 (m, 1H), 3.10 (sq., J=7.5 Hz, 2H), 2.72 (t, J=5.3 Hz, 3H), 2.21-1.93 (m, 3H), 1.81-1.64 (m, 1H), 1.51 (t, J=7.1 Hz, 3H), 1.43 (t, J=7.5 Hz, 3H), 1.21 (d, J=6.2 Hz , 3H); RX-MS m/z (ESI+) for (C ₂₅ H ₃₂ N ₈ O), 461.3 (M+H) ⁺ .

Example 67: 2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4-[(methylamino)methyl]-6[methyl(propane) -2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-e]pyridin-1-one

Step 1: tert-butyl ({2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[methyl(propan-2yl) amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate

To a solution of tert-butyl methyl({6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4e]pyridin-4-yl}methyl)carbamate ( see synthesis in Example 63) (100 mg, 0.287 mmol), intermediate 18 (80.7 mg, 0.287 mmol) and K3PO4 (183 mg, 0.861 mmol) in 1,4-dioxane (5.0 mL) under N2 Pd ₂ (dba) ₃ (26.3 mg, 0.0287 mmol) and Xantphos (33.2 mg, 0.0574 mmol) were added. The mixture was bubbled with N2 for 2 min, sealed, and stirred at 85°C for 18 h. X-ray MS analysis showed consumption of the starting material. The mixture was filtered through Celite®. The filter cake was washed with EtOAc (100 ml). The combined filtrate was concentrated to dryness and purified using preparative TLC (EtOAc) to give tert-butyl ({2-[6-(4,5-diethyl-4H-1,2,4-triazol-3yl)pyridin-2-yl] -6-[methyl(propan-2-yl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-e]pyridin-4yl}methyl)methylcarbamate (120 mg, 76% yield) as a yellow solid.

1H NMR (400 MHz, CDC13) δ 8.70 (d, J=8.2 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.99-7.80 (m , 1H), 6.89 (s, 1H), 5.12-5.01 (m, 1H), 4.98-4.84 (m, 2H), 4.71-4.62 (m, 2H ), 4.58-4.26 (m, 2H), 3.04-2.96 (m, 3H), 2.94 (s, 3H), 2.89 (sq., J=7.5 Hz , 2H), 1.51 (t, J=7.5 Hz, 3H), 1.45-1.34 (m, 12H), 1.23 (s, 3H), 1.21 (s, 3H) . X-ray MS m/z (ESI+) for (C29H40N8O3), 549.2 (M+H) ⁺ .

Step 2: 2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4-[(methylamino)methyl]-6[methyl(propane) -2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-e]pyridin-1-one hydrochloride

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Solution of tert-butyl ({2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[methyl(propan-2yl)amino] -1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl}methyl)methylcarbamate (120 mg, 0.219 mmol) in EtOAc (1.0 ml) was cooled to 0°C and treated dropwise with HCl solution (4.0 N in EtOAc, 5.0 ml). The mixture was stirred for 2 hours at room temperature. X-ray MS analysis showed consumption of the starting material. The resulting solids were collected by filtration. The filtered cake was dried in vacuum to obtain 2-[6-(4,5-diethyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-6- [methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, isolated as hydrochloric acid salt (95 mg, 90% yield) as yellow solid matter.

1H NMR (400 MHz, DMSO-d6) δ 9.23 (b.s., 2H), 8.67 (d, J=8.4 Hz, 1H), 8.19-8.09 (m, 17 ,9H), 9 (d, J=7.7 Hz, 1H), 6.92 (s, 1H), 5.16 (s, 2H), 5.11-4.97 (m, 1H), 4 .57 (sq., J=6.4 Hz, 2H), 4.33 (t, J=6.0 Hz, 2H), 3.01-2.88 (m, 5H), 2.72 (t , J=5.4 Hz, 3H), 1.45 (t, J=7.1 Hz, 3H), 1.39 (t, J=7.5 Hz, 3H), 1.18 (s, 3H ), 1.16 (s, 3H); RXMS m/z (ESI+) for (C ₂ 4H3 ₂ N8O), 449.2 (M+H)+.

Example 68: 4-(aminomethyl)-2-{6-[(4R)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}6-[(2R )-2-methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Step 1: tert-butyl [(6-chloro-2-{6-[(4K)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2yl}-1-oxo -2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate

To a solution of intermediate 20 (462 mg, 1.68 mmol), intermediate 7 (500 mg, 1.68 mmol), K ₂ CO ₃ (511 mg, 3.69 mmol), and N,N-dimethylethylenediamine (74 .0 mg, 0.840 mmol) CuI (80.0 mg, 0.420 mmol) was added. The mixture was bubbled with N ₂ for 5 minutes and then stirred at 120°C for 1.5 hours under microwave irradiation. X-ray MS analysis showed consumption of the starting material. The mixture was diluted with H ₂ O (8 ml) and MeCN (1 ml), and the resulting solids were collected by filtration. The filter cake was washed with _H2O (3x2 ml) and MeCN (4x1 ml) and dried in vacuum to give tert-butyl [(6-chloro-2-{6-[(4R)-4-(fluoromethyl)-2-oxo -1,3-oxazolidin-3yl]pyridin-2-yl}-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate (595 mg, 72 % yield) as a white solid.

1H NMR (400 MHz, DMSOL) δ 8.22 (d, J=7.9 Hz, 1H), 8.03-7.97 (m, 1H), 7.92 (d, J=8.1 Hz , 1H), 7.80 (s, 1H), 7.54 (t, J=6.2 Hz, 1H), 5.31-5.00 (m, 4H), 4.87-4.71 ( m, 1H), 4.65 (t, J=8.9 Hz, 1H), 4.59-4.50 (m, 1H), 4.41 (d, J=6.0 Hz, 2H), 1.39 (s, 9H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -238.40 (s, 1F); m/z (ESI+) for (C ₂₂ H ₂₃ ClFN ₅ O ₅ ), 436.1 (M-tBu+H)+.

Step 2: tert-butyl [(2-{6-[(4R)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-6[(2R) -2-methylnyrolidinyl-1-yl]-1-oxo-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate

A solution of tert-butyl [(6-chloro-2-{6-[(4K)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate (595 mg, 1.21 mmol), (2R)-2methylpyrrolidinyl (294 mg, 2.42 mmol) and Cs ₂ CO ₃ (2.36 g, 7.26 mmol) in 1,4-dioxane was bubbled with argon for 3 min and RuPhos Pd G3 (101 mg, 0.121 mmol) was added. The mixture was bubbled with argot

- 110 044841 nom for 3 minutes, sealed tightly, and stirred at 100°C for 16 hours. X-ray MS analysis showed consumption of the starting material. The mixture was filtered and the filter cake was washed with EtOAc (2x10 ml). The combined filtrate was concentrated to dryness. The crude material was purified by flash chromatography (8 g SiO ₂ , 1:1 EtOAc/petroleum ether). The desired fractions were concentrated to dryness. The residue was suspended in EtOAc/petroleum ether (2:1, 10 ml) for 5 min at room temperature, and the solids were collected by filtration. The filter cake was washed with EtOAc/petroleum ether (2:1, 3x10 ml) and dried in vacuum. The solids were dissolved in MeOH/EtOAc (1:10, 30 ml). Ultra-pure Si-Thio SiO ₂ (1 g) was added and the mixture was stirred at 50°C for 30 minutes. The mixture was filtered and the filter cake was washed with MeOH/EtOAc (1:10, 3x30 ml). The filtrate was concentrated to dryness. The Ultra-pure Si-Thio SiO ₂ treatment was repeated in an identical manner (4 times). The crude material was purified by flash chromatography (SiO ₂ , 1:10 MeOH/EtOAc) to give tert-butyl [(2-{6-[(4R)-4-(fluoromethyl)-2-oxo-1,3-oxazolidine- 3-yl]niridin-2-yl}-6-[(2R)-2methylpyridinyl-1-yl]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl )methyl]carbamate (330 mg, 51% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J=8.0 Hz, 1H), 8.01-7.91 (m, 1H), 7.87 (d, J=8 ,1 Hz, 1H), 7.25 (t, J=6.0 Hz, 1H), 6.56 (s, 1H), 5.20-4.90 (m, 4H), 4.79 (dd , J=45.8, 10.0 Hz, 1H), 4.64 (t, J=8.9 Hz, 1H), 4.574.48 (m, 1H), 4.26 (dd, J=6, 0, 2.0 Hz, 2H), 4.21 (t, J=6.2 Hz, 1H), 3.58-3.50 (m, 1H), 3.33-3.29 (m, 1H ), 2.102.01 (m, 2H), 1.97-1.87 (m, 1H), 1.73-1.58 (m, 1H), 1.39 (s, 9H), 1.20 ( d, J=5.4 Hz, 3H); ¹⁹ F NMR (377 MHz, DMSO-d6) δ -238.33 (s, 1F); m/z (ESI+) for (C ₂₇ H ₃₃ FN ₆ O ₅ ), 541.3 (M+H) ⁺ .

Step 3: 4-(aminomethyl)-2-{6-[(4R)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-6[(2R )-2-methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride

A solution of tert-butyl [(2-{6-[(4R)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-6-[(2R)2 -methylpyridinyl-1-yl]-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl]carbamate (300 mg, 0.610 mmol) in EtOAc (5.0 ml) and MeOH (10.0 ml) were cooled to 0°C and treated with HCl solution (4.0 N in EtOAc, 5.0 ml). The reaction mixture was stirred at room temperature for 9 hours. X-ray MS analysis showed consumption of the starting material. The mixture was concentrated to dryness. The solids were dissolved in H2O (25 ml) and washed with EtOAc (20 ml). The aqueous layer was concentrated to dryness. The residue was purified using preparative HPLC with a Phenomenex Gemini-NX column (150x30 mm, 5 μm particle size), which was eluted with 24-44% MeCN/H ₂ O (+0.05% HCl) at a flow rate of 30 ml/min to obtain 4-(aminomethyl)-2-{6-[(4R)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2yl}-6-[(2R)-2- methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4ω]pyridin-1-one, isolated as the hydrochloride salt (200 mg, 69% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-Y6) δ 8.53 (b.s., 3H), 8.24 (d, J=8.0 Hz, 1H), 8.08-7.94 (m, 1H ), 7.89 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 5.21-4.99 (m, 4H), 4.74 (b.d., J =9.8 Hz, 1H), 4.64 (t, J=8.9 Hz, 1H), 4.52 (dd, J=3.3, 8.5 Hz, 1H), 4.39-4 .29 (m, 1H), 4.25-4.15 (m, 2H), 3.63 (sh.t., J=8.7 Hz, 1H), 3.47-3.34 (m, 1H), 2.14-1.94 (m, 3H), 1.77-1.68 (m, 1H), 1.20 (d, J=6.0 Hz, 3H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -238.09 (s, 1F); m/z (ESI+) for (C22H2 ₅ FN6O ₃ ), 441.3 (M+H) ⁺ .

Additional compounds according to the invention in table. 1A and 1B were prepared using modifications of the methods given herein as examples. The use of or 1 in the structure and ξ in the name identifies a chiral center that has been separated into two separate enantiomers, but the specific enantiomer has not been confirmed; the structure shows a solid or dotted wedge, but the actual enantiomer may be a different enantiomer. They are labeled absolute stereochemistry unknown and involve optical rotation of the polarized area of light. Compounds labeled absolute stereochemistry known were usually prepared from intermediates having known stereochemistry.

The compounds and their corresponding characteristic data are presented in table. 1A below, where the method used to obtain the compound is indicated in parentheses under the example number:

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Table 1A

Etc. No. IUPAC structure/name RX-MS [M+H] ^{+ 1} NMR(m.h.); ¹⁹ F NMR (m.p.); rotation of the light polarization area; stereochemical notes 69 (WITH) 1 /A / N N x /u/r Jv HN \ 6-cyclobutyl-4- [(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1 /7pyrrolo[3,4-c]pyridin-1-one 418.3 ^1H NMR (400 MHz, DMSO- _s76 ) δ 9.17 -9.10 (m, 2H), 8.97 (s, 1H), 8.668.58 (m, 1H), 8.18-8, 09 (m, 1H), 7.98-7.91 (m, 1H), 7.71 (s, 1H), 5.42 (hept., 4=6.7 Hz, 1H), 5.25 ( s, 2H), 4.52 (t, 4=5.7 Hz, 2H), 3.88 (sq., 4=8.6 Hz, 1H), 2.78 (t, 4=5.1 Hz , ZN), 2.53 (s, 1H), 2.50-2.38 (m, 2H), 2.42 - 2.32 (m, 1H), 2.36 - 2.27 (m, 1H ), 2.14-1.97 (m, 1H), 1.98-1.84 (m, 1H), 1.59 (d, 4=6.7 Hz, 6H). 70 (R) / /\ / /N N\ - HN\ 6-[ethyl(propan-2-yl)amino]-4[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1,2,4-triazol-3yl ]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 449.0 ¹ H NMR (600 MHz, DMSO-de) δ 8.93 (s, 1H) 8.61 (d, 4=8.44 Hz, 1H) 8.07 8.13 (m, 1H) 7.93 ( d, 4=7.52 Hz, 1H) 6.77 (s, 1H) 5.49 (dt, 4=73.25, 6.67 Hz, 1H) 5.12 (s, 2H) 4.84 - 4.93 (m, 1H) 4.06 (s, 2H) 3.14 - 3.20 (m, 2H) 2.53 - 2.58 (m, ZN) 1.58 (d, 4=6, 60 Hz, 6H) 1.15-1.21 (m, 9H)

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71 (0) 1 Λ\av d A A' ΗΝ\ 2-[6-(4-ethyl-4/7-1,2,4-triazol-3yl)pyridin-2-yl]-4- [(methylamino)methyl]-6- [methyl(propan-2-yl)amino]-2,3- Dihydro-1/7-pyrrolo[3,4-c]pyridin1-one 421.0 ^1H NMR (400 MHz, DMSO-de) δ 8.64 - 8.74 (m, 1H) 8.60 (b.s., 1H) 8.04 8.12 (m, 1H) 7.98 - 8.02 (m, 1H) 6.78 (s, 1H) 5.18 (s, 2H) 4.90 (dt, 7=13.05, 6.37 Hz, 1H) 4.60 - 4.75 (m, 2N) 3.85 (sh.s., 2N) 2.91 (s, ZN) 2.41 (s, ZN) 1.52 (t, 7=7.09 Hz, ZN) 1.19 (d, 7=6.48 Hz, 6H). 72 ϊ Λ \Aj „a / \ ___/ / orl\ ----\ ^Z \ HN _F /\ 517.3 ^1H NMR (600 MHz, DMSO-s/b) δ 9.06 (s, 1H), 8.65 (d, 7=8.44 Hz, 1H), 8.10 (t, 7=7.98 Hz, 1H), 7.97 (d, 7=7.52 Hz, 1H), 6.79 (s, 1H), 5.94-6.15 (m, 1H), 5.05-5.22 (m, 2H), 4.81-5.01 (m, 1H), 3.86 (sh.s., 2H), 3.14-3.20 (m, (0) 4-[(methylamino)methyl]-6- [methyl(propan-2-yl)amino]-2-(6-{4[(3ξ)-1,1,1-trifluoropentan-3-yl]-4/71,2,4-triazol-3-yl }pyridin-2-yl)2,3-dihyde rho-1 /7-pyrrolo[3,4c]pyridin-1-one 1H), 2.94-3.05 (m, 1H), 2.89 (s, ZN), 1.90-2.14 (m, 2H), 1.34 (s, ZN), 1.15 (d, 7=6.42 Hz, 6H), 0.84 (t, 7=7.34 Hz, ZN). absolute stereochemistry unknown*

- 113 044841

73 (0) ι Λ US /S. / Ν Τ ⁵ ^ \ \^<JV 3 V ^Η \ 4 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-(6-{4[(3ξ)- 1,1,1-trifluoropentan-3-yl]-4/71,2,4-triazol-3-yl}pyridin-2-yl)2,3-dihyde rho-1/7-pyrrolo[3,4c] pyridin-1-one 74 (T) K,Od Ν G y— --- ^--N ^ ⁼ \HN\ 4-[(methylamino)methyl]-2-{6-[(48)-4methyl-2-oxo-1,3-oxazolidin-3yl ]pyridin-2-yl}-6-[methyl(propan2-yl)amino]-2,3-dihyde rho-1 Npyrrolo[3,4-c]pyridin-1-one 75 (0) ζ 1 Λ h ₂ n 4-(aminomethyl)-6-(diethylamino)-2[6-(4-ethyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-2, 3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

517.3 ^1H NMR (600 MHz, DMSO-< ₇₆ ) δ 9.06 (s, 1H), 8.64 (d, 7=8.44 Hz, 1H), 8.10 (t, 7=8.07 Hz, 1H), 7.97 (d, 7=7.52 Hz, 1H), 6.78 (s, 1H), 6.05 (d, 7=4.03 Hz, 1H), 5.04- 5.20 (m, 2H), 4.83-5.01 (m, 1H), 3.85 (sh.s., 2H), 3.10-3.21 (m, 1H), 2.95 -3.06 (m, 1H), 2.88 (s, ZN), 1.92-2.17 (m, 2H), 1.34 (s, ZN), 1.121.20 (m, 6H), 0.84 (t, 7=7.34 Hz, ZN). absolute stereochemistry unknown* [M+Na] ⁺ 447.2 ¹ H NMR (400 MHz, DMSO-sub) δ 9.34 - 9.10 (m, 2H) 8.23 (d, 7=8.0 Hz, 1H) 7.95 (t, 7=8.2 Hz, 1H) 7.82 (d, 7=8.0 Hz, 1H) 6.88 (s, 1H) 5.12 (m, 1H) 5.01 (sh.s., 2H) 4.98 - 4.90 (m, 1H) 4.61 (t, 7=8.3 Hz, 1H) 4.34 (wd„ 7=3.0 Hz, 2H) 4.17 (dd, 7=3, 8, 8.3 Hz, 1H) 2.93 (s, ZN) 2.72 (sh.t., 7=5.3 Hz, ZN) 1.49 (d, 7=6.0 Hz, ZN) 1.17 (d, 7=6.5 Hz, 6H). absolute stereochemistry is known [M+Na] ⁺ 429.2 ¹ H NMR (400 MHz, DMSO-sub) δ 9.08 (s, 1H) 8.66 (d, 7=8.3 Hz, 1H) 8.44 (b.s., ZN) 8.15 ( t, 7=8.0 Hz, 1H) 8.02 (d, 7=7.5 Hz, 1H) 6.85 (s, 1H) 5.16 (s, 2H) 4.67 (sq., 7 =7.2 Hz, 2H) 4.24 (sq., 7=5.0 Hz, 2H) 1.51 (t, 7=7.2 Hz, ZN) 1.16 (t, 7=6.9 Hz, 6H).

- 114 044841

76 (0) ι ΧΎ „ A—l 1 / ^Ν _ΗΝ —/ ν-* Cf ( ^Η \ 6-(ethylamino)-2-[6-(4-ethyl-4/7-1,2,4triazol-3-yl)pyridine -2-yl]-4[(methylamino)methyl]-2,3-dihydro1/7-pyrrolo[3,4-c]pyridin-1-one 77 (0) ι Λ --/ ^Ν ^ ⁼ \ ΗΝ\ 6-(ethylamino)-4-[(methylamino)methyl]-2-{6-[4-(propan-2-yl)-4/7-1,2, 4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 78 (WITH) 1 Λ / N \ _HN -yJ - HN\ 4-[(methylamino)methyl]-6-(propan-2ylamino)-2-{6-[4-(propan-2-yl)-4/71.2, 4-triazol-3-yl]pyridin-2-yl}2,3-dihyde po-1 /7-pyrrolo[3,4c]pyridin-1-one

393.3 ¹ H NMR (400 MHz, DMSO-db) δ 9.33 (b.s., 2H) 9.19 (s, 1H) 8.66 (d, 7=8.3 Hz, 1H) 8.15 ( t, 7 = 8.1 Hz, 1H) 8.02 (d, 7 = 7.6 Hz, 1H) 6.87 (s, 1H) 5.17 (s, 2H) 4.68 (sq., 7 =7.2 Hz, ZN) 4.28 (sh.t., 7=5.6 Hz, 2H) 3.45 (sq., 7=7.1 Hz, 2H) 2.76 - 2.66 ( m, ZN) 1.52 (t, 7=7.2 Hz, ZN) 1.19 (t, 7=7.2 Hz, ZN). 406.9 ¹ H NMR (400 MHz, DMSO-cO δ 9.23 (s, ZH) 8.65 (d, 7=8.3 Hz, 1H) 8.15 (t, 7=8.0 Hz, 1H) 7 .96 (d, 7=7.5 Hz, 1H) 6.86 (s, 1H) 5.57-5.40 (m, 1H) 5.16 (s, 2H) 4.25 (sh.s. , 2H) 3.45 (sq., 7=7.0 Hz, 2H) 2.72 (sh.t., 7=5.1 Hz, ZN) 1.61 (d, 7=6.5 Hz, 6H) 1.19 (t, 7 = 7.2 Hz, ZN). 421.2 ^1H NMR (500 MHz, DMSO-cO δ 8.88 (s, 1H) 8.55 (d, 7=7.78 Hz, 1H) 8.01 (t, 7=8.01 Hz, 1H) 7 .88 (d, 7=7.48 Hz, 1H) 6.60 (s, 1H) 6.55 (d, 7=7.73 Hz, 1H) 5.51 (quin., 7=6.68 Hz , 1H) 5.07 (s, 2H) 3.96 (dq, 7=13.41,6.57 Hz, 1H) 3.71 (s, 2H) 2.28 (s, ZN) 1.51 ( d, 7=6.71 Hz, 6H) 1.11 (d, 7=6.41 Hz, 6H).

- 115 044841

4-(aminomethyl)-6-[methyl(propan-2yl)amino]-2-{6-[4-(propan-2-yl)-4/71,2,4-triazol-3-yl]pyridin- 2-yl}2,3-dihyde rho-1 /7-pyrrolo[3,4c]pyridin-1-one

[M+Na]’

443.1

4-[(methylamino)methyl]-6[methyl(propan-2-yl)amino]-2-[6-(4methyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl] -2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

6-(diethylamino)-4[(methylamino)methyl]-2-[6-(4propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-2,3-dihydro-1Hpyrrolo [3,4-c]pyridin-1-one ^1H NMR (400 MHz, DMSO-cO δ 9.49 (s, 1H) 8.69 (d, >8.3 Hz, 1H) 8.56 (w .s., ZN) 8.17 (t, >8.0 Hz, 1H) 7.98 (d, >7.5 Hz, 1H) 6.89 (s, 1H) 5.58 5.47 (m , 1H) 5.19 (s, 2H) 5.13 -4.95 (m, 1H) 4.21 (w. d„ >5.5 Hz, 2H) 2.94 (s, ZN) 1.63 (d, >6.8 Hz, 6H) 1.17 (d, >6.8 Hz, 6H).

^1H NMR (600 MHz, DMSO-sub) δ 8.73 (s, 1H), 8.61 (d, >8.25 Hz, 1H), 8.048.15 (m, 1H), 8.00 (d , >7.52 Hz, 1H), 6.76 (s, 1H), 5.11 (s, 2H), 4.52-4.62 (m, 2H), 3.96 (s, 2H), 3.59 (sq., >6.97 Hz, ZN), 2.49 (s, ZN), 1.811.94 (m, 2H), 1.34 (s, 1H), 1.15 (t, > 6.97 Hz, 6H), 0.94 (t, >7.34 Hz, ZN).

¹ H NMR (400 MHz, DMSO-sub) δ 9.43 -9.30 (m, 2H) 9.21 (s, 1H) 8.67 (d, >8.5 Hz, 1H) 8.16 ( t, >8.0 Hz, 1H) 8.02 (d, >7.5 Hz, 1H) 6.91 (s, 1H) 5.21 (s, 2H) 5.14 - 4.93 (m, 1H) 4.36 (bt., >5.6 Hz, 2H) 4.20 (s, ZN) 2.93 (s, ZN) 2.74-2.68 (m, ZN) 1.17 (d, >6.5 Hz, 6H).

- 116 044841

82 (0) L i X . \^yJ O --/ h ₂ n 4-(aminomethyl)-6-[methyl(propan-2yl)amino]-2-[6-(4-propyl-4/7-1,2,4triazol-3- yl)pyridin-2-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one 83 (WITH) to XX' / Ν Ν \ <LfyJ X ^Р Ύ HN\ 2-{5-fluoro-6-[4-(propan-2-yl)-4/7- 1,2,4-triazol-3-yl]pyridin-2-yl}-4[(methylamino)methyl]-6-(1 - methylcyclopropyl)-2,3-dihydro-1/7- pyrrolo[3,4-c]pyridin-1-one 84 (WITH) / X \ //N\ \_f\J L/ Wed ( HN\ 6-[ethyl(propan-2-yl)amino]-2-[6-(4ethyl-4H-1,2,4-triazol-3- yl)pyridin-2-yl]-4- [(methylamino)methyl]-2,3-dihydro1 H-pyrrolo[3,4-c]pyridin-1-one

421.3 ^1H NMR (400 MHz, DMSO-sub) δ 9.08 (s, 1H) 8.67 (d, 4=8.3 Hz, 1H) 8.51 (b.s., ZN) 8.14 ( t, 4=7.9 Hz, 1H) 8.03 (d, 4=7.5 Hz, 1H) 6.89 (s, 1H) 5.15 (s, 2H) 5.10-4.98 ( m, 1H) 4.61 (sh.t., 4=7.2 Hz, 2H) 4.27-4.18 (m, 2H) 2.94 (s, ZN) 1.95 - 1.86 ( m, 2H) 1.17 (d, 4=6.8 Hz, 6H) 0.96 (t, 4=7.3 Hz, ZN). 436.1 ^1H NMR (400 MHz, DMSO-sub) δ 9.01 -9.05 (m, 1H) 8.66 -8.76 (m, 1H) 8.09-8.16 (m, 1H) 7, 53 -7.59 (m, 1H) 5.21 - 5.27 (m, 2H) 4.95 - 5.04 (m, 1H) 3.84 -3.90 (m, 2H) 2.30 2 .34 (m, ZN) 1.61 - 1.65 (m, 4N) 1.54 (d, 4=6.85 Hz, 6N) 1.24 (wd„ 4=2.69 Hz, 2N ) 0.85 - 0.87 (m, 2H). 435.1 ^1H NMR (600 MHz, DMSO-sub) δ 8.73 (s, 1H) 8.53 - 8.63 (m, 1H) 8.03 - 8.09 (m, 1H) 7.96 -8, 01 (m, 1H) 6.71 (s, 1H) 5.13 (s, 2H) 4.80 - 4.86 (m, 1H) 4.62 (sq., J=7.15 Hz, 2H) 3.86 (s, 2H) 3.18 - 3.35 (m, 2H) 2.40 (s, ZN) 1.49 (t, J=7.15 Hz, ZN) 1.13- 1.19 (m, 9N)

- 117 044841

\\ ίΑ /7 85 <Uy _Z U / Ν=/ (Μ) η ₂ ν 4-(aminomethyl)-2-{6-[(4/?)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-6( 1-methylcyclopropyl)-2,3-dihyde po1 H-pyrrolo[3,4-c]pyridin-1-one 86 moss A-/ ^Ν \ \ (Μ) η ₂ ν 4-(aminomethyl)-6-cyclopropyl-2{6-[(4R)-4-(fluoromethyl)-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}2,3- Dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one 87 (Μ) / A ^{7 N=} \ ί HN \ 6-cyclopropyl-2-{6-[(4/?)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl }-4[(methylamino)methyl]-2,3-dihydro1/-/-pyrrolo[3,4-c]pyridin-1-one

412.5 ¹ H NMR (600 MHz, DMSO-de) δ 8.33 - 8.16 (m, 4H), 7.98 (t, 4=8.1 Hz, 1H), 7.89 (d, 4=8 ,1 Hz, 1H), 7.65 (s, 1H), 5.25-4.96 (m, 4H), 4.74 (s, 1H), 4.64 (t, 4=8.8 Hz , 1H), 4.51 (dd, 4=8.7, 3.3 Hz, 1H), 4.35 (d, 4=9.1 Hz, 2H), 1.57 (s, ZN), 1 .50-1.37 (m, 2H), 0.89 (d, 4=2.7 Hz, 2H). absolute stereochemistry is known 398.5 ¹ H NMR (600 MHz, DMSO-sub) δ 8.28 - 8.17 (m, 4H), 7.97 (t, 4=8.1 Hz, 1H), 7.89 (d, 4=8 ,0 Hz, 1H), 7.71 (s, 1H), 5.20-4.97 (m, 4H), 4.77 (ddd, 4=45.6, 10.1, 1.8 Hz, 1H), 4.63 (t, 4=8.9 Hz, 1H), 4.51 (dd, 4=8.6, 3.3 Hz, 1H), 4.38-4.27 (m, 2H ), 2.33 (ddd, 4=8,1,4,8, 3.4 Hz, 1H), 1.21 1.12 (m, 2H), 1.03 (dd, 4=8.1, 3.1 Hz, 2H). absolute stereochemistry is known 412.3 ^1H NMR (400 MHz, DMSO-sub) δ 8.95 (s, 2H), 8.25 (dd, 4=8.0, 0.7 Hz, 1H), 7.99 (t, 4=8 ,1 Hz, 1H), 7.91 (dd, 4=8.2, 0.8 Hz, 1H), 7.76 (s, 1H), 5.23 - 4.96 (m, 4H), 4 .77 - 4.61 (m, 2H), 4.57-4.38 (m, ZN), 2.54 (s, 2H), 2.41-2.31 (m, 1H), 1.17 (dq, 4=5.2, 3.1 Hz, 2H), 1.06 (dt, 4=8.2, 3.1 Hz, 2H). absolute stereochemistry is known

- 118 044841 (Q)

^1H NMR (600 MHz, DMSO-s/ ₆ ) δ 8.73 (s, 1H), 8.62 (d, 4=8.25 Hz, 1H), 8.058.16 (m, 1H), 8, 01 (d, 4=7.52 Hz, 1H),

435.4

6.73 (s, 1H), 5.14 (s, 2H), 4.65 (sq., 4=7.21 Hz, 2H), 3.60 (s, 2H), 3.5489 (R)

6-(diethylamino)-4[(dimethylamino)methyl]-2-[6-(4-ethyl4/7-1,2,4-triazol-3-yl)pyridin-2yl]-2,3-dihydro-1H -pyrrolo[3,4c]pyridin-1-one

4-(aminomethyl)-2-[6-(4-ethyl-4/71,2,4-triazol-3-yl)pyridin-2-yl]-6[methyl(propan-2-yl)amino]- 2,3dihydro-1/7-pyrrolo[3,4-c]pyridine407.3

3.58 (m, 4H), 2.23 (s, 6H), 1.52 (t, 4=7.15 Hz, ZN), 1.14 (t, 4=6.97 Hz, 6H).

¹ H NMR (400 MHz, DMSO-<4 ₆ ) δ 8.75 (s, 1 H) 8.63 (dd, 4 = 8.38, 0.67 Hz, 1 H) 8.06 - 8.16 (m, 1 N) 7.93 - 8.04 (m, 1 N) 6.75 (s, 1 N) 5.21 (s, 2 N) 4.88 5.05 (m, 1 N) 4 .64 (sq., 4=7.25 Hz, 2 N) 3.88 (s, 2 N) 2.89 (s, 3 N) 1.50 (t, 4=7.09 Hz, 3 N) 1.16 (d, 4=6.72 Hz, 6 N).

1-on (O)

404.3

4-(aminomethyl)-6-(1 methylcyclopropyl)-2-[6-(4-propyl4/7-1,2,4-triazol-3-yl)pyridin-2yl]-2,3-dihydro-1/ 7-pyrrolo[3,4c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-<4 ₆ ) δ 8.75 (s, 1H) 8.63 (d, 4=8.3 Hz, 1H) 8.11 (t, 4=7.9 Hz, 1H) 8.03 (d, 4=7.5 Hz, 1H) 7.55 (s, 1H) 5.29 (s, 2H) 4.58 ( w.t., 4=7.3 Hz, 2H) 3.96 (s, 2H) 1.95-1.81 (m, 2H) 1.56 (s, ZN) 1.36-1.15 ( m, 2H) 0.94 (t, 4=7.3 Hz, ZN) 0.89 - 0.84 (m, 2H).

- 119 044841

2-{6-[(4/?)-4-(fluoromethyl)-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}-4[(methylamino)methyl]-6-(1 methylcyclopropyl )-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

6-(azetidin-1-yl)-2-[6-(4-ethyl-4H1,2,4-triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-2,3 -dihydro1/7-pyrrolo[3,4-c]pyridin-1-one

6-(azetidin-1-yl)-4[(methylamino)methyl]-2-[6-(4propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-2,3 -dihydro-1Hpyrrolo[3,4-c]pyridin- ¹ -one 1H NMR (600 MHz, DMSO-sub) δ 8.27 -8.12 (m, 2H), 7.96 (t, 7=8 ,1 Hz, 1H), 7.86 (d, 7=8.1 Hz, 1H), 7.54 (s, 1H), 5.20-4.98 (m, 4H), 4.78 (ddd , 7=45.6, 10.0, 1.7 Hz, 1H), 4.62 (t, 7=8.8 Hz, 1H), 4.48 (dd, 7=8.6, 3.3 Hz, 1H), 3.94 (d, 7=1.6 Hz, 2H), 2.38 (s, ZN), 1.54 (s, ZN), 1.26 (sq., 7=2, 9 Hz, 2H), 0.85 (t, 7 = 3.2 Hz, 2H). absolute stereochemistry known ¹ H NMR (400 MHz, DMSO-sub) δ 8.75 (s, 1H) 8.61 (d, 7=8.3 Hz, 1H) 8.07 (d, 7=8.0 Hz , 1H) 8.04- 7.98 (m, 1H) 6.54 (s, 1H) 5.18 (s, 2H) 4.63 (d, 7=7.0 Hz, 2H) 4.00 ( t, 7=7.4 Hz, 4H) 3.82 (s, 2H) 2.37 - 2.33 (m, 5H) 1.51 (t, 7=7.2 Hz, ZN).

^1H NMR (400 MHz, DMSO-sub) δ 8.74 (s, 1H) 8.62 (d, 7=7.8 Hz, 1H) 8.07 (d, 7=8.0 Hz, 1H) 8.04- 7.99 (m, 1H) 6.55 (s, 1H) 5.16 (s, 2H) 4.58 (t, 7 = 7.2 Hz, 2H) 4.00 (t, 7 =7.4 Hz, 4H) 3.80 (s, 2H) 2.37 - 2.32 (m, 5H) 1.88 (w. d„ 7 = 7.3 Hz, 2H) 0.94 (t , 7=7.4 Hz, zn).

- 120 044841

4-[(methyl amino)methyl]-6-(1 methylcyclopropyl)-2-[6-(4-propyl4/7-1,2,4-triazol-3-yl)pyridin-2yl]-2,3- Dihydro-1/7-pyrrolo[3,4c]pyridin-1-one

2-[6-(4-ethyl-4H-1,2,4-triazol-3yl)pyridin-2-yl]-4[(methylamino)methyl]-6-(1 methylcyclopropyl)-2,3-dihydro -1Hpyrrolo[3,4-c]pyridin-1-one

6-(d ethylamino)-2-[6-(1-ethyl-2methyl-1/7-imidago1-5-yl)pyridin-2yl]-4-[(methylamino)methyl]-2,3dihydro-1/7 -pyrrolo[3,4-c]pyridin1-one ¹ H NMR (400 MHz, DMSO-sub) δ 8.75 (s, 1H) 8.63 (d, 7=8.0 Hz, 1H) 8.168.07 (m, 1H) 8.07 - 8.00 (m, 1H) 7.57 (s, 1H) 5.26 (s, 2H) 4.58 (t, 7 = 7.2 Hz, 2H) 3, 93 (s, 2H) 2.36 (s, ZN) 1.89 (six., 7=7.1 Hz, 2H) 1.56 (s, ZN) 1.27 (w. d„ 7=2, 3 Hz, 2H) 0.95 (t, 7=7.4 Hz, ZN) 0.89 - 0.86 (m, 2H).

^1H NMR (400 MHz, DMSO-sub) δ 8.76 (s, 1H) 8.64 (d, 7=8.3 Hz, 1H) 8.168.08 (m, 1H) 8.07 - 7.99 (m, 1H) 7.58 (s, 1H) 5.29 (s, 2H) 4.64 (sq., 7 = 6.8 Hz, 2H) 3.97 (s, 2H) 2.37 (s , ZN) 1.62 -1.48 (m, 6N) 1.26 (sh.s., 2N) 0.88 (sh. d„ 7 = 2.3 Hz, 2N).

^1H NMR (600 MHz, DMSO-sub) δ 8.87 (s, 2H), 8.53 (d, 7=8.5 Hz, 1H), 8.5 (t, 7=8.1 Hz, 2H), 7.65 (d, 7=7.7 Hz, 1H), 6.85 (s, 1H), 5.07 (s, 2H), 4.59 (sq., 7=7.1 Hz , 2H), 4.32 (t, 7=5.4 Hz, 2H), 3.63 (sq., 7=7.0 Hz, 4H), 2.74 (m, ZN), 2.64 ( s, ZN), 1.41 (t, 7=7.1 Hz, ZN), 1.14 (t, 7=7.0 Hz, 6N).

- 121 044841

6-[ethyl(propan-2-yl)amino]-2-{6[(4R)-4-(fluoromethyl)-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}-4[ (methylamino)methyl]-2,3-dihydro1H-pyrrolo[3,4-c]pyridin-1-one

6-(diethylamino)-2-[6-(4-ethyl-5methyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-4[(methylamino)methyl]-2,3 -dihydro1H-pyrrolo[3,4-c]pyridin-1-one

6-[ethyl(propan-2-yl)amino]-4[(methylamino)methyl]-2-[6-(4propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl] -2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1-one ^1H NMR (400 MHz, DMSO-s/b) δ 8.60 (d, 7=8.4 Hz, 1H), 8.05 (t, 7=7.9 Hz, 1H), 7.96 (d, 7=7.4 Hz, 1H), 6.71 (s, 1H), 5.15 (s, 2H), 4.53 (d, 7=7.0 Hz, 2H), 3.80 (s, 2H), 3.56 (sq., 7=6.8 Hz, 4H), 2.52 (s, ZN) , 2.36 (s, ZN), 1.46 (t, 7=7.0 Hz, ZN), 1.13 (t, 7=7.0 Hz, 6H).

^1H NMR (700 MHz, DMSO-s/b) δ 8.18 - 8.26 (m, 1H) 7.94 (t, 7=8.07 Hz, 1H) 7.85 (d, 7=8 ,17 Hz, 1H) 6.69 (s, 1H) 4.94-5.13 (m, 4H) 4.72 -4.87 (m, 2H) 4.62 (t, 7=8.82 Hz , 1H) 4.44 4.52 (m, 1H) 3.78 - 3.85 (m, 2H) 3.35 - 3.39 (m, ZN) 2.40 (s, ZN) 1.10 - 1.20 (m, 9H).

^1H NMR (600 MHz, DMSO-s/b) δ 8.72 (s, 1H) 8.59 - 8.63 (m, 1H) 8.05 - 8.10 (m, 1H) 7.99 ( dd, 7=7.70, 0.73 Hz, 1H) 6.71 (s, 1H) 5.12 (s, 2H) 4.78 4.84 (m, 1H) 4.57 (t, 7= 7.15 Hz, 2H) 3.79 (s, 2H) 3.33 - 3.36 (m, 2H) 2.33 2.38 (m, ZN) 1.87 (six., 7=7.30 Hz, 2H) 1.14 -1.20 (m, 9H) 0.93 (t, 7 = 7.43 Hz, ZN).

- 122 044841

100 (T)

411.3

4-(aminomethyl)-2-{6-[(45)-4-methyl2-oxo-1,3-oxazolidin-3 yl]pyridin-2-yl}-6-[methyl(propan2-yl)amino]- 2,3-dihyd rho-1 Npyrrolo[3,4-c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-cfe) δ 8.59 - 8.40 (m, ZN) 8.23 (d , 4=8.0 Hz, 1H) 7.95 (t, 4=8.0 Hz, 1H) 7.82 (d, 4=8.3

Hz, 1H) 6.86 (s, 1H) 5.17-5.08 (m, 1H) 5.08-4.91 (m, ZN) 4.60 (sh.t., 4=8.2 Hz, 1H) 4.29-4.20 (m, 2H)

4.17-4.14 (m,1N) 2.93 (s, ZN) 1.49 (w. d„ 4=6.0 Hz, ZN) 1.16 (w.

d.,4=6.3 Hz, 6H).

absolute stereochemistry is known

^1H NMR (400 MHz, DMSO-sub) δ 8.76 (s, 1H) 8.63 (d, 4=8.3 Hz, 1H) 8.158.07 (m, 1H) 8.06 - 8.00 (m, 1H) 7.53

404.3 (s, 1H) 5.32 (s, 2H) 4.65 (sq., 4=7.2

Hz, 2H) 4.00 (s, 2H) 3.79 (quin., 4 = 8.7 Hz, 1H) 2.37 (s, ZN) 2.35 - 2.29

6-cyclobutyl-2-[6-(4-ethyl-4/7-1,2,4triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-2,3-dihydro1/7 -pyrrolo[3,4-c]pyridin-1-one

102 (C)

6-{b|s[(pentabeu(epo)ethyl]amino}-2[6-(4-ethyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-4[( methylamino)methyl]-2,3-dihydro1/7-pyrrolo[3,4-c]pyridin-1-one (m, 4H) 2.10-1.98 (m, 1H) 1,941.81 (m, 1H ) 1.53 (t, 4=7.2 Hz, ZN).

¹ H NMR (400 MHz, DMSO-sub) δ 9.23 (b.s., 2H) 9.00 (b.s., 1H) 8.65 (d, 4=8.3 Hz, 1H) 8 .15 (t, 4=8.0 Hz, 1H) 8.02 (d, 4=7.5 Hz, 1H) 6.87 (s, 1H) 5.16 (s, 2H) 4.66 (kv ., 4=7.2 Hz, 2H) 4.33 (w. d„ 4=5.5 Hz, 2H) 2.73 (t, 4=5.3 Hz, ZN) 1.51 (t, 4 =7.2 Hz, ZN).

- 123 044841

103 (W) / Ν Ν \ ζ^ ^{Ν Ν} ^ ⁼ \ \ ΗΝ\ 6-cyclobutyl-4-[(methylamino)methyl]-2-[6-(4propyl-4/7-1,2,4-triazol-Zyl)pyridine -2-yl]-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 418.3 ^1H NMR (400 MHz, DMSO-sub) δ 8.75 (s, 1H) 8.63 (d, 4=8.3 Hz, 1H) 8.158.07 (m, 1H) 8.06 - 8.01 (m, 1H) 7.54 (s, 1H) 5.30 (s, 2H) 4.59 (t, 4 = 7.2 Hz, 2H) 4.00 (s, 2H) 3.80 (quin. , 4=8.7 Hz, 1H) 2.38 (s, ZN) 2.35 - 2.27 (m, 4H) 2.10- 1.98 (m, 1H) 1,951.81 (m, ZN) 0.95 (t, 4=7.4 Hz, ZN). 104 (WITH) " /A ! /ΛΊN\ HN\ 4-[(methylamino)methyl]-6-[(2R)-2methylpyrolidinyl-1-yl]-2-{6-[4(propan-2-yl)-4/7-1,2,4-triazol- 3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 447.3 ^1H NMR (600 MHz, DMSO-sub) δ 8.91 (d, 4=2.0 Hz, 1H), 8.77 (s, 1H), 8.59 (d, 4=8.7 Hz, 1H), 8.08 (t, 4=8.0 Hz, 1H), 7.90 (d, 4=7.8 Hz, 1H), 6.71 (s, 1H), 5.44 - 5, 32 (m, 1H), 5.06 (s, 2H), 4.29 (s, 2H), 3.60 (m, 1H), 3.333.23 (m, 2H), 2.95 (d, 4 =2.1 Hz, ZN), 2.09 - 1.93 (m, ZN), 1.66 - 1.72 (m, 1H), 1.54 (dd, 4 = 6.8, 2.1 Hz, 6H), 1.16 (dd, 4=6.4, 2.1 Hz, ZN). 105 (WITH) . 1 Λ A / Ν \ rVryJ V ^N ^\ \ HN\ 6-[(2R,5R)-2,5-dimethylpyrrolidinyl-1-yl]-4[(methylamino)methyl]-2-[6-(4propyl- 4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 461.7 ^1H NMR (600 MHz, DMSO-sub) δ 8.74 (s, 2H), 8.61 (dd, 4=8.4, 0.8 Hz, 1H), 8.10 (t, 4=8 .0 Hz, 1H), 8.05-7.94 (m, 1H), 6.75 (s, 1H), 5.15-5.01 (m, 2H), 4.53 (t, 4= 7.3 Hz, 2H), 4.31 (m, 4H), 2.74 (t, 4=5.3 Hz, ZN), 2.23 (s, 2H), 1.83 (sq., 4 =7.3 Hz, 2H), 1.74 1.58 (m, 2H), 1.11 (d, 4=6.2 Hz, 6H), 0.89 (t, 4=7.4 Hz, ZN). absolute stereochemistry is known

- 124 044841

106 (WITH) . ϊ l L / Ν Ν \ HN\ 6-[(2R,5R)-2,5- dimethylpyrolidinyl-1-yl]-2-[6-(4ethyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-4- [(methylamino)methyl]-2,3-dihydro1/7-pyrrolo[3,4-c]pyridin-1-one 107 (AA) . I HA 1 / Ν \ h ₂ n 4-(aminomethyl)-6-[(2R)-2methylpyrrolidinyl-1-yl]-2-{6-[4(propan-2-yl)-4/7-1, 2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 108 (R) ϊ HA //N\ U-J ΗΝ\ 6-[ethyl(propan-2-yl)amino]-4[(methylamino)methyl]-2-[6-(4-methyl4/7-1,2,4-triazol-3-yl)pyridin-2yl] -2,3-dihydro-1/7-pyrrolo[3,4c]pyridin-1-one

447.6 ¹ H NMR (400 MHz, DMSO-sub) δ 8.77 (s, 2H), 8.63 (d, 2=8.2 Hz, 1H), 8.13 (t, 2=8.0 Hz, 1H), 8.01 (d, 2=7.5 Hz, 1H), 6.78 (s, 1H), 5.18-5.03 (m, 2H), 4.62 (sq., 2= 7.1 Hz, 2H), 4.37 (m, 4H), 2.78 (t, 2=5.4 Hz, ZN), 2.26 (s, 2H), 1.69 (d, 2= 5.8 Hz, 2H), 1.48 (t, 2=7.2 Hz, ZN), 1.14 (d, 2=6.1 Hz, 6H). absolute stereochemistry is known 433.2 ^1H NMR (600 MHz, DMSO-sub) δ 8.92 -8.94 (m, 1H) 8.57 -8.63 (m, 1H) 8.04-8.11 (m, 1H) 7, 91 -7.96 (m, 1H) 6.55 - 6.57 (m, 1H) 5.50 - 5.57 (m, 1H) 5.14-5.17 (m, 2H) 4.154.26 ( m, 2H) 3.80 - 3.88 (m, 2H) 3.31 -3.35 (m, ZN) 2.04-2.07 (m, 2H) 1.92-1.98 (m, 2H) 1.56-1.59 (m, 6H) 1.19 (w. d„ 2 = 6.05 Hz, ZN). 421.1 ^1H NMR (600 MHz, DMSO-sub) δ 8.64 - 8.66 (m, 1H) 8.58 (d, 2=8.44 Hz, 1H) 8.04 - 8.10 (m, 1H ) 7.96 (d, 2=7.52 Hz, 1H) 6.72-6.74 (m, 1H) 5.135.16 (m, 2H) 4.79 -4.89 (m, 1H)4, 10 -4.12 (m, ZN) 3.88-3.98 (m, 2H) 3.41 -3.46 (m, 5H) 1.15-1.19 (m, 9H).

- 125 044841

109 (WITH) > 1 L \ Ν Ι ¹ ^ \ ΗΝ\ 6-(2,2-dimethylpyrolidinyl-1-yl)4-[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/ 7-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 110 (WITH) . ί t / Ν N \ r. CAJ \j H '5 < η ₂ ν 4-(aminomethyl)-6-[(2/?,5R)-2,5-dimethylpyrrolidinil-1-yl]-2-[6-(4-ethyl-4/ 7-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1/7-pyrrolo[3,4-c]pyridin-1-one 111 (U) f/Ν\ HN\ 6-[(2K,5K)-2.5- dimethylpyrolidinyl-1-yl]-2-[6-(4ethyl-5-methyl-4/7-1,2,4-triazol-3yl)pyridin-2-yl]-4- [(methylamino)methyl]-2,3-dihydro1/7-pyrrolo[3,4-c]pyridin-1-one

461.0 ^1H NMR (400 MHz, DMSO-sub) δ 8.92 -8.96 (m, 1H) 8.60-8.66 (m, 1H) 8.08 (t, 7=8.01 Hz, 1H ) 7.93 - 8.02 (m, 1H) 6.55 (s, 1H) 5.57 (dt, 7 = 13.33, 6.54 Hz, 1H) 5.15 (s, 2H) 4, 09 (sq., 7=5.09 Hz, 1H) 3.86 (s, 2H) 3.40 - 3.48 (m, 2H) 2.37 - 2.40 (m, ZN) 1.89- 1.95 (m, 4H) 1.58 (d, 7=6.72 Hz, 6H) 1.53 (s, 6H). 433.2 ^1H NMR (600 MHz, DMSO-sub) δ 8.52 (d, 7=1.5 Hz, 1H), 8.37 (d, 7=8.4 Hz, 1H), 7.97 (s, ZN), 7.87 (t, 7=8.1 Hz, 1H), 7.75 (d, 7=7.6 Hz, 1H), 6.49 (s, 1H), 4.94-4, 82 (m, 2H), 4.37 (sq., 7=7.2 Hz, 2H), 4.28 - 3.92 (m, 4H), 2.08 - 1.94 (m, 2H), 1.43 (d, 7=5.5 Hz, 2H), 1.28-1.19 (m, ZN), 0.90 (d, 7=6.1 Hz, 6H). 461.3 ^1H NMR (600 MHz, DMSO-sub) δ 8.53 (d, 7=8.25 Hz, 1H) 7.93 - 8.04 (m, 1H) 7.90 (d, 7=7.70 Hz, 1H) 6.65 (s, 1H) 5.31 (s, 2H) 4.48 (sq., 7 = 6.97 Hz, 2H) 3.54 - 3.58 (m, 2H) 3, 52 (br, s, ZN, assumed; partially overlaps with the water peak) 2.98 (s, ZN) 2.42 (s, ZN) 1.35- 1.43 (m, 9N) 1.03 (t, 7=6.97 Hz, ZN).

- 126 044841

112 (WITH) Ch/Ν\ Kommersant \--Ν / ΗΝ \ 6-[2,6-dimethylmorpholin-4-yl]-4[(methylamino)methyl]-2-{6-[4(propan-2-yl)-4/7-1,2,4-triazol-3yl ]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 113 (WITH) \\ P Qyyj ΗΝ\ 4-[(methylamino)methyl]-2-[6-(4- propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-6-[(28)-2(trifluoromethyl)pyrolidinyl-1-yl]2,3-dihyde rho-1/7 -pyrrolo[3,4c]pyridin-1-one 114 (WITH) - ΐ ? / N \ ^W =\ \ HN\ 2-[6-(4-ethyl-4/7-1,2,4-triazol-3yl)pyridin-2-yl]-4-[(methylamino)methyl]-6 -[(28)-2methylpyrrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin-1-one 115 (WITH) , to Λ [ / ^Χ Ν ^Ζ \ L/ y ( HN\ 2-[6-(4-ethyl-4/7-1,2,4-triazol-3yl)pyridin-2-yl]-4- [( methylamino)methyl]-6-[(2R)-2methylpyrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one

477.0 ^1H NMR (600 MHz, DMSO-sub) δ 8.83 - 8.89 (m, 1H) 8.54 (d, 7=8.44 Hz, 1H) 8.01 -8.06 (m, 1H ) 7.86 -7.89 (m, 1H) 6.99 - 7.02 (m, 1H) 6.46 - 6.53 (m, 2H) 5.41 -5.47 (m, 1H) 5.055 .09 (m, 2H) 3.93 - 4.04 (m, 2H) 3.67 -3.73 (m, 4H) 2.35-2.43 (m, ZN) 1.48- 1.54 (m, 6H) 1.13 (w. d„ 7 = 6.05 Hz, 6H). 501.1 ^1H NMR (400 MHz, DMSO-sub) δ 8.75 (s, 1H) 8.64 (d, 7=8.0 Hz, 1H) 8.158.07 (m, 1H) 8.05 - 7.99 (m, 1H) 6.92 (s, 1H) 5.23-5.11 (m, ZN) 4.58 (t.7=7.3 Hz, 2H) 3.87 (s, 2H) 3, 82 3.72 (m, 1H) 3.52 - 3.38 (m, 1H) 2.37 (s, ZN) 2.14 (sh.s., 4H) 1.89 (six., 7=7 ,2 Hz, 2H) 0.95 (t, 7=7.3 Hz, ZN). 433.2 ^1H NMR (600 MHz, DMSO-sub) δ 8.71 -8.73 (m, 1H) 8.51 -8.59 (m, 1H) 8.03-8.09 (m, 1H) 7, 93 -7.98 (m, 1H) 6.60 -6.65 (m, 1H) 5.04-5.10 (m, 2H) 4.54 - 4.62 (m, 2H) 4.17 4 .25 (m, 1H) 4.06 - 4.11 (m, 2H) 3.53 -3.58 (m, 2H) 3.29 -3.37 (m, 1H) 2.58-2.62 (m, ZN) 1.99-2.08 (m, 2N) 1.92-1.98 (m, 1N) 1.66-1.73 (m, 1N) 1.45-1.49 (m , ZN) 1.141.21 (m, ZN). 433.2 ^1H NMR (600 MHz, DMSO-de) δ 8.69 -8.74 (m, 1H) 8.53-8.60 (m, 1H) 8.06-8.10 (m, 1H) 7, 94 -8.00 (m, 1H) 6.60 -6.65 (m, 1H) 5.07-5.14 (m, 2H) 4.55 -4.65 (m, 2H) 4.20 4 .24 (m, 1H) 3.97 - 4.04 (m, 4H) 3.30 -3.35 (m, 1H) 2.52 -2.54 (m, ZN) 2.01 -2.09 (m, 2H) 1.92-1.98 (m, 1H) 1.66-1.74 (m, 1H) 1.43-1.50 (m, ZN) 1.12-1.19 (m , ZN).

- 127 044841

116 (U) 4 A Λ / Ν Ν \ ΗΝ\ 6-[(2K,5K)-2,5- dimethylpyrolidinyl-1-yl]-4[(methylamino)methyl]-2-{6-[5-methyl4-(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2 -yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 117 (AA) ί Al \_j\y A ⁷ ”\ A η ₂ ν 4-(aminomethyl)-6-(dimethylamino)2-{6-[4-(pentan-3-yl)-4/7-1,2,4triazole -3-yl]pyridin-2-yl}-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one 118 (Μ) J /U Uy x-' ΗΝ\ 6-[(2K,5K)-2.5- dimethylpyrolidinyl-1-yl]-2-{6[(4R)-4-(fluoromethyl)-2-oxo-1,3oxazolidin-3-yl]pyridin-2-yl}-4[(methylamino)methyl]-2 ,3-dihydro1H-pyrrolo[3,4-c]pyridin-1-one 119 (R) , 1 Λ / /А / X f / Ν 1^* \ h ₂ n 4-(aminomethyl)-6-[(2/?,5/?)-2,5dimethylpyrolidinyl-1-yl]-2-{6 -[4(pentan-3-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1Hpyrrolo[3,4-c]pyridin-1- He

475.3 ¹ H NMR (600 MHz, DMSO-<4 ₆ ) δ 8.58.6 (m, 1H), 8.0-8.1 (m, 1H), 7.78 (d, 4=7.0 Hz , 1H), 6.59 (s, 1H), 5.4-5.6 (m, 1H), 5.0-5.2 (m, 2H), 4.22 (sh.s., 2H) , 3.75 (dd, 4=2.5, 3.9 Hz, 2H), 2.58 (s, ZN), 2.2-2.3 (m, 2H), 1.6-1.6 (m, 2H), 1.55 (d, 4=7.0 Hz, 6H), 1.12 (d, 4=5.5 Hz, 6H). 421.2 ^1H NMR (400 MHz, DMSO-s/ ₆ ) δ 8.90 (s, 1H) 8.63 (dd, 4=8.31, 0.73 Hz, 1H) 8.04 - 8.13 (m , 1H) 7.93 (dd, 4=7.58, 0.73 Hz, 1H) 6.77 (s, 1H) 5.33 - 5.44 (m, 1H) 5.17 (s, 2H) 3.86 (w. d„ 4 = 11.49 Hz, 2H) 3.11 (s, 7H) 1.85 1.99 (m, 4H) 0.78 (t, 4 = 7.34 Hz, 6H ). 469.3 ^1H NMR (400 MHz, DMSO-<46) δ 8.24 (d, 4=8.0 Hz, 1H) 8.00 - 7.92 (m, 1H) 7.86 (d, 4=8, 1 Hz, 1H) 6.59 (s, 1H) 5.13 (b.d., 4=7.4 Hz, 1H) 5.10-4.96 (m, ZN) 4.88-4.70 (m, 1H)4.684.60 (m, 1H) 4.50 (dd, 4=3.1, 8.6 Hz, 1H)4.25 (sh.s.,2H) 3.82 -3.71 (m, 2H) 2.37 (s, ZN) 2.23 (w.s., 2H) 1.64 (w. d„ 4=5.5 Hz, 2H) 1.13 (d, 4=6 ,1 Hz, 6H). ¹⁹ F NMR (377 MHz, DMSOά6) δ-237.98 (s, 1F). absolute stereochemistry is known 475.3 ¹ H NMR (400 MHz, DMSO-<4 ₆ ) δ 8.78 (s, 1H), 8.6-8.6 (m, 1H), 8.07 (t, 4=8.0 Hz, 1H ), 7.9-8.0 (m, 1H), 6.61 (s, 1H), 5.3-5.5 (m, 1H), 5.15 (d, 4=1.2 Hz, 2H), 4.29 (quin., 4=6.3 Hz, 2H), 3.89 (sh.s., 2H), 2.27 (dt, 4=2.2, 7.5 Hz, 2H ), 1.9-2.0 (m, 4H), 1.6-1.7 (m, 2H), 1.17 (d, 4=6.2 Hz, 6H), 0.80.9( m, 6H).

- 128 044841

4-[(methylamino)methyl]-2-[6-(4propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-6-[(2/?)-2(trifluoromethyl )pyrrolidinyl-1-yl]2,3-dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one

2-[6-(4-ethyl-5-methyl-4H-1,2,4triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-6-[(2/?)- 2methylpyrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one ¹ H NMR (400 MHz, DMSO-sub) δ 9.46 (br.s., 1H) 9 .17 (sh.s., 1H) 8.79 (s, 1H) 8.64 (d, 4=8.3 Hz, 1H) 8.12 (t, 4=8.0 Hz, 1H) 8, 02 (d, 4=7.5 Hz, 1H) 7.07 (s, 1H) 5.46 (sh.s., 1H) 5.235.12 (m, 2H) 4.57 (sh.t., 4 =7.2 Hz, 2H) 4.37 (wt., 4=5.1 Hz, 2H) 3.83 (wd„ 4=9.5 Hz, 1H) 3.59-3.47 (m, 1H) 2.77 - 2.68 (m, ZN) 2.22 - 2.07 (m, 4H) 1.86 (six., 4=7.2 Hz, 2H) 0.92 (t , 4=7.4 Hz, ZN).

^1H NMR (700 MHz, DMSO-sub) δ 8.52 -8.59 (m, 1H) 8.04 -8.09 (m, 1H) 7.90-7.95 (m, 1H) 6, 67 -6.72 (m, 1H) 5.01 -5.10 (m, 2H) 4.46-4.53 (m, 2H) 4.28 -4.33 (m, 2H) 3.563.62 ( m, ZN) 3.34 - 3.40 (m, 1N) 2.73 -2.79 (m, ZN) 2.45-2.49 (m, ZN) 2.01 -2.11 (m, ZN) 2H) 1.94-1.98 (m, 1H) 1.67-1.76 (m, 1H) 1.38-1.45 (m, ZN) 1.16-1.22 (m, ZN) .

- 129 044841

4-(aminomethyl)-6-[ethyl(propan-2yl)amino]-2-{6-[(4R)-4-(fluoromethyl)2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl }-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

4-(aminomethyl)-6-(diethylamino)-2{6-[4-(pentan-3-yl)-4/7-1,2,4triazol-3-yl]pyridin-2-yl}-2, 3dihydro-1/7-pyrrolo[3,4-c]pyridine-

4-(aminomethyl)-6-[(2/?,5/?)-2,5dimethylpyrrolidinil-1-yl]-2-{6[(4R)-4-(fluoromethyl)-2-oxo-1,3oxazolidine -3-yl]pyridin-2-yl}2,3-dihyd rho-1 /7-pyrrolo[3,4c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-cO δ 8.91 (s, 1H), 8.64 (d, >7.8 Hz, 1H), 8.10 (t, >8.0 Hz, 1H), 7.94 (d, >7.0 Hz, 1H), 6, 71 (s, 1H), 5.3-5.5 (m, 1H), 5.16 (s, 2H), 3.85 (b.s., 2H), 3.5-3.6 (m , 4H), 1.8-2.0 (m, 4H), 1.15 (t, >6.9 Hz, 6H), 0.79 (t, >7.3 Hz, 6H).

¹ H NMR (400 MHz, DMSO-sub) δ 8.47 (b.s., ZN) 8.25 (d, >8.0 Hz, 1H) 8.01 -7.95 (m, 1H) 7 .92 -7.86 (m, 1H) 6.80 (s, 1H) 5.23 - 4.92 (m, 5H) 4.89 4.72 (m, 1H) 4.65 (t, >8 .8 Hz, 1H) 4.52 (dd, >3.1, 8.7 Hz, 1H) 4.23 4.16 (m, 2H) 3.49 (sq., >6.7 Hz, 2H) 1.22-1.13 (m, 9H).

¹ H NMR (400 MHz, DMSO-cO δ 8.36 (b.s., ZN) 8.24 (d, >7.9 Hz, 1H) 8.01 -7.95 (m, 1H) 7, 92 -7.86 (m, 1H) 6.71 (s, 1H) 5.22 - 5.08 (m, 2H) 5.07 4.98 (m, 2H) 4.85 (w. d„ > 10.5 Hz, 1H) 4.65 (t, >8.9 Hz, 1H) 4.52 (dd, >3.1, 8.7 Hz, 1H) 4.28 - 4.11 (m, 2H ) 2.24 (w. d„ >0.9 Hz, 2H) 2.05 - 1.94 (m, 2H) 1.67 (b. d., >5.4 Hz, 2H) 1.19- 1.08 (m, 6H).

absolute stereochemistry is known

- 130 044841

125 (T) h ₂ n 4-(aminomethyl)-2-{6-[(48)-4-methyl-2-oxo-1,3-oxazolidin-3yl]pyridin-2-yl}-6-[(2/?) -2methylpyrolidinyl-1-yl]-2,3-dihydro-1/7-pyrrolo[3,4-c]pyridin1-one 1 Λ Ζ Ν\ ^1 Λ---/ / 1 ,Ν Χ У VV Ζ^^/ — 126 ' Ν^=< ' \ (S) η ₂ ν 4-(aminomethyl)-6-(1 - methylcyclopropyl)-2-{6-[4-(pentan3-yl)-4/7-1,2,4-triazol-Zyl]pyridin-2-yl }-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 1 HA /N N\ 4/V X/ 127 /-=( \ / (AD) h ₂ n 4-(aminomethyl)-2-[6-(4-ethyl-5methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-(1 - methylcyclopropyl)- 2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

423.3 ¹ H NMR (400 MHz, DMSO-<4 ₆ ) δ 8.45 (b.s., ZN) 8.23 (d, 4=7.8 Hz, 1H) 7.95 (t, 4=8, 1 Hz, 1H) 7.82 (d, 4=7.8 Hz, 1H) 6.69 (s, 1H) 5.17 - 5.00 (m, 2H) 4.96 (dt, 4=2, 4, 4.0 Hz, 1H) 4.60 (t, 4=8.3 Hz, 1H) 4.34 (sh.s., 1H) 4.22 (sh. dd, 4=6.1, 7 ,8 Hz, 2H) 4.16 (dd, 4=3.8, 8.4 Hz, 1H) 3.63 (wd„ 4=2.6 Hz, 1H) 2.14- 1.94 ( m, ZN) 1.771.70 (m, 1H) 1.49 (d, 4=6.2 Hz, ZN) 1.20 (d, 4=6.2 Hz, ZN). absolute stereochemistry is known 432.3 ¹ H NMR (400 MHz, DMSO-<4 ₆ ) δ 8.92 (s, 1H) 8.64 (d, 4=8.5 Hz, 1H) 8.11 (t, 4=8.0 Hz, 1H) 7.95 (d, 4=7.5 Hz, 1H) 7.55 (s, 1H) 5.38 - 5.30 (m, 1H) 5.29 (s, 2H) 3.97 (s , 2N) 2.10 (sh.s., 2N) 2.00 - 1.82 (m, 4N) 1.56 (s, ZN) 1.30 1.20 (m, 2N) 0.89 - 0 .70 (m, 2H) 0.78 (sh.t., 4=7.3 Hz, 6H). 404.3 ¹ H NMR (400 MHz, Methanol-R ₄ ) δ 8.77-8.67 (m, 1H) 8.09-8.00 (m, 1H) 7.99-7.92 (m, 1H) 7 .71 -7.63 (m, 1H) 5.28 -5.20 (m, 2H) 4.66 (sq.,4=7.1 Hz, 2H) 4.05 (s, 2H) 2.60 (s, ZN) 1.61 (s, ZN) 1.57 (t, 4=7.2 Hz, ZN) 1.43 - 1.38 (m, 2N) 0.95 - 0.89 (m, 2H).

- 131 044841

4-(aminomethyl)-6-(1 methylcyclopropyl)-2-[6-(5-methyl-4propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-2,3- Dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

4-(aminomethyl)-6-cyclopropyl-2{6-[4-(pentan-3-yl)-4/7-1,2,4triazol-3-yl]pyridin-2-yl}-2,3dihydro- 1H-pyrrolo[3,4-c]pyridin6-[ethyl(methyl)amino]-4[(methylamino)methyl]-2-[6-(5-methyl4-propyl-4/7-1,2,4- triazol-Zyl)pyridin-2-yl]-2,3-dihyd rho-1/7pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-s/ ₆ ) δ 8.64 (dd, 4=8.4, 0.9 Hz, 1H), 8.32 (s, ZN), 8.12 (dd, 4=8.4, 7.7 Hz, 1H), 7.99 ( dd, 4=7.6, 0.9 Hz, 1H), 7.70 (s, 1H), 5.25 (s, 2H), 4.50-4.41 (m, 2H), 4.38 (s, 2H), 2.51 (s, ZN), 1.83 (dt, 4=9.3, 7.3 Hz, 2H), 1.60 (s, ZN), 1.47 (sq. , 4=3.4 Hz, 2H), 0.97 (t, 4=7.4 Hz, ZN), 0.92 (sq., 4=3.5 Hz, 2H).

^1H NMR (600 MHz, DMSO-< ₄₆ ) δ 8.77 -8.86 (m, 1H) 8.50 -8.59 (m, 1H) 7.99-8.06 (m, 1H) 7.83 -7.94 (m, 1H) 7.41 - 7.51 (m, 1H) 5.27 -5.35 (m, 1H) 5.14 - 5.24 (m, 2H) 3, 85 - 3.94 (m, 1H) 3.03-3.19 (m, 2H) 2.162.33 (m, 1H) 1.76 - 1.91 (m, 5H) 0.88 - 0.99 ( m, 4H) 0.64 - 0.77 (m, 6H).

¹ H NMR (400 MHz, DMSO-<4 ₆ ) δ 9.00 - 8.80 (m, 2H), 8.64 (dd, 4=8.4, 0.9 Hz, 1H), 8.21 -8.03 (m, 1H), 7.97 (dd, 4=7.7, 0.9 Hz, 1H), 6.93 (s, 1H), 5.10 (s, 2H), 4, 44 (dd, 4=8.7, 6.6 Hz, 2H), 4.35 (t, 4=5.9 Hz, 2H), 3.72 (sq., 4=7.0 Hz, 2H) , 3.13 (s, ZN), 2.75 (t, 4=5.3 Hz, ZN), 2.53 (s, ZN), 1.80 (sq., 4=7.5 Hz, 2N ), 1.12 (t, 4=7.0 Hz, ZN), 0.94 (t, 4=7.4 Hz, ZN).

- 132 044841

131 (WITH) , ι XX / ALAA Ay Ja ^/ A \ ^H \ 6-[ethyl(methyl)amino]-2-[6-(4-ethyl4/7-1,2,4-triazol-3-yl)pyridin-2yl] -4-[(methylamino)methyl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one 132 (Μ) h ₂ n 4-(aminomethyl)-2-{6-[(48)-4-methyl2-oxo-1,3-oxazolidin-3-yl]pyridin-2-yl}-6-[(28)-2methylpyrrolidinyl -1-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin-1-one 133 (AF) i XX 1 A \ / / Ν N \ QAd yA h ₂ n 4-(aminomethyl)-2-[6-(5-methyl-4propyl-4/7-1,2,4-triazol-Zyl)pyridine-2 -yl]-6-[(2R)-2methylpyrrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one

407.3 ¹ H NMR (400 MHz, DMSO-de) δ 9.20 -9.12 (m, 2H) 8.90 (s, 1H) 8.64 (d, 7=8.5 Hz, 1H) 8.13 (t, 7=8.0 Hz, 1H) 8.01 (d, 7=7.8 Hz, 1H) 6.91 (s, 1H) 5.15 (s, 2H) 4.64 (sq., 7=7.0 Hz, 2H) 4.34 (t, 7=5.8 Hz, 2H) 3.75 - 3.67 (m, 2H) 3.12 (s, ZN) 2.73 (t, 7=5.4 Hz, ZN)1.49(t, 7=7.2 Hz, ZN) 1.12 (t, 7=7.0 Hz, ZN). 423.6 ^1H NMR (400 MHz, DMSO-bb) δ 8.31 -8.15 (m, 4H), 7.96 (t, 7=8.1 Hz, 1H), 7.86-7.78 (m , 1H), 6.70 (s, 1H), 5.18 - 4.97 (m, 2H), 4.97 - 4.90 (m, 1H), 4.61 (t, 7=8.3 Hz, 1H), 4.35 (m, 1H), 4.26 (d, 7=5.8 Hz, 2H), 4.17 (dd, 7=8.4, 3.8 Hz, 1H), 3.64 (t, 7=9.0 Hz, 1H), 3.39 (m, 1H), 2.06 (m, ZN), 1.75 (m, 1H), 1.49 (d, 7 =6.2 Hz, ZN), 1.21 (d, 7 = 6.2 Hz, ZN). absolute stereochemistry is known 447.2 ^1H NMR (600 MHz, DMSO-s/ ₆ ) δ 8.52 (d, 7=8.25 Hz, 1H) 7.97 (t, 7=7.98 Hz, 1H) 7.88 (d, 7=7.52 Hz, 1H) 6.51 (s, 1H) 5.03 (s, 2H) 4.31 - 4.44 (m, 2H) 4.13-4.26 (m, 1H) 3 .82 -3.92 (m, 1H) 3.45 - 3.55 (m, 4H) 2.41 (s, ZN) 1.93-2.05 (m, 2H) 1.86- 1.93 (m, 1H) 1.83 (b.s., 1H) 1.69- 1.79 (m, 2H) 1.62- 1.67 (m, 1H) 1.13 (d, 7=6, 24 Hz, ZN) 0.89 (t, 7 = 7.34 Hz, ZN).

- 133 044841

134 (AE) - Ϊ Λ f / N \ y^ h ₂ n 4-[(methylamino)methyl]-2-[6-(5methyl-4-propyl-4/7-1,2,4-triazol-3yl)pyridin-2 -yl]-6-[(28)-2-methylpyrrolidinil-1-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one 135 (AE) - 1 O Control control system gi{ HN\ 4-[(methylamino)methyl]-2-{6-[5methyl-4-(pentan-3-yl)-4/7-1,2,4triazol-3-yl]pyridin-2-yl}-6- [(28)- 2-methylpyrrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin- 1-he 136 (C) ff / N \ η ₂ ν 4-(aminomethyl)-6-[(2R,5R)-2,5dimethylpyrrolidinyl-1-yl]-2-[6-(4propyl-4/7-1,2,4-triazole -Zyl)pyridin-2-yl]-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

461.6 ^1H NMR (400 MHz, DMSO-de) δ 8.87 (s, 2H), 8.63 (d, 7=8.4 Hz, 1H), 8.168.04 (m, 1H), 7.96 ( d, 7=7.6 Hz, 1H), 6.76 (s, 1H), 5.11 (d, 7=1.6 Hz, 2H), 4.49 _ 4.40 (m, 2H), 4.40 - 4.29 (m, ZN), 3.74-3.59 (m, 2H), 2.77 (t, 7=5.3 Hz, ZN), 2.50 (s, ZN) , 2.21 1.94 (m, ZN), 1.79 (dt, 7=15.3, 7.4 Hz, ZN), 1.21 (d, 7=6.2 Hz, ZN), 0 .94 (t, 7=7.4 Hz, ZN). 489.6 ¹ H NMR (700 MHz, DMSO-sub) δ 8.90 (s, 2H), 8.64 (d, 7=8.4 Hz, 1H), 8.11 (t, 7=7.9 Hz, 1H), 7.78 (d, 7=7.5 Hz, 1H), 6.75 (s, 1H), 5.06 (s, 2H), 4.434.21 (m, 4H), 3.65 ( t, 7=9.2 Hz, 2H), 2.78 (m, ZN), 2.50 (s, ZN). 447.1 ^1H NMR (400 MHz, DMSO-sub) δ 8.74 (s, 1H), 8.62 (d, 7=7.9 Hz, 1H), 8.08 (t, 7=8.0 Hz, 1H), 8.01 (d, 7=7.3 Hz, 1H), 6.59 (s, 1H), 5.20 - 5.06 (m, 2H), 4.64 - 4.49 (m , 2H), 4.27 (s, 2H), 3.84 (s, 2H), 2.24 (m, 2H), 1.88 (m, 2H), 1.65 (m, 2H), 1 .14 (d, 7=6.1 Hz, 6N), 0.94 (t, 7=7.4 Hz, ZN).

- 134 044841

137 (D) j U Cy h ₂ n 4-(aminomethyl)-6-[(2R,5R)-2,5dimethylpyrrolidinyl-1-yl]-2-{6[(48)-4-methyl-2-oxo-1,3oxazolidine -3-yl]pyridin-2-yl}2,3-dihyde rho-1 /7-pyrrolo[3,4c]pyridin-1-one 138 (WITH) - 1 Λ 0— ΗΝ\ 4-[(methylamino)methyl]-6-[(28)-2methylpyrolidinyl-1-yl]-2-{6-[4(pentan-3-yl)-4/7-1,2,4-triazol- 3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 139 (S) 1 Λ US /'S. / Ν Ν \ Λ-----X 1 I , Ν ΓΛΓ .Μ ^Ν ^\ \ ΗΝ \ 2-(6-{4-[(2I)-butan-2-yl]-4H-1,2, 4triazol-3-yl}pyridin-2-yl)-4[(methylamino)methyl]-6-(1 - methylcyclopropyl)-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1- He

437.2 ¹ H NMR (400 MHz, Methanol-sU ₄ ) δ 8.32 (t, 7 = 4.4 Hz, 1H) 7.90 (m, 2H) 6.89 (s, 1H) 5.20 - 5, 03 (m, ZN) 4.63 (t, 7=8.3 Hz, 1N) 4.40 (sh.s., 2N) 4.37 - 4.30 (m, 2N) 4.20 (dd, 7=4.0, 8.5 Hz, 1H) 2.37 (b.s., 2H) 1.78 (b.d. 7=5.5 Hz, 2H) 1.57 (d., 7=6 ,2 Hz, ZN) 1.24 (d, 7=6.1 Hz, 6H). absolute stereochemistry is known 475.7 ¹ H NMR (700 MHz, DMSO-sub) δ 8.91 (s, ZN), 8.62 (d, 7=8.4 Hz, 1H), 8.11 (t, 7=7.9 Hz, 1H), 7.91 (d, 7=7.5 Hz, 1H), 6.73 (s, 1H), 5.20 (m, 1H), 5.08 (s, 2H), 4.28 - 4.33 (m, ZN), 3.64 (m, 2N), 2.77 (m, ZN), 2.11 -1.97 (m, ZN), 1.92 (m, 4N), 1 .73 (m, 1H), 1.20 (d, 7=6.3 Hz, ZN), 0.79 (t, 7=7.3 Hz, 6H). 432.2 ¹ H NMR (600 MHz, DMSO-sub) δ 9.14 -9.18 (m, 1 H) 8.93 (s, 1 H) 8.61 (d, 7 = 8.44 Hz, 1 H) 8, 12 (t, 7=7.97 Hz, 1H) 7.93 (d, 7=7.52 Hz, 1H) 7.69 (s, 1H) 5.24-5.31 (m, 1H) 5, 18-5.24 (m, 2N) 4.47 (sh.s., 2N) 2.77 (s, ZN) 1.87-2.03 (m, 2N) 1.56-1.61 (m , 6H) 1.38 - 1.49 (m, 2H) 0.89 - 0.95 (m, 2H) 0.82 (t, 7 = 7.34 Hz, ZN). absolute stereochemistry is known

- 135 044841

4-(aminomethyl)-6-[ethyl(propan-2yl)amino]-2-[6-(1,3,4-thiadiazol-2yl)pyridin-2-yl]-2,3-dihydro-1/7pyrrolo [3,4-c]pyridin-1-one

4-(aminomethyl)-6-[ethyl(propan-2yl)amino]-2-[6-(4-ethyl-4/7-1,2,4triazol-3-yl)pyridin-2-yl]-2 ,3dihydro-1H-pyrrolo[3,4-c]pyridin6-cyclopropyl-4[(methylamino)methyl]-2-{6-[4(pentan-3-yl)-4/7-1,2,4- triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-sub) δ 9.76 (s, 1H) 8.69 (d, 4=8.0 Hz, 1H) 8.198.14 (m, 1H) 8.13 - 8.09 (m, 1H) 6.77 (s, 1H) 5.70 (w .s., 2H) 5.16 (s, 2H) 4.98- 4.88 (m, 1H) 4.08 (s, 2H) 3.52 3.43 (m, 2H) 1.21 - 1 .16 (m, 9H).

¹ H NMR (400 MHz, DMSO-sub) δ 9.17 (s, 1H) 8.67 (d, 4=8.0 Hz, 1H) 8.49 (b.s., ZN) 8.16 ( t, 4=8.0 Hz, 1H) 8.03 (d, 4=7.0 Hz, 1H) 6.84 (s, 1H) 5.17 (s, 2H) 5.05 - 4.93 ( m, 1H) 4.69 (sq., 4=7.2 Hz, 2H) 4.23 (sq., 4=5.3 Hz, 2H) 3.50 (sq., 4=6.7 Hz, 2H) 1.52 (t, 4=7.2 Hz, ZN) 1.21 - 1.15 (m, 9H).

^1H NMR (600 MHz, DMSO-sub) δ 8.84 -8.92 (m, 1H) 8.54-8.63 (m, 1H) 8.03-8.10 (m, 1H) 7, 85-7.94 (m, 1H) 7.48-7.54 (m, 1H) 5.31 -5.38 (m, 1H) 5.18 -5.23 (m, 2H) 3.853.86 ( m, 2H) 2.30 - 2.34 (m, ZN) 2.21 -2.27 (m, 1H) 1.83- 1.95 (m, 4H) 0.93- 1.04 (m, 1H) 5H) 0.73-0.79 (m, 6H).

- 136 044841

143 (R) o , L-AL / Ν Ν X όΆΎ' ¹ η ₂ ν 4-(aminomethyl)-6-[(2/?)-2methylpyrrolidinyl-1-yl]-2-{6-[4(pentan-3- yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 461.4 ^1H NMR (400 MHz, DMSO-sub,) δ 8.84 (s, 1H), 8.57 (d, 4=8.4 Hz, 1H), 8.02 (t, 4=8.0 Hz , 1H), 7.87 (d, 4=7.2 Hz, 1H), 6.50 (s, 1H), 5.3-5.4 (m, 1H), 5.09 (s, 2H) , 4.1-4.3 (m, 1H), 3.78 (b.s., 2H), 3.5-3.6 (m, 2H), 2.0-2.1 (m, 2H ), 1.7-1.9 (m, 5H), 1.6-1.6 (m, 1H), 1.13 (d, 4=6.1 Hz, ZN), 0.71 (t, 4=7.3 Hz, 6H). 144 (WITH) . 1 /A f / Ν X HN \ 4-[(methylamino)methyl]-6-[(2/?)-2methylpyrrolidinyl-1-yl]-2-{6-[4(pentan-3-yl)-4/7-1,2,4- triazol-3yl]pyridin-2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 475.2 ¹ H NMR (400 MHz, DMSO-cO δ 8.91 (s, 1H) 8.64 (d, 4=7.95 Hz, 1H) 8.09 (t, 4=7.95 Hz, 1H) 7 .94 (d, 4=7.09 Hz, 1H) 6.60 (s, 1H) 5.32 - 5.50 (m, 1H) 5.14 (s, 2H) 4.12 - 4.28 ( m, 1N) 3.82 (sh.s., 2N) 3.51 - 3.61 (m, 1N) 2.27 2.47 (m, ZN) 2.02 - 2.12 (m, 2N ) 1.86 - 1.99 (m, 6H) 1.62-1.75 (m, 1H) 1.20 (d, 4=6.11 Hz, ZN) 0.79 (t, 4=7, 34 Hz, 6H). 145 (AN) 1 Λ / / \ / / Ν \ XX a h ₂ n 4-(aminomethyl)-6-[ethyl(propan-2yl)amino]-2-{6-[4-(propan-2-yl)-4 /71,2,4-triazol-3-yl]pyridin-2-yl}2,3-dihyde rho-1 /7-pyrrolo[3,4c]pyridin-1-one 434.9 ¹ H NMR (400 MHz, DMSO-sub) δ 9.61 (s, 1H) 8.70 (d, 4=8.3 Hz, 1H) 8.57 (b.s., ZN) 8.18 ( t, 4=8.0 Hz, 1H) 7.98 (d, 4=7.3 Hz, 1H) 6.84 (s, 1H) 5.59 5.48 (m, 1H) 5.20 (s , 2H) 5.05 - 4.90 (m, 1H) 4.20 (w. d„ 4 = 5.5 Hz, 2H) 3.57 - 3.44 (m, 2H) 1.64 (d, 4=6.8 Hz, 6H) 1.22-1.15 (m, 9H). 146 (AN) k /A ___/ / Ν N x Yj G'X > h ₂ n 4-(aminomethyl)-6-[ethyl(propan-2yl)amino]-2-[6-(4-propyl-4/7-1 ,2,4triazol-3-yl)pyridin-2-yl]-2,3dihydro-1/7-pyrrolo[3,4-c]pyridin1-one 435.3 ^1H NMR (400 MHz, DMSO-sub) δ 9.08 (s, 1H) 8.70 - 8.64 (m, 1H) 8.46 (b.s., ZN) 8.19-8.11 (m, 1H) 8.03 (dd, 4=0.6, 7.6 Hz, 1H) 6.84 (s, 1H) 5.15 (s, 2H) 5.05-4.93 (m, 1H) 4.61 (t, 4=7.3 Hz, 2H) 4.21 (sq., 4=5.6 Hz, 2H) 3.50 (sq., 4=6.6 Hz, 2H) 1 .96 - 1.84 (m, 2H) 1.24- 1.13 (m, 9H) 0.96 (t, 4 = 7.4 Hz, ZN).

* The use of or 1 in structure and ξ for stereochemistry in the name denotes the identification of chiral centers that have been resolved into enantiomers, but the specific enantiomer has not been identified; the structure shows a solid or dotted wedge, but it could be a different enanathiomer.

- 137 044841

Table 1B

Etc.

No.

150 (C)

151 (C)

4-(aminomethyl)-6-[methyl(propan2-yl)amino]-2-{6-[4-(pentan-3-yl)4/7-1,2,4-triazol-3-yl]pyridine -2yl}-2,3-dihyde rho-1 /7-pyrrolo[3,4c]pyridin-1-one

4-(aminomethyl)-6-(2,2dimethylpyrolidinyl-1-yl)-2-{6[4-(pentan-3-yl)-4/7-1,2,4triazol-3-yl]pyridin-2 -yl}-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one

152 (C)

4-(aminomethyl)-6-[(25)-2methylpyrrolidinyl-1-yl]-2-{6-[4(pentan-3-yl)-4/7-1,2,4-triazol-3yl]pyridine -2-yl}-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one

153

435.3 (C)

4-(aminomethyl)-6[ethyl(methyl)amino]-2-{6-[4(pentan-3-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl} -2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one ¹ NMR (pure grade); ¹⁹ F NMR (m.p.);

rotation of the light polarization area; stereochemical notes ¹ H NMR (400 MHz, Methanol-F) b 9.10 (s, 1H), 8.81 (d, 7=8.1 Hz, 1H), 8.10 (d, 7=8.4 Hz, 1H), 7.92 (d, 7=7.1 Hz, 1H), 7.01 (s, 1H), 5.38 - 5.30 (m, 1H), 5.14 (s, 2H ), 5.06 (td, 7=6.7, 13.3 Hz, 1H), 4.33 (s, 2H), 3.02 (s, ZN), 2.14 - 1.95 (m, 4H), 1.27 (d, 7=6.7 Hz, 6H), 0.93 (t, 7=7.4 Hz, 6H).

^1H NMR (400 MHz, Methanol-f) δ 8.93 (s, 1H), 8.79 (d, 7=8.3 Hz, 1H), 8.10 (t, 7=8.1 Hz, 1H), 7.90 (d, 7=7.2 Hz, 1H), 6.95 (s, 1H), 5.29 (s, 1H), 5.14 (s, 2H), 4.32 ( s, 2H), 3.70 - 3.63 (m, 2H), 2.09 1.97 (m, 8H), 1.61 (s, 6H), 0.92 (t, 7=7.4 GC, 6N).

^1H NMR (400 MHz, Methanol-ph) δ 8.89 (s, 1H), 8.78 (d, 7=8.0 Hz, 1H), 8.13 8.07 (m, 1H), 7 .90 (d, 7=7.0 Hz, 1H), 6.85 (s, 1H), 5.28 (s, 1H), 5.14 (s, 2H), 4.37 - 4.31 ( m, ZN), 3.72 (sh.s., 1N), 3.50 (sh.s., 1N), 2.22 - 1.95 (m, 7N), 1.86 (sh. d„ 7=4.0 Hz, 1H), 1.31 (d, 7=6.3 Hz, ZN), 0.92 (dt, 7=1.1, 7.3 Hz, 6H).

^1H NMR (400 MHz, Methanol-f) δ 9.96 (s, 1H), 8.93 (d, 7=8.4 Hz, 1H), 8.25 8.17 (m, 1H), 8 .01 (d, 7=7.3 Hz, 1H), 7.02 (s, 1H), 5.59 (s, 1H), 5.17 (s, 2H), 4.35 (s, 2H) , 3.77 (sq., 7=7.1 Hz, 2H), 3.21 (s, ZN), 2.24 - 2.03 (m, 4H), 1.24 (t, 7=7, 0 Hz, ZN), 0.99 (t, 7 = 7.4 Hz, 6H).

- 138 044841

154 (Al) h ₂ n 4-(aminomethyl)-6-(2,2-dimethylpyrolidinyl-1-yl)-2-[6(4-ethyl-5-methyl-4/7-1,2,4-triazol-3- yl)pyridin-2-yl]-2,3-dihydro-1/7-pyrrolo[3,4-c]pyridin-1-one 447.3 ^1H NMR (400 MHz, Methanol-ch) δ 8.75 (d, 4=8.8 Hz, 1H), 8.15-8.06 (m, 1H), 7.97 (d, 4=7 ,0 Hz, 1H), 7.02 (s, 1H), 5.18 (s, 2H), 4.65 (sq., 4=7.1 Hz, 2H), 4.34 (s, 2H) , 3.02 (s, ZN), 2.62 (s, ZN), 1.55 (t, 4=7.2 Hz, ZN), 1.27 (d, 4=6.8 Hz, 6N) . 155 (Al) h ₂ n 4-(aminomethyl)-6-(2,2-dimethylpyrolidinyl-1-yl)-2-[6(5-methyl-4-propyl-4/7-1,2,4triazol-3-yl) pyridin-2-yl]-2,3dihydro-1/7-pyrrolo[3,4с]pyridin-1-one 461.3 ^1H NMR (400 MHz, Methanol-ch) δ 8.85 (d, 4=8.4 Hz, 1H), 8.13 (d, 4=8.2 Hz, 1H), 8.02 (d, 4=7.6 Hz, 1H), 6.95 (s, 1H), 5.18 (s, 2H), 4.74 - 4.68 (m, 2H), 4.36 (s, 2H), 3.67 (s, 2H), 2.78 (s, ZN), 2.08 - 1.95 (m, 6H), 1.62 (s, 6H), 1.10 (t, 4=7, 5 Hz, ZN). 156 (Al) η ₂ ν 4-(aminomethyl)-2-{6-[5-methyl-4(propan-2-yl)-4H-1,2,4-triazol-3yl]pyridin-2-yl}-6-[ (2/?)-2methylpyrrolidinil-1-yl]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 447.3 ^1H NMR (400 MHz, Methanol-ch) δ 8.91 (d, 4=8.3 Hz, 1H), 8.23 -8.14 (m, 1H), 7.89 (d, 4=7 ,0 Hz, 1H), 6.87 (s, 1H), 5.72 (quin., 4=7.0 Hz, 1H), 5.17 (s, 2H), 4.35 (s, ZN) , 3.78 - 3.66 (m, 1H), 3.56 3.47 (m, 1H), 2.96 (s, ZN), 2.26 - 2.05 (m, ZN), 1, 91 - 1.83 (m, 1H), 1.78 (d, 4=7.0 Hz, 6H), 1.31 (d, 4=6.3 Hz, ZN).

- 139 044841

157 (Al) oy % h ₂ n 4-(aminomethyl)-2-[6-(4-ethyl-5methyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-6-[(28) -2methylpyrrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 433.2 ^1H NMR (400 MHz, Methanol-ch) δ 8.84 (d, 4=8.0 Hz, 1H), 8.15 (t, 4=8.0 Hz, 1H), 8.03 (d, 4=7.3 Hz, 1H), 6.85 (s, 1H), 5.19 (s, 2H), 4.84 - 4.78 (m, 2H), 4.37 (s, 2H), 4.33 (w. d„ 4 = 6.5 Hz, 1H), 3.71 (w. d„, 4 = 7.9, 10.4 Hz, 1H), 3.56 3.44 (m, 1H ), 2.82 (s, ZN), 2.26 - 2.04 (m, ZN), 1.89 - 1.80 (m, 1H), 1.63 (t, 4 = 7.2 Hz, ZN), 1.30 (d, 4=6.3 Hz, ZN). 158 (Al) h ₂ n 4-(aminomethyl)-2-[6-(4-ethyl-5methyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-6-[methyl(propan-2 -yl)amino]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 421.3 ^1H NMR (400 MHz, Methanol-f) δ 8.75 (d, 4=8.8 Hz, 1H), 8.15-8.06 (m, 1H), 7.97 (d, 4=7 ,0 Hz, 1H), 7.02 (s, 1H), 5.18 (s, 2H), 4.65 (sq., 4=7.1 Hz, 2H), 4.34 (s, 2H) , 3.02 (s, ZN), 2.62 (s, ZN), 1.55 (t, 4=7.2 Hz, ZN), 1.27 (d, 4=6.8 Hz, 6N) . 159 (Al) ~ V JL1 A h ₂ n 4-(aminomethyl)-2-[6-(5-methyl-4propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-6-[( 28)-2methylpyrrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 447.3 ^1H NMR (400 MHz, Methanol-ch) δ 8.86 (d, 4=8.4 Hz, 1H), 8.14 (t, 4=8.1 Hz, 1H), 8.02 (d, 4=7.5 Hz, 1H), 6.87 (s, 1H), 5.17 (s, 2H), 4.74 - 4.65 (m, 2H), 4.36 (s, ZN), 3.72 (w. d„ 4 = 2.6 Hz, 1H), 3.51 (w. d„ 4 = 9.9 Hz, 1H), 2.78 (s, ZN), 2.29 - 1 .94 (m, 5N), 1.86 (sh.s., 1N), 1.31 (d, 4=6.4 Hz, ZN), 1.10 (t, 4=7.4 Hz, ZN ).

- 140 044841

160 (Al) kХХh h ₂ n 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-{6-[5methyl-4-(propan-2-yl)-4/7-1,2,4triazol-3- yl]pyridin-2-yl)-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 421.2 ^1H NMR (400 MHz, Methanol-ph) δ 8.89 (d, 4=8.5 Hz, 1H), 8.22 - 8.13 (m, 1H), 7.88 (d, 4=7 .5 Hz, 1H), 7.00 (s, 1H), 5.68 (quin., 4=7.1 Hz, 1H), 5.16 (s, 2H), 4.35 (s, 2H) , 3.77 (sq., 4=7.1 Hz, 2H), 3.20 (s, ZN), 2.92 (s, ZN), 1.76 (d, 4=7.0 Hz, 6H ), 1.24 (t, 4=7.0 Hz, ZN). 161 (Al) h ₂ n 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-[6-(5methyl-4-propyl-4/7-1,2,4triazol-3-yl)pyridin-2-yl ]-2,3dihydro-1/7-pyrrolo[3,4с]pyridin-1-one 421.2 ^1H NMR (400 MHz, Methanol-ph) δ 8.90 (dd, 4=0.7, 8.6 Hz, 1H), 8.21 - 8.13 (m, 1H), 8.05 (dd , 4=0.7, 7.6 Hz, 1H), 7.01 (s, 1H), 5.18 (s, 2H), 4.81 -4.74 (m, 2H), 4.38 ( s, 2H), 3.77 (d, 4=7.1 Hz, 2H), 3.21 (s, ZN), 2.90 - 2.83 (m, ZN), 2.03 (s, 2H ), 1.24 (t, 4=7.1 Hz, ZN), 1.13 (t, 4=7.4 Hz, ZN). 162 (Al) o ii A η ₂ ν 4-(aminomethyl)-2-{6-[5-methyl-4(propan-2-yl)-4/7-1,2,4-triazol-3yl]pyridin-2-yl }-6-[(28)-2-methylpyrrolidinyl-1-yl]-2,3-dihydro-1/7-pyrrolo[3,4-c]pyridin-1-one 447.3 ^1H NMR (400 MHz, Methanol-^) δ 8.65 (d, 4=8.5 Hz, 1H), 7.96 (t, 4=8.1 Hz, 1H), 7.65 (d, 4=7.6 Hz, 1H), 6.73 (s, 1H), 5.30 (td, 4=7.0, 14.1 Hz, 1H), 5.01 (s, 2H), 4 .20 (s, ZN), 3.65 - 3.55 (m, 1H), 3.44 - 3.35 (m, 1H), 2.59 (s, ZN), 2.13 1.92 ( m, ZN), 1.73 (sh.s., 1H), 1.54 (d, 4=7.1 Hz, 6H), 1.18 (d, 4=6.3Hz, ZN).

- 141 044841

4-(aminomethyl)-6-(diethylamino)2-[6-(4-ethyl-5-methyl-4/7-1,2,4triazol-3-yl)pyridin-2-yl]-2,3dihydro- 1/7-pyrrolo[3,4c]pyridin-1-one

4-(aminomethyl)-6-(2,2dimethylpyrolidinyl-1 -yl)-2-{6[5-methyl-4-(propan-2-yl)-4H1,2,4-triazol-3-yl]pyridine -2yl}-2,3-dihyde rho-1 H-pyrrolo[3,4c]pyridin-1-one

η ₂ ν

4-(aminomethyl)-6-[methyl(propan2-yl)amino]-2-{6-[5-methyl-4(propan-2-yl)-4/7-1,2,4-triazol-3yl ]pyridin-2-yl}-2,3-dihyde rho-1 Npyrrolo[3,4-c]pyridin-1-one

Ή NMR (400 MHz, Methanol-^) δ 8.88 (d, 2=8.4 Hz, 1H), 8.16 (t, 2=8.1 Hz, 1H), 8.04 (d, 2 =7.5 Hz, 1H), 6.99 (s, 1H), 5.19 (s, 2H), 4.37 (s, 2H), 3.71 (sq., 2 = 6.9 Hz, 4H), 2.83 (s, ZN), 1.64 (t, 2=7.2 Hz, ZN), 1.27 (t, 2=7.0 Hz, 6H). ¹ H NMR (400 MHz, Methanol-ph + O ₂ O) δ 8.85 (d, 2 = 8.3 Hz, 1H), 8.19 - 8.12 (m, 1H), 8.07 - 8 .00 (m, 1H), 6.98 (s, 1H), 5.19 (s, 2H), 4.83 - 4.75 (m, 2H), 4.36 (s, 2H), 3, 71 (sq., 2=7.0 Hz, 4H), 2.80 (s, ZN), 1.63 (t, 2=7.2 Hz, ZN), 1.27 (t, 2=7, 0 Hz, 6H) ^1H NMR (400 MHz, Methanol-sU ₄ ) δ 8.88 (d, 2=8.3 Hz, 1H), 8.16 (t, 2=8.0 Hz, 1H), 7.86 (d, 2=7.0 Hz, 1H), 6.96 (s, 1H), 5.62 (wd„ 2=7.5 Hz, 1H), 5.15 (s, ZN ), 4.33 (s, 2H), 3.67 (s, 2H), 2.88 (s, ZN), 2.05 (s, 4H), 1.74 (d, 2=7.0 Hz , 6H), 1.61 (s, 6H).

^1H NMR (400 MHz, Methanol-f) δ 8.91 (d, 2=7.8 Hz, 1H), 8.22 - 8.13 (m, 1H), 7.88 (d, 2=7 .5 Hz, 1H), 7.02 (s, 1H), 5.73 - 5.62 (m, 1H), 5.16 (s, 2H), 5.09 5.05 (m, 1H), 4.34 (s, 2H), 3.02 (s, ZN), 2.93 (s, ZN), 1.76 (d, 2=7.0 Hz, 6H), 1.27 (d, 2 =6.5 Hz, 6H).

- 142 044841

166 (WITH) 1 ίΥ _Z V cy Ci h ₂ n 4-(aminomethyl)-6-[ethyl(propan-2yl)amino]-2-{6-[4-(pentan-3-yl)4/7-1,2, 4-triazol-3-yl]pyridin-2yl}-2,3-dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one 463.2 ^1H NMR (400 MHz, Methanol-f) δ 9.40 (s, 1H), 8.86 (d, 4=8.4 Hz, 1H), 8.15 (dd, 4=7.7, 8 .4 Hz, 1H), 7.96 (d, 4=7.6 Hz, 1H), 7.00 (s, 1H), 5.49 - 5.38 (m, 1H), 5.16 (s , 2H), 5.11 - 5.03 (m, 1H), 4.33 (s, 2H), 3.57 (sq., 4=6.9 Hz, 2H), 2.15 - 2.00 (m, 4H), 1.29 (d, 4=6.7 Hz, 9H), 0.95 (t, 4=7.3 Hz, 6H). 167 (Al) o U η ₂ ν 4-(aminomethyl)-2-[6-(4-ethyl-5methyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-6-[ethyl(propane - 2-yl)amino]-2,3-dihyde rho-1 Npyrrolo[3,4-c]pyridin-1-one 435.3 ^1H NMR (400 MHz, Methanol-ph) δ 8.92 (d, 4=8.5 Hz, 1H), 8.19 (t, 4=8.0 Hz, 1H), 7.90 (d, 4=7.3 Hz, 1H), 7.05 (sh.s., 1H), 5.81 - 5.68 (m, 1H), 5.19 (s, 2H), 5.03 (sh. s., 1H), 4.36 (s, 2H), 3.58 (b.d., 4=7.3 Hz, 2H), 2.97 (s, ZN), 1.79 (b.d. „ 4 = 7.0 Hz, 6H), 1.36 - 1.26 (m, 8H), 1.36 - 1.26 (m, 1H). 168 (Al) η ₂ ν 4-(aminomethyl)-6-[(2R,5R)-2,5dimethylpyrrolidinyl-1-yl]-2-[6(4-ethyl-5-methyl-4/7-1,2,4triazol- 3-yl)pyridin-2-yl]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 447.3 ^1H NMR (400 MHz, DMSO-s/ ₆ ) δ 8.71 (dd, 4=4.9, 8.3 Hz, 1H), 8.18 (dt, 4=3.5, 8.0 Hz , 1H), 7.98 (dd, 4=1.6, 7.6 Hz, 1H), 6.72 (s, 1H), 5.12 (sh.s., 2H), 4.63 (w d„ 4 = 6.4 Hz, 2H), 4.52 - 4.15 (m, 4H), 2.72 (w. d„ 4 = 5.9 Hz, ZN), 2.23 (w. s., 2N), 1.66 (w. d„ 4 = 5.3 Hz, 2N), 1.57 - 1.45 (m, ZN), 1.12 (w. d„ 4 = 5.9 GC, 6N).

- 143 044841

169 (Al) h ₂ n 4-(aminomethyl)-6-[(2R,5R)-2,5dimethylpyrrolidinyl-1-yl]-2-{6[5-methyl-4-(propan-2-yl)-4/71, 2,4-triazol-3-yl]pyridin-2yl}-2,3-dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one 461.1 ^1H NMR (400 MHz, Methanol-f) δ 8.79 (d, 7=8.5 Hz, 1H), 8.16 (dd, 7=7.8, 8.5 Hz, 1H), 7, 84 (d, 7=7.5 Hz, 1H), 6.87 (s, 1H), 5.53 (quin., 7=7.0 Hz, 1H), 5.16 (s, 2H), 4 .83 - 4.77 (m, 2H), 4.56 - 4.21 (m, 4H), 2.86 (s, ZN), 2.35 (sh.s., 2H), 1.77 ( w. 170 (Al) Ώ h ₂ n 4-(aminomethyl)-6-(diethylamino)2-[6-(5-methyl-4-propyl-4/7-1,2,4triazol-3-yl)pyridin-2-yl] -2,3dihydro-1/7-pyrrolo[3,4- c]pyridin-1-one 435.2 ^1H NMR (400 MHz, Methanol-^) δ 8.86 (d, 7=8.5 Hz, 1H), 8.14 (t, 7=8.0 Hz, 1H), 8.02 (d, 7=7.0 Hz, 1H), 6.99 (s, 1H), 5.17 (s, 2H), 4.73 - 4.65 (m, 2H), 4.35 (s, 2H), 3.71 (sq., 7=7.0 Hz, 4H), 2.77 (s, ZN), 2.00 (w.d„ 7=7.8 Hz, 2H), 1.27 (t, 7=7.0 Hz, 6H), 1.10 (t, 7=7.4 Hz, ZN). 171 (Al) / k »1 Jx / \=ζ ( \ h ₂ n 4-(aminomethyl)-6-[ethyl(methyl)amino]-2-[6-(4-ethyl5-methyl-4/7-1,2, 4-triazol-Zyl)pyridin-2-yl]-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 407.3 ^1H NMR (400 MHz, Methanol-^) δ 8.88 -8.82 (m, 1H), 8.19-8.10 (m, 1H), 8.078.00 (m, 1H), 7.00 (s, 1H), 5.19 (s, 2H), 4.83 - 4.76 (m, 2H), 4.37 (s, 2H), 3.77 (sq., 7=7.0 Hz , 2Н), 3.20 (s, ZN), 2.81 (s, ZN), 1.63 (t, 7=7.3 Hz, ZN), 1.24 (t, 7=7.0 Hz , ZN).

- 144 044841

172 (Al) ο / λ,Ι> μ η ₂ ν 4-(aminomethyl)-6-[methyl(propan2-yl)amino]-2-[6-(5-methyl-4propyl-4/7-1,2,4- triazol-Zyl)pyridin-2-yl]-2,3-dihydro-1/7pyrrolo[3,4-c]pyridin-1-one 435.1 ^1H NMR (400 MHz, Methanol-^) δ 8.91 (d, >7.9 Hz, 1H), 8.17 (d, >8.5 Hz, 1H), 8.05 (d, >7 ,0 Hz, 1H), 7.03 (s, 1H), 5.19 (s, 2H), 5.06 (td, >6.7, 13.1 Hz, 1H), 4.83 - 4, 76 (m, 2H), 4.38 (s, 2H), 3.02 (s, ZN), 2.88 (s, ZN), 2.05 (w. d„ >7.5 Hz, 2H) , 1.28 (d, >6.8 Hz, 6H), 1.13 (t, >7.4 Hz, ZN). 173 (WITH) 1 fl / / \ / / Ν N \ \M~\J JL/ ⁷ >1' HN\ 2-(6-{4-[(25)-butan-2-yl]-4H-1,2,4triazole -3-yl}pyridin-2-yl)-6[ethyl(methyl)amino]-4[(methylamino)methyl]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 435.3 ^1H NMR (400 MHz, DMSO-cfe) δ 9.29 (b.s., 2H), 9.19 (s, 1H), 8.66 (d, >8.5 Hz, 1H), 8, 15 (t, >8.0 Hz, 1H), 7.95 (d, >7.5 Hz, 1H), 6.92 (s, 1H), 5.33 (sq., >7.0 Hz, 1H), 5.15 (s, 2H), 4.37 - 4.24 (m, 2H), 3.72 (sq., >6.8 Hz, 2H), 3.12 (s, ZN), 2.78 - 2.69 (m, ZN), 2.04 - 1.87 (m, 2H), 1.60 (d, >6.6 Hz, ZN), 1.12 (t, >7, 0 Hz, ZN), 0.83 (t, >7.4 Hz, ZN). 174 (Η) L/CU / \ Г f h ₂ n 4-(aminomethyl)-6-(dimethylamino)-2-{6-[(4/?)-4-(fluoromethyl)-2-oxo-1,3-oxazolidine-3 -yl]pyridin-2-yl}2,3-dihyde rho-1 /7-pyrrolo[3,4c]pyridin-1-one 401.1 ^1H NMR (400 MHz, DMSO-s( ₆ ) δ 8.54 (b.s., 2H), 8.24 (d, >7.5 Hz, 1H), 8.01 7.94 (m, 1H), 7.91 - 7.87 (m, 1H), 6.87 (s, 1H), 5.22 - 5.09 (m, 2H), 5.08 - 4.97 (m, 2H) , 4.88 - 4.71 (m, 1H), 4.65 (t, >8.9 Hz, 1H), 4.52 (dd, >3.3, 8.7 Hz, 1H), 4, 27 - 4.17 (m, 2H), 3.16 (s, 6H).absolute stereochemistry known

- 145 044841

2-[6-(5-ethyl-4-propyl-4H-1,2,4triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-6-[(2R)-2methylpyrolidinyl- 1-yl]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one

4-[(methylamino)methyl]-2-{6-[5methyl-4-(2-methylpropyl)-4/71,2,4-triazol-3-yl]pyridin-2yl}-6-[(2/ ?)-2-methylpyrrolidinyl1 -yl]-2,3-dihyde rho-1 Npyrrolo[3,4-c]pyridin-1-one

6-(dimethylamino)-4[(methylamino)methyl]-2-{6-[4-(2methylpropyl)-4/7-1,2,4-triazol3-yl]pyridin-2-yl}-2,3 -dihyde rho1/7-pyrrolo[3,4-c]pyridin-1-one ¹ H NMR (400 MHz, DMSO-sub) δ 9.43 9.24 (m, 2H), 8.70 (d, 7 =8.3 Hz, 1H), 8.16 (t, 7=7.8 Hz, 1H), 7.99 (d, 7=7.8 Hz, 1H), 6.75 (s, 1H), 5.15 (s, 2H), 4.59 - 4.46 (m, 2H), 4.38 - 4.33 (m, 1H), 4.29 (sh.t., 7 = 5.1 Hz , 2H), 3.70 - 3.52 (m, 1H), 3.41 (w. d„ 7 = 9.8 Hz, 1H), 3.01 (sq., 7 = 7.5 Hz, 2H ), 2.77 - 2.69 (m, ZN), 2.14 - 1.96 (m, ZN), 1.88 - 1.71 (m, ZN), 1.41 (t, 7=7 .5 Hz, ZN), 1.20 (d, 7=6.0 Hz, ZN), 0.96 (t, 7=7.4 Hz, ZN).

¹ H NMR (400 MHz, DMSO-sub) δ 9.53 9.28 (m, 2H), 8.68 (d, 7=8.1 Hz, 1H), 8.17 (t, 7=8, 1 Hz, 1H), 7.96 (d, 7=7.1 Hz, 1H), 6.74 (s, 1H), 5.14 (s, 2H), 4.50 (wd„ 7= 7.7 Hz, 2H), 4.35 (w. d„ 7=6.0 Hz, 1H), 4.28 (w.t., 7=5.2 Hz, 2H), 3.64 (w .t., 7=8.4 Hz, 1H), 3.46 - 3.32 (m, 1H), 2.71 (t, 7=5.3 Hz, ZN), 2.67 (s, ZN ), 2.15 - 1.93 (m, 4H), 1.74 (b.d., 7=7.3 Hz, 1H), 1.20 (d, 7=6.2 Hz, ZN), 0.84 (d, 7=6.6 Hz, 6H).

¹ H NMR (600 MHz, DMSO-sub) δ wt. 9.05 - 9.08 (m, 1 N) 8.67 (s, 1 N) 8.53 (d, 7=8.44 Hz, 1 N) 8.00 (t, 7=7.98 Hz , 1 N) 7.91 (d, 7=7.52 Hz, 1 N) 6.83 (s, 1 N) 5.01 (s, 2 N) 4.39 (sh.d., 7=7 .52 Hz, 2 N) 4.29 (sh.s., 2 N) 3.09 (s, 6 N) 2.69 (s, 3 N) 2.05 (s, 1 N) 0.79 ( d, 7=6.42 Hz, 6 N).

- 146 044841

2-[6-(4-cyclopentyl-4/7-1,2,4triazol-3-yl)pyridin-2-yl]-4[(methylamino)methyl]-6-(1 methylcyclopropyl)-2,3- Dihyde rho1H-pyrrolo[3,4-c]pyridin-1-one

6-(dimethylamino)-4[(methylamino)methyl]-2-(6-{4[(25)-3-methylbutan-2-yl]-4H1,2,4-triazol-3-yl}pyridin-2yl )-2,3-dihyde rho-1/7-pyrrolo[3,4с]pyridin-1-one

4-[(methylamino)methyl]-6-(1 methylcyclopropyl)-2-(6-{4-[^)1,1,1-trifluoropentan-3-yl]-4/71,2,4-triazol- 3-yl}pyridin-2yl)-2,3-dihyde rho-1 /7-pyrrolo[3,4с]pyridin-1-one ¹ H NMR (400 MHz, DMSO-de) δ 9.31 (b.s. ., 2H), 9.10 (s, 1H), 8.64 (dd, 4=0.6, 8.4 Hz, 1H), 8.18-8.08 (m, 1H), 7.95 (dd, 4=0.6, 7.6 Hz, 1H), 6.94 (s, 1H), 5.25 - 5.04 (m, ZN), 4.27 (sh.t., 4= 5.4 Hz, 2H), 3.17 (s, 6H), 2.71 (t, 4=5.4 Hz, ZN), 2.18 (qd, 4=6.7, 15.4 Hz, 1H), 1.58 (d, 4=6.8 Hz, ZN), 0.98 (d, 4=6.7 Hz, ZN), 0.73 (d, 4=6.7 Hz, ZN) .

absolute stereochemistry is known ¹ H NMR (400 MHz, DMSSM _b ) b 9.37 (b. d„ 4 = 4.3 Hz, 2H), 9.19 (s, 1H), 8.67 (d, 4 = 8 ,4 Hz, 1H), 8.17 (t, 4=8.0 Hz, 1H), 7.98 (d, 4=7.5 Hz, 1H), 7.71 (s, 1H), 5, 67 - 5.54 (m, 1H), 5.30 (s, 2H), 4.42 (sh.t., 4=5.7 Hz, 2H), 2.71 (bt., 4= 5.2 Hz, ZN), 2.35 - 2.26 (m, 2H), 2.00 -1.85 (m, 4H), 1.79 (sh.s., 2H), 1.60 ( s, ZN), 1.46 (w. d„ 4 = 2.2 Hz, 2H), 0.96 0.87 (m, 2H).

^1H NMR (400 MHz, DMSO-s( ₆ ) b 9.08 (s, 1H), 8.67 - 8.63 (m, 1H), 8.12 (t, 4=8.0 Hz, 1H ), 7.99 (d, 4=7.0 Hz, 1H), 7.57 (s, 1H), 6.07 (sh.s., 1H), 5.24 (d, 4=6.5 Hz, 2H), 3.90 (s, 2H), 3.18 (s, 1H), 3.05 2.90 (m, 1H), 2.32 (s, ZN), 2.10-1, 95 (m, 2H), 1.56 (s, ZN), 1.29 - 1.22 (m, 2H), 0.90-0.78 (m, 5H).

absolute stereochemistry unknown

- 147 044841

181 (S) / NN \ / N^=Z \ HN ³ \ 4-[(methylamino)methyl]-6-(1 methylcyclopropyl)-2-(6-{4-[^)- 1,1,1-trifluoropentane-3- yl]-4/71,2,4-triazol-3-yl}pyridin-2yl)-2,3-dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one 500.1 ^1H NMR (400 MHz, DMSO-s( ₆ ) δ 9.08 (s, 1H), 8.65 (d, 4=7.8 Hz, 1H), 8.12 (t, 4=8.0 Hz, 1H), 7.99 (d, 4=7.5 Hz, 1H), 7.57 (s, 1H), 6.13-6.00 (m, 1H), 5.305.14 (m, 2H ), 3.91 (s, 2H), 3.27-3.11 (m, 1H), 3.01 (w. d„ 4 = 11.5 Hz, 1H), 2.33 (s, ZN) , 2.09 - 1.94 (m, 2H), 1.56 (s, ZN), 1.29 - 1.22 (m, 2H), 0.91 - 0.78 (m, 5N).absolute stereochemistry unknown 182 1 Λ US. ^Ech. / Ν 1^ \ ^ζ \ ΗΝ 435.3 ^1H NMR (400 MHz, DMSO-sub) δ 9.33 (b.s., 2H), 9.07 (s, 1H), 8.64 (d, 4=7.9 Hz, 1H), 8 .13 (t, 4=8.0 Hz, 1H), 7.94 (d, 4=7.1 Hz, 1H), 6.93 (s, 1H), 5.25 - 5.05 (m, ZN), 4.35 - 4.17 (m, 2N), 3.17 (s, (IN) \ 6-(dimethylamino)-4- [(methylamino)methyl]-2-(6-{4[(2R)-3-methylbutan-2-yl]-4/71,2,4-triazol-3-yl}pyridin-2yl)-2,3 -dihyde rho-1/7-pyrrolo[3,4c]pyridin-1-one 6H), 2.71 (t, 4=5.4 Hz, ZN), 2.17 (qd, 4=6.6, 15.3 Hz, 1H), 1.58 (d, 4=6.8 Hz, ZN), 0.98 (d, 4=6.7 Hz, ZN), 0.73 (d, 4=6.6 Hz, ZN). absolute stereochemistry is known

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2-(6-{4-[(2^)-1-hydroxybutan-2yl]-4/7-1,2,4-triazol-Zyl}pyridin-2-yl)-4[(methylamino)methyl]- 6-(1 methylcyclopropyl)-2,3-dihyde rho1/7-pyrrolo[3,4-c]pyridin-1-one

4-(aminomethyl)-2-[6-(4,5-diethyl4/7-1,2,4-triazol-3-yl)pyridin-2yl]-6-[(2R)-2-methylpyrolidinyl1 -yl] -2,3-dihyde rho-1 Npyrrolo[3,4-c]pyridin-1-one

2-(6-{4-[(2ξ)-1-hydroxybytan-2yl]-4/7-1,2,4-triazol-Zyl}pyridin-2-yl)-4[(methylamino)methyl]-6 -(1 methylcyclopropyl)-2,3-dihyde rho1/7-pyrrolo[3,4-c]pyridin-1-one

^1H NMR (400 MHz, DMSO-sub) δ 8.82 (s, 1H), 8.63 (d, 4=8.3 Hz, 1H), 8.11 (t, 4=7.8 Hz, 1H), 7.96 (d, 4=7.5 Hz, 1H), 7.57 (s, 1H), 5.51-5.35 (m, 1H), 5.25 (s, 2H), 5.06 (b.s., 1H), 3.90 (s., 2H), 3.78 (b. d„ 4 = 12.3 Hz, 2H), 2.34 (s, ZN), 2, 08 - 1.92 (m, 2H), 1.56 (s, ZN), 1.28 - 1.22 (m, 2H), 0.92 - 0.84 (m, 5H). absolute stereochemistry unknown* ¹ H NMR (400 MHz, DMSO-sub) δ 8.83 8.80 (m, 1H), 8.63 (d, 4=8.3 Hz, 1H), 8.11 (t, 4=7.9 Hz, 1H), 7.96 (d, 4=7.3 Hz, 1H), 7.57 (s, 1H), 5.49 - 5.42 (m, 1H), 5, 25 (s, 2H), 5.07 (w. d„ 4 = 6.3 Hz, 1H), 3.90 (s, 2H), 3.84 - 3.70 (m, 2H), 2.34 (s, ZN), 2.05 - 1.92 (m, 2N), 1.56 (s, ZN), 1.28 - 1.22 (m, 2N), 0.92 - 0.84 (m , 5H).

absolute stereochemistry unknown'* ^1H NMR (400 MHz, DMSO-cfe) δ 8.69 (d, 4=8.3 Hz, 1H), 8.40 (br.s., ZN), 8.16 (t , 4=8.2 Hz, 1H), 7.99 (d, 4=7.5 Hz, 1H), 6.72 (s, 1H), 5.17 (s, 2H), 4.59 (kv ., 4=7.0 Hz, 2H), 4.46-4.30 (m, 1H), 4.29 -4.18 (m, 2H), 3.86-3.60 (m, 1H) , 3.00 (sq., 4=7.3 Hz, 2H), 2.57 (w. dd, 4=1.8, 3.8 Hz, 1H), 2.16 - 1.96 (m, ZN), 1.77 1.70 (m, 1H), 1.47 (t, 4=7.0 Hz, ZN), 1.40 (t, 4=7.4 Hz, ZN), 1.21 (d, 4=6.3 Hz, ZN).

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186 (AD) h ₂ n 4-(aminomethyl)-2-[6-(5-ethyl-4propyl-4/7-1,2,4-triazol-Zyl)pyridin-2-yl]-6-[(2/?) -2methylpyrrolidinyl-1-yl]-2,3dihydro-1/7-pyrrolo[3,4c]pyridin-1-one 461.3 ^1H NMR (400 MHz, DMSO-cO δ 8.69 (d, 7=8.5 Hz, 1H), 8.43 (b.s., ZN), 8.15 (t, 7=8.0 Hz, 1H), 7.99 (d, 7=7.5 Hz, 1H), 6.72 (s, 1H), 5.15 (s, 2H), 4.54 - 4.48 (m, 2H ), 4.40-4.33 (m, 1H), 4.24-4.16 (m, 2H), 3.66 (w. d„ 7 = 8.5 Hz, 1H), 3.45 - 3.38 (m, 1H), 2.98 (sq., 7=7.5 Hz, 2H), 2.13-1.96 (m, ZN), 1.88-1.79 (m, 2H ), 1.77 - 1.72 (m, 1H), 1.40 (t, 7=7.4 Hz, ZN), 1.21 (d, 7=6.0 Hz, ZN), 0.98 (t, 7=7.4 Hz, ZN). 187 (AD) η yau fch HN\ 2-[6-(4-cyclobutyl-5-methyl-4/7- 1,2,4-triazol-3-yl)pyridin-2yl]-4-[(methylamino)methyl]-6-(1 methylcyclopropyl)-2,3-dihyde po1/7-pyrrolo[3,4-c] pyridin-1-one 444.2 ^1H NMR (400 MHz, CDCI ₃ ) δ 8.78 - 8.70 (m, 1H), 7.99 - 7.91 (m, 1H), 7.91 - 7.82 (m, 1H), 7.71 (s, 1H), 5.57 (quin., 7=9.0 Hz, 1H), 5.19 (s, 2H), 3.99 (s, 2H), 2.73 (s, ZN), 2.63 - 2.54 (m, 2N), 2.53 (s, ZN), 2.50 - 2.42 (m, 2N), 1.98 - 1.80 (m, 2N) , 1.61 (s, ZN), 1.40 - 1.32 (m, 2H), 0.95-0.87 (m, 2H). 188 (AD) c Xi / Ν N \ X h ₂ n 4-(aminomethyl)-2-[6-(4cyclobutyl-5-methyl-4/7-1,2,4triazol-3-yl)pyridin-2-yl]-6 -(1-methylcyclopropyl)-2,3-dihyde po1H-pyrrolo[3,4-c]pyridin-1-one 430.0 ^1H NMR (400 MHz, CDCI ₃ ) δ 8.72 (d, 7=8.3 Hz, 1H), 7.93 (t, 7=7.9 Hz, 1H), 7.83 (d, 7 =6.9 Hz, 1H), 7.69 (s, 1H), 5.51 (t, 7 = 8.9 Hz, 1H), 5.14 (s, 2H), 4.09 (s, 2H ), 2.71 (s, ZN), 2.62 - 2.39 (m, 4N), 1.95 - 1.79 (m, 2N), 1.61 (s, ZN), 1.38- 1.33 (m, 2H), 0.92 - 0.87 (m, 2H).

* The use of or 1 in structure and ξ for stereochemistry in the name denotes the identification of chiral centers that have been resolved into enantiomers, but the specific enantiomer has not been identified; a solid or dotted wedge is drawn in the structure, but this may be a different enanatiomer.

Biological assays and data biochemical enzymatic analysis of HPK1.

HPK1 enzyme inhibition was measured using a microfluidic mobility shift assay (MSA). Reactions were performed in 50 μl volumes in 96-well plates and contained 0.5 nM full-length recombinant human HPK1, 3 μM phosphoacceptor peptide, 5FAMAKRRRLSSLRA-COOH (CPC Scientific, Sunnyvale, CA), test compound (11-dose 3-fold serial dilutions , 2% DMSO, at the end) or DMSO only, 0.002% Tween -20, 1 mM DTT and 2.5 mM MgCl ₂ in 50 mM MOPS (3-(N-morpholino)propanesulfonic acid), pH 7.8, buffer and initiated by adding 75 μM ATP after a 20-min preincubation. Reactions were carried out for 60 min at 37°C, stopped by adding 50 μl of 0.015 M EDTA, pH 8, and the extent of the reaction (~1520% conversion without inhibitor) was determined after electrophoretic separation of the fluorescently labeled peptide substrate and phosphorylated product on a LabChip EZ Reader II (PerkinElmer, Inc., Waltham, MA).

HPK1 inhibition was also measured using a chelation-enhanced fluorescence (CHEF) method (1), using a proprietary fluorescent peptide substrate in which a cysteine residue is alkylated with a sulfonamidooxine derivative to produce an amino acid called C-Sox (CSx). The assay was performed as described above for the MSA method, but using 3 μM Ac-[CSx]HSLPRFNR amide peptide substrate (also known as AQT0178, purchased from AssayQuant Technologies Inc., Hopkinton, MA) and 45 μM ATP. Start

- 150 044841 the actual reaction rates were determined by the fluorescence of the peptides (X _ex =360 nm, X _em =500 nm) at 30°C for 15 minutes using a Tecan M1000 plate reader (Tecan Group Ltd., Mannedorf, Zurich, Switzerland) . Inhibition constant (Ki) values were calculated by fitting initial rates based on % conversion (MSA method) or fluorescence (CHEF method) to the Morrison equation (2) for competitive inhibition with strong binding using a nonlinear regression method and experimentally measured ATP Km (29 μM based on MSA and 19 µM based on CHEF, respectively). Kinetic and crystallographic studies have shown that the inhibitors are ATP-competitive. The HPK1 protein was produced in-house and preactivated by autophosphorylating the enzyme with MdATP as described in the section Production of recombinant autophosphorylated full-length HPK1.

Cell-based assay.

Phospho-SLP-76 (Ser376) homogeneous time-spaced fluorescence (HTRF) assay.

Jurkat cells were seeded at 90,000 cells/well in 90 μl of RPMI1640 growth medium containing 10% FBS and incubated at 37°C with 5% CO ₂ overnight. The next day, compounds were gradually diluted, starting at a maximum dose of 10 mM, to obtain an 11-point curve of threefold dilution in DMSO. Compounds were intermediately diluted 1:100 in growth medium before diluting 1:10 on cells to a final concentration of 10 μM to 0.1 nM in 0.1% DMSO. After a 30-minute compound pretreatment, cells were stimulated with 200 μg/ml anti-CD3 F(ab) ₂ complex (clone UCTH1) for 15 min at 37°C with 5% _CO2 . Stimulation was stopped with ice-cold PBS, and cells were collected by centrifugation before lysis in Cisbio lysis buffer (Cisbio, Bedford, MA). Lysates were transferred to small volume white plates containing anti-phospho-SLP-76-cryptate antibodies 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 IC ₅₀ values were calculated by fitting a concentration-response curve using four-parameter nonlinear regression analysis.

Biological activity data for selected compounds in HPK1 mobility shift assays and Phospho-SLP-76 (Ser376) homogeneous time-lapse fluorescence (HTRF) assays are presented in Table. 2 as IC50 (µM).

table 2

Example # NRK1 Enzymatic analysis_K| (µM) Number of runs (“n”) SLP76 Analysis_1C ₅₀ (µM) Number of runs (“n”) 1 0.00015 6 0.112 eleven 2 0.00028 3 0.086 5 3 0.00077 1 - - 4 0.00039 3 0.106 4 5 0.00039 1 0.186 2 6 0.00013 1 0.039 3 7 0.00146 1 0.73 2

- 151 044841

8 0.00025 1 0.089 3 9 0.00027 2 0.088 3 10 0.00026 2 0.0976 2 eleven 0.00009 3 0.159 3 12 0.0002 2 0.155 3 13 <0.00008 5 0.085 4 14 0.00017 2 0.102 3 15 <0.00007 2 0.134 3 16 0.00056 2 0.358 2 17 <0.00005 7 0.07 5 18 <0.00005 3 0.101 3 19 0.0069 2 >10 1 20 0.0028 2 0.158 4 21 0.00062 2 0.245 3 22 0.0004 1 0.105 2 23 0.14 1 - - 24 0.00072 2 0.488 1 25 0.001 1 - - 26 0.0009 2 0.439 4 27 0.00019 1 - - 28 0.00041 4 0.119 5 29 0.0032 2 0.396 3 thirty 0.0021 3 0.573 1 31 0.00066 1 - - 32 0.00034 2 0.21 3 33 0.00028 2 0.134 2 34 0.00132 1 0.379 2 35 0.00012 1 0.183 3 36 0.0051 1 1.11 2 37 0.0015 1 0.487 2 38 0.00038 2 0.147 5 39 0.0018 2 0.672 1 40 0.00081 3 0.137 2 41 0.0046 1 0.315 1 42 0.00033 2 0.192 1 43 0.00192 3 0.561 1 44 0.0004 1 0.244 1 45 0.00017 1 0.173 5 46 0.00014 1 0.094 4 47 0.0071 1 1.52 2 48 0.00014 1 0.094 4 49 0.00146 1 0.73 2 50 0.00014 1 0.094 4 51 0.0071 1 1.52 2 52 0.0899 1 - - 53 0.00061 3 0.489 1

Biological activity data from HPK1 mobility shift assays and Phospho-SLP-76 (Ser376) homogeneous time-lapse fluorescence (HTRF) assays are presented in Table. 3 for examples 55-68.

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Table 3

Example # NRK1 Enzymatic analysis_K| (mykm) Number of runs (“n”) SLP76 Analysis_1C ₅₀ (µm) Number of runs (“n”) 55 <0.00006 2 0.034 3 56 0.00034 1 0.139 3 57 0.00021 2 0.074 4 58 0.00016 1 0.103 1 59 0.00019 1 0.059 2 60 0.00017 2 0.070 2 61 0.00018 2 0.088 4 62 0.00009 1 0.042 2 63 <0.00009 2 0.087 4 64 <0.00017 10 0.091 eleven 65 0.00035 1 0.114 2 66 0.00052 1 0.108 2 67 0.00129 1 ND N.A. 68 <0.00007 3 0.05 2

In table 3-5 ND indicates not determined, with NA (not applicable) in the column for the number of runs.

Biological activity data from HPK1 mobility shift assays and Phospho-SLP-76 (Ser376) homogeneous time-lapse fluorescence (HTRF) assays are presented in Table. 4 for examples in table. 1A.

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Table 4

Example # NRK1 Enzymatic analysis_K| (µm) Number of runs (“n”) SLP76 Analysis_1C ₅₀ (µm) Number of runs (“n”) 69 0.00053 1 0.248 3 70 0.00016 1 0.062 2 71 0.00018 2 0.040 4 72 0.00448 1 1.02 2 73 0.00022 1 0.061 3 74 0.00006 1 0.077 2 75 0.00052 1 0.118 2 76 0.00064 1 0.583 1 77 0.00068 1 ND N.A. 78 0.00073 1 0.307 1 79 <0.00005 1 0.048 2 80 0.00016 1 0.184 2 81 0.00058 1 0.406 1 82 0.00012 1 0.095 2 83 0.0352 1 6.64 1 84 0.00014 1 0.138 2 85 0.00111 1 0.345 2 86 0.00304 1 0.652 2 87 0.00144 1 0.299 2 88 0.00252 1 2,682 2 89 <0.00008 3 0.054 3 90 0.00146 1 0.694 1 91 0.00033 1 0.257 2 92 0.00043 1 0.226 2 93 0.00042 1 0.713 1 94 0.00034 1 0.280 1 95 0.00051 1 0.168 1 96 0.00040 1 0.142 1 97 0.00034 1 0.186 2 98 0.00096 1 0.514 1 99 0.00083 1 ND N.A. 100 <0.00005 1 0.034 3

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101 0.00094 1 0.217 1 102 0.00029 1 0.074 2 103 0.00115 1 0.199 1 104 0.00013 2 0.051 1 105 0.00021 1 0.064 3 106 0.00026 2 0.083 2 107 0.00004 1 0.022 2 108 0.00370 1 0.583 1 109 0.00006 1 0.012 1 110 0.00032 1 0.086 2 111 0.00101 1 0.147 1 112 0.00149 1 0.431 1 113 0.00022 2 0.083 1 114 0.00012 2 0.037 2 115 <0.00009 3 0.021 2 116 0.00104 2 0.381 1 117 0.00046 1 0.089 2 118 0.00089 1 0.149 1 119 0.00052 1 0.104 2 120 <0.00009 2 0.056 1 121 0.00009 1 0.062 3 122 0.00041 1 0.070 1 123 0.00103 1 0.273 1 124 0.00150 1 0.375 1 125 0.00010 2 0.050 2 126 0.00080 1 0.114 2 127 0.00152 2 0.435 1 128 0.00063 1 0.874 1 129 0.00031 1 0.093 1 130 0.00078 1 0.201 1 131 0.00011 1 0.057 2 132 0.00020 1 0.067 1 133 0.00028 2 0.232 1 134 0.00047 1 0.053 2 135 0.00080 1 >10 1 136 0.00073 2 0.106 1 137 0.00028 1 0.076 2 138 0.00009 1 >10 1 139 0.00046 1 0.266 1 140 0.00207 1 0.464 1 141 0.00074 1 0.122 2 142 0.00052 1 0.239 1 143 0.00009 1 0.028 3 144 <0.00005 1 0.015 3 145 0.00047 1 0.061 2 146 0.00091 1 0.106 2

Bioactivity data from HPK1 mobility shift assays and Phospho-SLP-76 (Ser376) homogeneous time-traced fluorescence (HTRF) assays are shown in Table. 5 for examples in table. 1B.

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Table 5

Example # NRK1 Enzymatic analysis_K| (µm) Number of runs (“n”) SLP76 Analysis_1C ₅₀ (µm) Number of runs (“η”) 150 0.00006 1 0.033 1 151 0.0001 1 0.014 1 152 0.00012 1 0.046 1 153 0.00014 1 0.065 1 154 0.00015 1 0.151 1 155 0.00016 1 0.055 1 156 0.00019 1 0.104 1 157 0.00023 1 0.085 1 158 0.00038 1 0.083 1 159 0.00045 1 0.112 1 160 0.00048 1 0.272 1 161 0.00068 1 0.217 1 162 0.00076 1 0.136 1 163 0.00088 1 0.196 1 164 0.0001 1 0.065 2 165 0.00028 1 0.114 2 166 0.0005 1 0.104 1 167 0.0007 1 0.391 1 168 0.00076 1 0.3 1 169 0.00095 1 0.179 1 170 0.00036 1 0.264 1 171 0.00034 1 0.18 1 172 0.00055 1 0.085 2 173 0.00006 1 0.043 1 174 0.00037 1 0.207 1 175 0.00094 1 0.185 1 176 0.00022 2 0.64 1 177 0.00026 1 0.152 1 178 0.00017 2 ND ΝΑ 179 0.00047 2 ND ΝΑ 180 0.02509 1 ND ΝΑ 181 0.00013 1 ND ΝΑ 182 0.00037 1 ND ΝΑ 183 0.00035 1 ND ΝΑ 184 0.00115 1 ND ΝΑ 185 0.00079 1 0.136 2 186 0.00191 2 ND ΝΑ 187 0.026 1 ND ΝΑ 188 0.041 1 ND ΝΑ

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

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Claims (20)

CLAIM 1. Compound of formula I or a pharmaceutically acceptable salt thereof, in which R ¹ is selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1O6)alkoxy, halogen(C1-C6)alkoxy, -N( ^R6 )( ^R7 ) , and (C3- _C6 )cycloalkyl, wherein said ( _C1 - _C6 )alkyl, halogen( _C1 - _C6 )alkyl and ( _C3 - _C6 )cycloalkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy; R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C1-C6)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 containing 1 or 2 heteroatoms, each independently selected from N or O, wherein said heterocycloalkyl is optionally substituted with one to three substituents selected from the group consisting of halogen, (C1- _C6 )alkyl, halogen( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy and halogen(C ₁ -C ₆ )alkoxy, wherein said (C 1 -C ₆ )alkyl and halogen(C ₁ -C ₆ )alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano , (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy; R ^1a is selected from the group consisting of hydrogen and halogen; R ² represents: i) -(CH ₂ )mN(R ⁸ )(R ⁹ ), in which m is an integer selected from 0, 1, 2 or 3, and R ⁸ and R ⁹ are each independently selected from the group consisting of from hydrogen and (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkoxy, cyano and hydroxy, or ii) (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkoxy, -N( ^R6 )( ^R7 ), cyano and hydroxy, wherein ^R6 and ^R7 are each independently selected from the group consisting of hydrogen and ( _C1 - _C6 )alkyl; R ³ is selected from the group consisting of hydrogen, halogen, hydroxy, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy; X represents carbon or nitrogen; R ⁴ is a (4- to 6-membered) heterocycloalkyl containing 2 heteroatoms, each independently selected from N or O, or (5- to 10-membered) heteroaryl containing 2 or 3 heteroatoms, each independently selected from N or S, wherein said (4- to 6-membered) heterocycloalkyl and (5- to 10-membered) heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, oxo, hydroxy, - N(R ¹⁰ )(R ¹¹ ), (C1-C6)alkyl, halogen(C1-C6)alkyl, (C1-C6)alkoxy, halogen(C1-C6)alkoxy and -(CH2)n(C3C6)cycloalkyl, wherein said (C1-C6)alkyl and halogen(C1-C6)alkyl are optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano and (C1-C6)alkoxy, and wherein n is an integer selected from 0, 1 or 2; and wherein R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen and (Cr C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 substituents selected from the group, which consists of halogen and hydroxy; R ⁵ is selected from the group consisting of hydrogen, halogen, hydroxy, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy and halogen(C ₁ -C ₆ ) alkoxy; and a is an integer selected from 0 or 1, with the proviso that when X is nitrogen, a is 0. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen and (C ₁ -C ₆ )alkyl, wherein said (C ₁ -C ₆ )alkyl is optionally substituted with 1 to 3 halogen atoms. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is -N(R ⁶ )(R ⁷ ), and R ⁶ and R ⁷ taken together with the nitrogen to which they are attached form (from A 4- to 8-membered heterocycloalkyl which is optionally substituted with one to three substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halogen(C ₁ -C ₆ )alkyl, (C _r C ₆ )alkoxy and halogen(C ₁ -C ₆ )alkoxy. - 157 044841 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R ¹ represents a (4- to 8-membered) heterocycloalkyl selected from the group consisting of azetidinyl, pyrrolidinyl and azabicyclo[2.2.1]heptyl, with azetidinyl, pyrrolidinyl and azabicyclo[2.2.1]heptyl are optionally substituted with one to three substituents selected from the group consisting of halogen, (C1- _C6 )alkyl, halo(C1- _C6 )alkyl, (C1- C ₆ )alkoxy and halogen(C1-C ₆ )alkoxy. 5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R ¹ represents pyrrolidinyl, optionally substituted with one to three substituents selected from the group consisting of halogen, (C1-C ₆ )alkyl, halogen(C1- _C6 )alkyl, (C1- _C6 )alkoxy and halogen(C1- _C6 )alkoxy. 6. A compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R is -(CH ₂ ) _m N(R )(R ), m is 1, and one of R and R is hydrogen, and the other is methyl. 7. Connection according to any one of the pi. 1-5 or a pharmaceutically acceptable salt thereof, wherein R ² is -(CH ₂ ) _m N(R ⁸ )(R ⁹ ), m is 1, and R ⁸ and R ⁹ are both hydrogen. 8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a (5- to 6-membered) heteroaryl, optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, ( C1- _C6 )alkyl, halogen( _C1C6 )alkyl, (C1- _C6 )alkoxy, halogen(C1- _C6 )alkoxy and -( _CH2 ) _p (C3- _C6 )cycloalkyl, wherein η represents an integer selected from 0 or 1. 9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the (5- to 6-membered) heteroaryl is 1,2,3-triazolyl, 1,2,4-triazolyl or pyrazolyl. 10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2-yl ]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-[(methylamino)methyl]-6-[(2K)-2-methylpyrolidinyl-1-yl]-2-[6-(4-propyl-4H-1,2,4-triazol-3yl)pyridin-2 -yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-[(MeTHnaMHHo)MeTHn]-2-[6-(5-MeTHn-4-nponHn-4H-l,2,4-TpHa3on-3-Hn)nHpHflHH-2-Hn]-6-[(2R) -2methylpyrrolidinyl-1 -yl]-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridin-1 -one; 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H-1,2,4-triazol-3yl)pyridine -2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; And 4-(aminomethyl)-2-[6-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl]-6-[(28)-2methylpyrolidinyl- 1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one. 11. Connection via i. 10 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(4-propyl-4H-1,2, 4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one. 12. Connection via i. 10 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-[(mestylamio)mesty.p]-6-[(2P)-2-mestypyrolidinyl-1-yl]-2-[6-(4-propy. p-411-1,2,4-triazol-3-yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one. 13. Connection via i. 10 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-[(mestylamio)mestil]-2-[6-(5-mestyl-4-propyl-411-1,2,4-triazol-3-yl)pyrylium- 2-yl]-6-[(2P)-2methylpyrrolidinyl-1 -yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one. 14. Connection via i. 10 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-[(methylamino)methyl]-6-[methyl(propan-2-yl)amino]-2-[6-(5-methyl-4-propyl-4H- 1,2,4-triazol-3yl)pyridin-2-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one. 15. Connection via i. 10 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-(aminomethyl)-2-[6-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl ]-6-[(28)-2-methylpyrrolidinyl-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one. 16. A pharmaceutical composition containing a compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 17. Application of a connection according to any of the pi. 1-15 or a pharmaceutically acceptable salt thereof as a drug. 18. Application of a connection according to any of the pi. 1-15 or a pharmaceutically acceptable salt thereof in the treatment of abnormal cell growth in a mammal. 19. Use of the compound or its pharmaceutically acceptable salt according to i. 18, where abnormal cell growth represents cancer. 20. A pharmaceutical combination of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and an additional anti-cancer therapeutic agent or palliative agent. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 158 -