EA043752B1 - 9-Substituted aminotriazoloquinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use - Google Patents

Description

Field of technology to which the present invention relates

The present invention relates to new compounds that inhibit at least one of the adenosine receptors A2a and A2b, and pharmaceutically acceptable salts thereof, as well as compositions containing such compound(s) and salts, methods for the synthesis of such compounds and their use in the treatment of a variety of diseases, conditions or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor. Such diseases, conditions and disorders include, without limitation, cancer and immune-mediated disorders. The present invention also relates to combination therapy, which includes, without limitation, a combination containing a compound of the present invention and a PD-1 antagonist.

Background of the present invention

Adenosine is a purine nucleoside compound consisting of adenine and ribofuranose, the sugar molecule ribose. Adenosine occurs naturally in mammals and plays important roles in various biochemical processes, including energy transmission (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate). Adenosine also causes processes associated with vasodilation, including dilation of blood vessels related to the heart. It also acts as a neuromodulator (for example, it is thought to promote sleep). In addition to its role in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic agent for the treatment of supraventricular tachycardia and other indications.

Adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. The four types of adenosine receptors in humans are designated A1, A2a, A2b, and A3. A1 modulation has been proposed for the maintenance and treatment of neurological disorders, asthma, and heart and kidney failure, among others. A3 modulation has been proposed for the maintenance and treatment of asthma and chronic obstructive pulmonary disease, glaucoma, cancer, stroke and other indications. Modulation of the A2a and A2b receptors is also believed to have potential therapeutic applications.

In the central nervous system, A2a antagonists are thought to exhibit antidepressant properties and stimulate cognitive function. A2a receptors are present in high density in the basal ganglia, which is known to play an important role in the control of movement. Therefore, A2a receptor antagonists are considered useful in the treatment of depression and improvement of movement disorders caused by neurodegenerative diseases such as Parkinson's disease, senile dementia (as in Alzheimer's disease), and various psychoses of organic origin.

In the immune system, adenosine signaling through A2a receptors and A2b receptors expressed on various immune cells and endothelial cells has been found to play an important role in tissue protection during inflammatory responses. In this way (and other ways), tumors have been shown to evade host responses by suppressing immune function and promoting tolerance. (See, for example, Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441). Moreover, adenosine receptors on the surface of A2a and A2b cells were found to be activated in various tumor cells. Thus, adenosine A2a and/or A2b receptor antagonists represent a new class of promising oncology therapeutics. For example, activation of adenosine A2a receptors leads to inhibition of the immune response to tumors by various cell types, including but not limited to: inhibition of natural killer cell cytotoxicity, inhibition of tumor-specific CD4+/CD8+ activity, stimulation of LAG-3 and Foxp3+ regulatory T cells and mediation inhibition of regulatory T cells. Inhibition of the adenosine A2a receptor has also been shown to increase the effectiveness of PD-1 inhibitors by enhancing antitumor T cell responses. Because each of these immunosuppressive pathways has been identified as a mechanism by which tumors evade host responses, a cancer immunotherapy regimen that includes an A2a and/or A2b receptor antagonist, alone or together with one or more other therapeutic agents designed to attenuate immune suppression may lead to increased tumor immunotherapy. (See, for example, P. Beavis, et al., Cancer Immunol. Res. DOI: 10.1158/2326-6066. CIR-14-0211, February 11, 2015; Willingham, SB., et al., Cancer Immunol. Res., 6(10), 1136-49; and Leone RD, et al., Cancer Immunol. Immunother., Aug 2018, Vol. 67, Issue 8, 1271-1284).

When treated with chemotherapy and radiation therapy, cancer cells release ATP into the tumor microenvironment, which is subsequently converted to adenosine. (See Martins, I., et al., Cell Cycle, vol. 8, issue 22, pp. 3723 to 3728). Adenosine can then bind to A2a receptors and blunt the antitumor immune response through mechanisms similar to those described above. It has been suggested that administration of A2a receptor antagonists during chemotherapy or radiation therapy results in the expansion of tumor-specific T cells while preventing the induction of tumor-specific regulatory T cells. (Young, A., et al., Cancer Discovery (2014) 4:879-888).

It is believed that the combination of an A2a receptor antagonist with antitumor vaccines will provide

- 1 043752 provides at least an additional therapeutic effect, taking into account the different mechanisms of their action. In addition, A2a receptor antagonists may be useful in combination with checkpoint blockers. As an example, the combination of a PD-1 inhibitor and an adenosine A2a receptor inhibitor is thought to reduce the ability of tumors to inhibit the activity of tumor-specific effector T cells. (See, for example, Willingham, SB., et al., Cancer Immunol. Res.; 6(10), 1136-49; Leone, RD., et al., Cancer Immunol. Immunother., Aug 2018, Vol. 67, Issue 8, pp. 1271-1284; Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193:399-441; and Sitkovsky, M. V., et al., (2014) Cancer Immunol Res 2:598605).

The A2b receptor is a G protein-coupled receptor found in various cell types. A2b receptors require higher concentrations of adenosine for activation than other adenosine receptor subtypes, including A2a. (Fredholm, VV., et al., Biochem. Pharmacol. (2001) 61:443-448). Conditions that activate A2b have been observed, for example, in tumors where there is hypoxia. Thus, the A2b receptor may play an important role in pathophysiological conditions associated with massive adenosine release. Although the pathway(s) involved in A2b receptor-mediated inhibition is not entirely understood, it is believed that inhibition of A2b receptors (alone or together with A2a receptors) may block the protumorigenic functions of adenosine in the tumor microenvironment, including suppression of T-cell function. cells and angiogenesis and thus increase the number of cancers treatable by inhibition of these receptors.

A2b receptors are expressed mainly on myeloid cells. Binding of A2b receptors on myeloid suppressor cells (MDSCs) leads to their proliferation in vitro (Ryzhov, S. et al., J. Immunol. 2011, 187:6120-6129). MDSCs suppress T cell proliferation and antitumor immune responses. Selective A2b receptor inhibitors and A2b receptor knockouts inhibit tumor growth in mouse models by increasing MDSCs in the tumor microenvironment (Iannone, R., et al., Neoplasia Vol. 13 No. 12, (2013) pp. 1400-1409; Ryzhov, S., et al., Neoplasia (2008) 10: 987-995). Thus, inhibition of the A2b receptor has become an attractive biological target for the treatment of various forms of cancer involving myeloid cells. Examples of cancers that express A2b receptors can be easily obtained by analyzing the publicly available TCGA database. Such forms of cancer include, but are not limited to, lung, colon, head and neck, and cervical cancer, which are discussed in more detail below.

Angiogenesis plays an important role in tumor growth. The process of angiogenesis is strictly regulated by multiple factors and is triggered by adenosine under certain circumstances associated with hypoxia. The A2b receptor is expressed in human microvascular endothelial cells, where it plays an important role in regulating the expression of angiogenic factors such as vascular endothelial growth factor (VEGF). In some tumor types, hypoxia causes activation of A2b receptors, suggesting that inhibition of A2b receptors may limit tumor growth by limiting the supply of oxygen to tumor cells. In addition, adenylate cyclase activation experiments indicate that A2b receptors are the only subtype of adenosine receptor in some tumor cells, suggesting that A2b receptor antagonists may have an effect on certain tumor types. (See, for example, Feoktistov, I., et al., (2003) Circ. Res. 92:485-492; and P. Fishman, P., et al., Handb. Exp. Pharmacol. (2009) 193 :399-441).

Because of their promising and diverse therapeutic potential, there remains a need in the art for potent and selective inhibitors of the adenosine A2a and/or A2b receptors for use alone or in combination with other therapeutic agents. The present invention is aimed at solving this and other problems.

Summary of the present invention

In one aspect, the present invention relates to compounds (hereinafter referred to as compounds of the present invention) which are surprisingly and preferably prepared as inhibitors of the adenosine A2a receptor and/or the adenosine A2b receptor. The compounds of the present invention are characterized by a structure according to structural formula (I):

R ¹ (I), or a pharmaceutically acceptable salt thereof, wherein ring A, R ¹ and R ² are defined below: R ¹ is selected from F and Cl;

R ² represents O(C ₁ -C ₆ )alkyl;

ring A is a fragment selected from:

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R ³ is selected from pyrazolyl, triazolyl and pyridinyl, wherein said pyrazolyl and said triazolyl are substituted with 1 or 2 R ^3A groups and wherein said pyridinyl is substituted with 1, 2 or 3 R ^3A groups, wherein each R ^3A is independently selected from (C1-C6)alkyl , O(C1-C6)alkyl, (C1- _C6 )alkyl-OH, (C _g C6)haloalkyl, O(C1-C6)haloalkyl, oxo, ( _C1 - _C4 )alkylC(O)(C ₁ -C ₃ )alkyl, (C ₁ -C ₄ )alkylCH(OH)(C ₁ C ₃ )alkyl, (C ₁ -C ₄ )alkyl-S(O) ₂ (C ₁ -C ₃ )alkyl, -( CH ₂ ) _P (C ₃ -C ₇ )cycloalkyl and -(CH ₂ ) _p 4-7-membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected from oxygen and nitrogen, and the specified (C ₃ -C ₇ )cycloalkyl and said 4-7 membered monocyclic heterocycloalkyl is each unsubstituted or substituted with 1, 2 or 3 groups independently selected from F, Cl, OH, (C1-C6)alkyl and (C1-C6)haloalkyl;

n is 0, 1 or 2;

R ^A1 is selected from H and (C1-C ₄ )alkyl;

RA ² is selected from H, F and (C1-C ₄ )alkyl;

R ^A3 is selected from H, F and (C1-C ₄ )alkyl;

R ^A4 is selected from H and OH; And

R ^A5 is selected from H, F and (C1-C ₄ )alkyl.

In one embodiment, R ¹ represents F; and R ² represents OCH ₃ . In one embodiment, ring A is a fragment selected from:

where R ³ is selected from

where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C1- _C4 )alkyl, O(C1- _C4 )alkyl, (C1- _C4 )haloalkyl and O(C1C4)haloalkyl.

In one embodiment, ring A is a fragment:

where R ³ is selected from

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where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C1- _C4 )alkyl, O( _CrC4 )alkyl, ( _C1 - _C4 )haloalkyl and O( _C1C4 )haloalkyl.

In one embodiment, ring A is a fragment:

where R ³ is selected from

where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl.

In one embodiment, ring A is a fragment:

where R ³ is selected from

- 4 043752 where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl.

In one embodiment, ring A is a fragment:

where R ³ is selected from

where each R ^3A is a fragment selected from:

wherein R ³ is selected from each R ^3Aa independently selected from (C ₁ -C ₄ )alkyl, O(C1-C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl.

In one embodiment, ring A is a fragment:

where each R ^3A is a fragment selected from:

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and each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl.

In one embodiment, ring A is a fragment:

where R ³ is selected from

where each R ^3A is a fragment selected from:

each R ^Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1-C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl.

In one embodiment, a compound or a pharmaceutically acceptable salt thereof is provided, wherein said compound is selected from:

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In one embodiment, a compound or a pharmaceutically acceptable salt thereof is provided, wherein the compound is:

According to another aspect, the present invention relates to pharmaceutical compositions containing at least one compound of the present invention or pharmaceutically

- 21 043752 an acceptable salt in a pharmaceutically acceptable carrier or diluent. Such compositions of the present invention may optionally further include one or more additional therapeutic agents as described in the present invention.

According to another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of adenosine A2a and/or A2b receptor-mediated cancer. In one embodiment, the cancer is selected from melanoma, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, cancer with high microsatellite instability, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, kidney cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary gland cancer, prostate cancer and metastatic castration-resistant prostate cancer. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is used in combination with a PD-1 antagonist. the PD-1 antagonist is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab. Such and other aspects and embodiments of the present invention are described in more detail below.

Detailed Description of the Present Invention

For each of the following embodiments, any variable that is not precisely defined in the embodiment is as defined in formula (I). In each of the embodiments described in the present invention, each variable is selected independently of the other, unless otherwise noted.

According to one embodiment, the compounds of the present invention are characterized by structural formula (I):

R ¹ (I) or a pharmaceutically acceptable salt thereof, where: R ¹ is selected from F, Cl, (C1-C6)alkyl and O(C1-C6)alkyl; R ² is selected from H, F, Cl, (C1-C ₆ )alkyl and O(C ₁ -C ₆ )alkyl; ring A is a fragment selected from:

R ³ is selected from pyrazolyl, triazolyl and pyridinyl, wherein said pyrazolyl and said triazolyl are substituted with 1 or 2 R ^3A groups and wherein said pyridinyl is substituted with 1, 2 or 3 R ^3A groups, wherein each R ^3A is independently selected from (C ₁ -C ₆ )alkyl, O(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-OH, (C _r C ₆ )haloalkyl, O(C ₁ -C ₆ )haloalkyl, oxo, (C ₁ -C ₄ )alkylC(O)(C ₁ -C ₃ )alkyl, (C1-C ₄ )alkylCH(OH)(C1C ₃ )alkyl, (C ₁ -C ₄ )alkyl-S(O) ₂ (C ₁ -C ₃ )alkyl, -(CH ₂ ) _n (C ₃ -C ₇ )cycloalkyl and -(CH ₂ ) _n 4-7-membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected from oxygen and nitrogen, with said (C ₃ -C ₇ )cycloalkyl and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2 or 3 groups independently selected from F, Cl, OH, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )haloalkyl;

n is 0, 1 or 2;

R ^A1 is selected from H and (C1-C ₄ )alkyl;

R ^A2 is selected from H, F and (C1-C ₄ )alkyl;

R ^A3 is selected from H, F and (C1-C ₄ )alkyl;

R ^A4 is selected from H and OH; And

R ^A5 is selected from H, F, and (C1-C ₄ )alkyl.

According to another embodiment, the compounds of the present invention are characterized by structural formula (I.1):

- 22 043752 or a pharmaceutically acceptable salt thereof, wherein ring A, R ¹ and R ² are defined in formula (I). According to another embodiment, the compounds of the present invention are characterized by the structural formula (I.2):

or a pharmaceutically acceptable salt thereof, wherein ring A, R ¹ and R ² are defined in formula (I).

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

R ¹ is selected from F, Cl and OCH ₃ ;

R ² is selected from H, F, Cl, CH3 and OCH3.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

R ¹ represents F; And

R ² is selected from H, F, Cl, CH3 and OCH3.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

R ¹ represents Cl; And

R ² is selected from H, F, Cl, CH3 and OCH3.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

R ¹ represents F; And

R ² represents OCH3.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

R ¹ represents F; And

R ² represents F.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

R ¹ represents F; And

R ² represents H.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment selected from:

R ³

R

R ³

R ^A1

K' “ RA5 ^|Л and , where R ³ , R ^a1 , R ^A2 , Ra ³ and RA ⁵ are defined in formula (I); and wherein R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment selected from:

where R ³ is selected from

where each R ^3A is defined in formula (I);

each R ^Aa is independently selected from (C1- _C4 )alkyl, O(C1- _C4 )alkyl, ( _C1 - _C4 )haloalkyl and O(C1- 23 043752

C ₄ )haloalkyl;

R ^a1 , R ^A2 , R ^A3 and R ^A5 are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment selected from:

where R ³ is selected from

where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl;

R ^a1 , R ^A2 , R ^A3 and R ^A5 are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

As an alternative to the immediately preceding embodiment:

R ^a1 is selected from H, CH ₃ and CH ₂ CH ₃ ;

R ^A2 is selected from H, F, CH ₃ and CH ₂ CH ₃ ;

R ^A3 selected from H and F; And

R ^A5 represents H.

As another alternative to the immediately preceding embodiment:

R ^a1 is selected from H and CH ₃ ;

R ^A2 represents H;

R ^A3 represents H; And

R ^A5 represents H.

As another alternative to the immediately preceding embodiment:

R ^a1 represents H;

R ^A2 represents H;

R ^A3 represents H; And

R ^A5 represents H.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

R ³

ΝΛ

R ^A3 where R ³ and R ^A3 are defined in formula (I); and wherein R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above. According to another option

- 24 043752 where R ³ is selected from the embodiment in each of formulas (I), (I.1) and (I.2): ring A is a fragment:

where each R ^3A is defined in formula (I);

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C4)haloalkyl; R ^A3 is defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2): ring A is a fragment:

where R ³ is selected from

where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl;

R ^A3 is defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

As an alternative to the immediately preceding embodiment:

R ^A3 is selected from H and F.

As another alternative to the immediately preceding embodiment:

R ^A3 represents H.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

- 25 043752 where R ³ is defined in formula (I); and wherein R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above. According to another embodiment, in each of formulas (I), (I.1) and (I.2): ring A is a fragment:

R ³ where R ³ is selected from

where each R ^3A is defined in formula (I);

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl; And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

N

R'

where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl; And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

- 26 043752 ring A is a fragment:

where R ³ is defined in formula (I); and wherein R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2): ring A is a fragment:

where R ³ is selected from

where each R ^3A is defined in formula (I);

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl; And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl; And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

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According to another embodiment, in each of formulas (I), (I.1) and (I.2): ring A is a fragment:

where R ³ , R ^a1 , Ra ² and R ^A3 are defined in formula (I); and wherein R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

where each R ^3A is defined in formula (I);

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C4)haloalkyl;

R ^a1 , R ^A2 and R ^A3 are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C 1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C 1 where each R ^3A is a moiety selected from:

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C ₄ )haloalkyl;

Ra ¹ , Ra ² and RA ³ are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

As an alternative to the immediately preceding embodiment:

R ^a1 is selected from H, CH ₃ and CH ₂ CH ₃ ;

Ra ² is selected from H, F, CH ₃ and CH ₂ CH ₃ ; And

RA ³ is selected from H and F.

As another alternative to the immediately preceding embodiment:

R ^a1 is selected from H and CH ₃ ;

Ra ² represents H; And

RA ³ represents H.

As another alternative to the immediately preceding embodiment:

R ^a1

Ra ²

RA ³ represents H; represents H; and represents N.

According to another embodiment, in each of formulas (I), (I.1) and (I.2): ring A is a fragment:

R ³ r ^a1

r ^A2 o o where R ³ , R ^a1 , Ra ² and R ^A3 are defined in formula (I); and wherein R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

where each R ^3A is defined in formula (I);

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl;

R ^a1 , Ra ² and RA ³ are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

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where each R ^3A is a fragment selected from:

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C ₁ C ₄ )haloalkyl;

R ^a1 , Ra ² and R ^A3 are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

As an alternative to the immediately preceding embodiment:

R ^a1 is selected from H, CH ₃ and CH ₂ CH ₃ ;

R ^A2 is selected from H, F, CH ₃ and CH ₂ CH ₃ ; And

R ^A3 is selected from H and F.

As another alternative to the immediately preceding embodiment:

R ^a1 is selected from H and CH ₃ ;

r ^a2 r ^a3 represents H; and represents N.

As another alternative to the immediately preceding embodiment:

R ^a1 r ^A2 _R A3 represents H; represents H; and represents N.

According to another embodiment, in each of formulas (I), (I.1) and (I.2): ring A is a fragment:

where R ³ , R ^a1 , Ra ² , Ra ³ and Ra ⁴ are defined in formula (I); and wherein R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments, R ¹ and R ² are defined above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

- 30 043752

where each R ^3A is defined in formula (I);

each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl;

R ^A1 , Ra ² , R ^A3 and R ^A4 are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

According to another embodiment, in each of formulas (I), (I.1) and (I.2):

ring A is a fragment:

where R ³ is selected from

independently selected from (C ₁ -C ₄ )alkyl, O(C 1 -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C 1 where each R ^3A is a moiety selected from:

τϊ Aa every R

C ₄ )haloalkyl;

r ^a1 r ^A2 r ^A3 and R ^A4 are defined in formula (I); And

R ¹ and R ² are defined in formula (I) or as defined in any of the alternative embodiments of R ¹ and R ² described above.

As an alternative to the immediately preceding embodiment:

R ^A1 is selected from H, CH ₃ and CH ₂ CH ₃ ;

Ra ² is selected from H, F, CH3 and CH2CH3;

R ^A3 selected from H and F; And

R ^A4 is selected from H and OH.

As an alternative to the immediately preceding embodiment:

R ^A1 represents H;

R ^A2 represents H;

R ^A3 represents H; And

R ^A4 is selected from H and OH.

According to another embodiment, the compounds of the present invention contain those compounds designated herein as examples in the tables below, and pharmaceutically acceptable salts thereof.

- 31 043752

According to another aspect, the present invention relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt thereof. Such compositions of the present invention may optionally further include one or more additional therapeutic agents as described in the present invention.

In another aspect, the present invention provides a method of producing a medicament or composition that may be useful for treating diseases, conditions or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor, comprising combining a compound of the present invention with one or more pharmaceutically acceptable carriers.

In another aspect, the present invention provides a method of treating or preventing a disease, condition or disorder that is mediated at least in part by the adenosine A2a receptor and/or the adenosine A2b receptor in a subject in need thereof (e.g., an animal or human), the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents. Specific, non-limiting examples of such diseases, conditions and disorders are described herein.

Oncology.

In some embodiments, the disease, condition, or disorder is cancer. Any cancer for which a PD-1 antagonist and/or an A2a and/or A2b inhibitor is considered suitable by those of ordinary skill in the art is considered a cancer treatable by this embodiment either as monotherapy or in combination with other therapeutic agents. by the means discussed below. Cancers that express high levels of A2a receptors or A2b receptors are among those cancers considered treatable with the compounds of the present invention. Examples of cancers that express high levels of A2a and/or A2b receptors can be found by those skilled in the art by reference to the Cancer Genome Atlas (TCGA) database. Non-limiting examples of cancers that express high levels of A2a receptors include kidney, breast, lung and liver cancers. Non-limiting examples of cancers that express high levels of the A2b receptor include lung cancer, colorectal cancer, head and neck cancer, and cervical cancer.

Thus, in one embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein said cancer is a cancer that expresses high levels of the A2a receptor. According to a related embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein said cancer is selected from kidney (or renal) cancer, breast cancer, lung cancer and liver cancer .

In another embodiment, a method of treating cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein said cancer is a cancer that expresses high levels of the A2b receptor. According to a related embodiment, there is provided a method of treating cancer comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein said cancer is selected from lung cancer, colorectal cancer, head and neck cancer and cervical cancer.

Additional non-limiting examples of forms of cancer that can be treated by administration of a compound of the present invention (alone or in combination with one or more additional agents described below) include prostate cancer (including, without limitation, metastatic castration-resistant prostate cancer gland), colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testicle, head, neck, skin (including melanoma and basal cancer), mesothelial membrane, white blood cells (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including, but not limited to, small cell lung cancer, non-small cell lung cancer and lung adenocarcinoma), adrenal gland, thyroid gland, kidney or bone. Additional forms of cancer that can be treated with a compound of the present invention include glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma and testicular seminoma, and Kaposi's sarcoma.

- 32 043752

CNS and neurological disorders.

In other embodiments, the disease, condition, or disorder is a central nervous system disorder or a neurological disorder. Non-limiting examples of such diseases, conditions or disorders include movement disorders such as tremor, bradykinesia, gait disorders, dystonia, dyskinesia, tardive dyskinesia, other extrapyramidal syndromes, Parkinson's disease and disorders associated with Parkinson's disease. The compounds of the present invention also have the potential or are believed to be useful in preventing or reducing the effects of drugs that cause or worsen such movement disorders.

Infections.

In other embodiments, the disease, condition, or disorder is an infectious disease. Non-limiting examples of such diseases, conditions or disorders include acute or chronic viral infection, bacterial infection, fungal infection or parasitic infection. In one embodiment, the viral infection is a human immunodeficiency virus. In another embodiment, the viral infection is a cytomegalovirus.

Immune disease.

In other embodiments, the disease, condition, or disorder is an immune-mediated disease, condition, or disorder. Non-limiting examples of immune-mediated diseases, conditions or disorders include multiple sclerosis and bacterial infections. (See, for example, Safarzadeh, E. et al., Inflamm Res 2016 65(7):511-20; and Antonioli, L., et al., Immunol Lett S0165-2478(18)30172-X 2018).

Additional indications.

Other diseases, conditions and disorders that can be treated or prevented, in whole or in part, by inhibition of the A2a and/or A2b adenosine receptor(s) are also potential indications for the use of the compounds of the present invention and their salts. Non-limiting examples of other diseases, conditions or disorders for which a compound of the present invention or a pharmaceutically acceptable salt thereof may be used include the treatment of a hypersensitivity reaction to a tumor antigen and the relief of one or more complications associated with a bone marrow transplant or a peripheral stem cell transplant. blood. Thus, in another embodiment, the present invention provides a method of treating a subject receiving a bone marrow transplant or a peripheral blood stem cell transplant by administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, sufficient to increase a delayed-type hypersensitivity response. on a tumor antigen, to delay the recurrence of post-transplant malignancy, to increase the time of relapse-free survival after transplantation and/or to increase the duration of the post-transplant survival period.

Combination therapy.

According to another aspect, the present invention relates to methods of using a compound of the present invention or a pharmaceutically acceptable salt thereof (or a pharmaceutically acceptable composition containing a compound of the present invention or a pharmaceutically acceptable salt thereof) in combination with one or more additional agents. Such additional agents may have some activity at the A2a and/or A2b adenosine receptors, or alternatively they may function through different mechanisms of action. The compounds of the present invention may be used in combination with one or more other drugs to treat, prevent, suppress or alleviate diseases or conditions for which the compounds of the present invention or other drugs described herein may be useful when a combination of drugs taken together is safer or more effective than either drug alone. Combination therapy may have additive or synergistic effects. Such other drug(s) may be administered in a commonly used amount simultaneously or sequentially with a compound of the present invention or a pharmaceutically acceptable salt thereof. If a compound of the present invention is administered concomitantly with one or more other drugs, the pharmaceutical composition may, in certain embodiments, contain such other drugs and the compound of the present invention or a pharmaceutically acceptable salt thereof in individual doses or unit dosage form. However, combination therapy may also include therapies in which a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more other drugs are administered sequentially, in different or overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower dosages than when used individually. Accordingly, pharmaceutical compositions containing the compounds of the present invention include those that contain one or more other active ingredients in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof.

The weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective dose of each ingredient. Typically, an effective dose of each will be used. Thus, for example, when a compound of the present invention is used in combination with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, according to in specific embodiments, from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the above range, but in each case an effective dose of each active ingredient should be used.

Given the immunosuppressive role of adenosine, administration of an A2a receptor antagonist, an A2b receptor antagonist, and/or a dual A2a/A2b receptor antagonist in accordance with the present invention may enhance the effectiveness of immunotherapies such as PD-1 antagonists. Thus, in one embodiment, the additional therapeutic agent includes an anti-PD-1 antibody. In another embodiment, the additional therapeutic agent is an anti-PD-L1 antibody.

As noted above, PD-1 is believed to play an important role in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T cells, B cells and NKT cells and is activated by T cell and B cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe et al., Nature Immunology (2007) ; 8:239-245).

Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in various tissues. In large samples, such as ovarian, kidney, colorectal, pancreatic and liver cancers, and melanoma, PD-L1 expression has been shown to correlate with poor prognosis and reduce overall survival regardless of subsequent treatment. (Dong et al., Nat Med. 8(8):793-800 (2002); Yang et al., Invest Ophthamol Vis Sci. 49: 2518-2525 (2008); Ghebeh et al., Neoplasia 8:190- 198 (2006);Hamanishi et al., Proc. Natl. Acad. Sci. USA 104: 3360-3365 (2007); Thompson et al., Cancer 5: 206-211 (2006); Nomi et al., Clin. Cancer Research 13:2151-2157 (2007); Ohigashi et al., Clin. Cancer Research 11: 2947-2953; Inman et al., Cancer 109: 1499-1505 (2007); Shimauchi et al., Int. J. Cancer 121:2585-2590 (2007); Gao et al., Clin. Cancer Research 15: 971-979 (2009); Nakanishi J., Cancer Immunol Immunother. 56: 1173-1182 (2007); and Hino et al. , Cancer 00: 19 (2010)).

Similarly, PD-1 expression on tumor-infiltrating lymphocytes has been found to mark dysfunctional T cells in breast cancer and melanoma (Ghebeh et al., BMC Cancer. 2008 8:5714-15 (2008) and Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and correlates with poor prognosis in kidney cancer (Thompson et al., Clinical Cancer Research 15: 1757-1761 (2007)). Thus, it has been proposed that PD-L1-expressing tumor cells interact with PD-1-expressing T cells to attenuate T-cell activation and evade immune surveillance, thereby contributing to the impairment of the immune response against the tumor.

Immune checkpoint therapies targeting the PD-1 axis have led to breakthrough improvements in clinical response in multiple human cancers (Brahmer, et al., N Engl J Med 2012, 366: 2455-65; Garon et al. , N Engl J Med 2015, 372: 2018-28; Hamid et al., N Engl J Med 2013, 369: 134-44; Robert et al., Lancet 2014, 384: 1109-17; Robert et al., N Engl J Med 2015, 372: 2521-32; Robert et al., N Engl J Med 2015, 372: 320-30; Topalian et al., N Engl J Med 2012, 366: 2443-54; Topalian et al., J Clin Oncol 2014, 32: 1020-30; and Wolchok et al., N Engl J Med 2013, 369: 122-33).

The term PD-1 antagonist means any chemical compound or biological molecule that blocks the binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell), and preferably also blocks the binding of PD-L2 expressed on the cancer cell to PD-1 expressed on the immune cell. Alternative names or synonyms for PD-1 and its ligands include PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1, and PDCD1L2, PDL2, B7DC, Btdc and CD273 for PD-L2. In any of the treatments, formulations and uses of the present invention that treat a human subject, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1 and preferably blocks the binding of both human PD-L1 and PD-1. Human L2 with human PD-1. The amino acid sequences of human PD-1 can be found in NCBI under locus number NP 005009. The amino acid sequences of human PD-L1 and PD-L2 can be found in NCBI NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in any of the treatments, formulations and applications of the present invention include a monoclonal antibody (mAb) or antigen binding fragment thereof that specifically binds to PD-1 or PD-L1 and preferably binds specifically to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments. Examples of PD-1 antagonists include, but are not limited to, pembrolizumab (KEYTRUDA®, Merck and Co., Inc., Kenilworth, NJ, USA). Pembrolizumab (formerly known as MK-3475, SCH 900475 and lambrolizumab and sometimes called pembro) is a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013). Additional examples of PD-1 antagonists include nivolumab (OPDIVO®, Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (MPDL3280A; TECENTRIQ®, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI ®, Astra Zeneca Pharmaceuticals, LP, Wilmington, DE) and avelumab (BAVENCIO®, Merck KGaA, Darmstadt, Germany, and Pfizer, Inc., New York, NY).

Examples of monoclonal antibodies (mAbs) that bind to human PD-1 and can be used in the treatments, formulations and applications of the present invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004/004771, WO2004/ 072286, WO2004/056875 and US2011/0271358.

Examples of mAbs that bind to human PD-L1 and can be used in the treatments, formulations and applications of the present invention are described in WO2013/019906, WO2010/077634 A1 and US8383796. Specific anti-human PD-L1 mAbs useful as a PD-1 antagonist in the treatment method, formulations and applications of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody that contains heavy chain variable regions and the light chain of SEQ ID NO: 24 and SEQ ID NO: 21, respectively, from WO2013/019906.

Other PD-1 antagonists useful in any of the treatments, formulations and applications of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1 and preferably specifically binds to human PD-1 or PD Human -L1, for example, a fusion protein comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342. Specific fusion proteins useful as a PD-1 antagonist in the treatments, formulations and applications of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein , which binds to human PD-1.

Thus, one embodiment provides a method of treating cancer comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist to a subject in need thereof. In such embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof and the PD-1 antagonist are administered simultaneously or sequentially.

Specific non-limiting examples of such cancers according to this embodiment include melanoma (including unresectable or metastatic melanoma), head and neck cancer (including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, microsatellite instability high (MSI-H) cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal cell carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, kidney cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer and salivary gland cancer.

In one embodiment, a method of treating cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary Mediastinal large cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer and hepatocellular carcinoma. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

Pembrolizumab is approved by the US FDA for the treatment of patients with unresectable or metastatic melanoma, and for the treatment of certain patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary Mediastinal large B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer and hepatocellular carcinoma as described in the instructions for use for KEYTRUDA™ (Merck & Co., Inc., Whitehouse Station, New Jersey, USA ; initial US approval in 2014, updated November 2018). In another embodiment, a method of treating cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with pembrolizumab, wherein said cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC), classical Hodgkin's lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer and hepatocellular carcinoma.

In another embodiment, a method of treating cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, squamous cell carcinoma head and neck cancer (HNSCC), Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, high microsatellite instability cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer and cervical cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab.

In another embodiment, a method of treating cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist, wherein said cancer is selected from melanoma, non-small cell lung cancer, small cell cancer lung, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, lymphoma, kidney cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, rectal cancer colon, cervical cancer, thyroid cancer and salivary gland cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab.

In one embodiment, a method of treating unresectable or metastatic melanoma is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating classical Hodgkin's lymphoma (cHL) is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof at

- 36 043752 combinations with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating urothelial carcinoma is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a human in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating urothelial carcinoma is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a human in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating gastric cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a human in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating cervical cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating primary mediastinal large B-cell lymphoma is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating microsatellite instability-high (MSI-H) cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a human in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating non-small cell lung cancer is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In one embodiment, a method of treating hepatocellular carcinoma is provided, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a human in need thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab.

In another embodiment, the additional therapeutic agent is at least one immunomodulator other than an A2a or A2b receptor inhibitor. Non-limiting examples of immunomodulators include CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1 , IL-4, IL-18, TNF, IL-15, MDC, IFN-a/-13, M-CSF, IL3, GM-CSF, IL-13, anti-IL-10 antibody and indoleamine-2,3 inhibitors -dioxygenase 1 (IDO1).

In another embodiment, the additional therapeutic agent comprises

- 37 043752 self-irradiation. This type of radiation includes localized radiation therapy and whole body radiation therapy.

In another embodiment, the additional therapeutic agent is at least one chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents intended for use in combination with the compounds of the present invention include pemetrexed, alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isophamide, mechlorethamine, melphalan and uracil mustard; aziridines such as thiotepa; methanesulfonic acid esters such as busulfan; nucleoside analogues (eg, gemcitabine); nitrosoureas such as carmustine, lomustine and streptozocin; topoisomerase 1 inhibitors (eg, irinotecan); platinum complexes such as cisplatin, carboplatin and oxaliplatin, such bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); anthracycline-based therapeutics (eg, doxorubicin, daunorubicin, epirubicin and idarubicin); DNA strand breakers (eg, bleomycin); topoisomerase II inhibitors (eg, amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide and teniposide); DNA minor groove binders (eg, plicadin); antimetabolites (eg, folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase ; and also such ribonucleotide reductase inhibitors such as hydroxyurea); tubulin-interacting agents (eg, vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives and paclitaxel); hormonal agents (eg, estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbesterol; chlorotrianisene; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone and methyltestosterone); adrenal corticosteroids (eg, prednisone, dexamethasone, methylprednisolone, and prednisolone); luteinizing hormone releasing agents or gonadotropin releasing hormone antagonists (eg, leuprolide acetate and goserelin acetate); antihormonal antigens (eg, tamoxifen, antiandrogens such as flutamide; and antiadrenals such as mitotane and aminoglutethimide).

In another embodiment, the additional therapeutic agent is at least one signal transduction inhibitor (STI). Non-limiting examples of signal transduction inhibitors include BCR/ABL kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, HER-2/neu receptor inhibitors, and farnesyl transferase inhibitors (FTIs).

In another embodiment, the additional therapeutic agent is at least one anti-infective agent. Non-limiting examples of anti-infective agents include cytokines, non-limiting examples of which include granulocyte-macrophage colony-stimulating factor (GM-CSF) and flt3 ligand.

In another embodiment, the present invention provides a method for treating or preventing a viral infection (eg, a chronic viral infection), including, but not limited to, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus, Coxsackie virus and human immunodeficiency virus (HIV).

In another embodiment, the present invention provides a method of treating an infectious disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a vaccine. In some embodiments, the vaccine is an antiviral vaccine, including, for example, an HTV vaccine. Other antiviral agents contemplated for use include anti-HIV, anti-HPV, anti-HCV, anti-HSV, and the like. In other embodiments, the vaccine is effective against tuberculosis or malaria. In further embodiments, the vaccine is a tumor vaccine (eg, a vaccine effective against melanoma), wherein the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that have been transfected to express granulocyte-macrophage colony-stimulating factor (GM-CSF). In another embodiment, the vaccine includes one or more immunogenic peptides and/or dendritic cells.

According to another embodiment, the present invention relates to the treatment of an infection by administering a compound in accordance with the present invention or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, wherein the symptom of infection observed after administration of both the compound in accordance with the present invention (or thereof) pharmaceutically acceptable salt) and additional therapeutic agent improves

- 38 043752 compared with the same symptom of infection observed after administration of one of them separately.

In some embodiments, the observed symptom of infection may be a decrease in viral load, an increase in the number of CD4+ T cells, a decrease in opportunistic infections, an increase in survival time, resolution of a chronic infection, or a combination thereof.

Definitions

Unless otherwise specified, the following terms as used herein have the following meanings.

Unsaturated valences in the text, diagrams, examples, structural formulas, and any tables are assumed to contain an atom or number of hydrogen atoms sufficient to saturate the valencies.

When a variable appears more than once in any moiety or compound of the present invention (e.g., aryl, heterocycle, N(R)2), the choice of moieties defining that variable for each occurrence is independent of its definition in each other occurrence. unless otherwise specified in the local variable definition.

Unless otherwise specified, as used herein, the term A2a receptor antagonist (equivalent to A2a antagonist) and/or A2b receptor antagonist (equivalent to A2b antagonist) means a compound exhibiting an potency (IC ₅₀ ) of less than about 1 μM at the A2a and/or receptors. or A2b, as appropriate, when analyzed in accordance with the procedures described herein. Preferred compounds exhibit at least 10-fold selectivity for antagonizing the A2a receptor and/or the A2b receptor over any other adenosine receptor (eg, A1 or A3).

As described herein, unless otherwise indicated, use of a compound in treatment means that an amount of the compound, typically provided as a component of a formulation that contains other excipients, is administered in aliquots of specified amounts and at time intervals that provide and maintain at least a therapeutic serum level of at least one pharmaceutically active form of the compound during the time interval between dosing.

The expression at least one, when used in relation to the number of components constituting a composition, for example, at least one pharmaceutical excipient, means that one member of the specified group is present in the composition and more than one may additionally be present. The components of the composition are typically aliquots of isolated pure material added to the composition, where the level of purity of the isolated material added to the composition is a generally accepted level of purity for a reagent of that type.

When used in relation to a substituent in a compound or component of a pharmaceutical composition, the expression one or more means the same as at least one.

In parallel and simultaneously, both include in their meaning (1) simultaneously in time (for example, at the same time) and (2) at different times, but within the overall treatment schedule.

Continuously means one thing following another.

Sequentially refers to a series of administrations of therapeutic agents that await a period of effectiveness to occur between the administration of each additional agent; this means that after one component is administered, the next component is administered after an effective period of time has elapsed after the first component; The effective period of time is the amount of time allocated to realize the benefits of introducing the first component.

An effective amount or a therapeutically effective amount means providing an amount of at least one compound of the present invention or a composition containing at least one compound of the present invention that is effective in treating or inhibiting a disease or condition described herein, and thus, produce the desired therapeutic, improving, inhibitory or prophylactic effect. For example, when treating cancer as described herein with one or more compounds of the present invention, optionally in combination with one or more additional agents, an effective amount (or a therapeutically effective amount) means, for example, providing an amount of at least one compound of the present invention that results in a therapeutic response in a patient characterized by the presence of a disease, condition or disorder, including a response useful for managing, alleviating, ameliorating or treating the condition or alleviating, ameliorating, reducing or eradicating one or more symptoms associated with the condition , and/or long-term stabilization of the condition, for example, which can be determined by analysis of pharmacodynamic markers or clinical evaluation of patients characterized by the presence of the condition.

Patient and subject mean an animal, such as a mammal (eg, a human), and is preferably a human.

Prodrug means compounds that are rapidly converted, for example by hydrolysis in the blood, in vivo, to the parent compound, for example, converting a prodrug of a compound of the present invention to a compound of the present invention or a salt thereof. A full discussion is presented in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; The scope of such an invention includes prodrugs of the new compounds of the present invention.

The term substituted means that one or more moieties are listed as substituents (or, if a list of substituents is not specifically listed, substituents are provided elsewhere in this application) for the particular type of substrate to which the specified substituent is attached, provided that such substitution does not exceed normal valency rules for an atom in the binding configuration present in the substrate, and that the substitution ultimately provides a stable compound, which means that such substitution does not provide a connection with co-reactive substituents located geminially or vicinally to each other; and wherein the substitution provides a compound that is sufficiently stable to persist after isolation to an acceptable degree of purity from the reaction mixture.

When optional substitution with a moiety is described (e.g., optionally substituted), the term means that if substituents are present, one or more of the listed (or standard) moieties indicated as optional substituents for a particular substrate may be present on the substrate at the binding position normally occupied by the standard by a substituent, for example, a hydrogen atom on an alkyl chain may be replaced by one of the optional substituents in accordance with the definition of substituted as provided herein.

Alkyl means an aliphatic hydrocarbon group, which may be straight or branched, containing from 1 to 10 carbon atoms. (C ₁ -C6)alkyl means an aliphatic hydrocarbon group, which may be straight or branched, containing from 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a straight alkyl chain. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.

Haloalkyl means alkyl, as defined above, where one or more hydrogen atoms on the alkyl (up to and including each available hydrogen group) are replaced by a halogen atom. As noted by those skilled in the art, halo or halogen as used in the present invention is intended to include chlorine (Cl), fluorine (F), bromine (Br) and iodine (I). The halogen atoms chlorine (Cl) and fluorine (F) are generally preferred.

Aryl means an aromatic monocyclic or polycyclic ring system containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. The aryl group may be optionally substituted by one or more ring system substituents, which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. Monocyclic aryl means phenyl.

Heteroaryl means an aromatic monocyclic or polycyclic ring system containing from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. Heteroaryl may be optionally substituted with one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the root name heteroaryl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The heteroaryl nitrogen atom may optionally be oxidized to the corresponding N-oxide. Heteroaryl may also include heteroaryl, as defined above, fused with aryl, as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which may alternatively be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxidolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, etc. The term heteroaryl also refers to partially saturated heteroaryl moieties, such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, and the like. The term monocyclic heteroaryl refers to monocyclic versions of heteroaryl as described above and includes 4-7 membered monocyclic heteroaryl groups containing from 1 to 4 ring heteroatoms, said ring heteroatoms independently selected from the group consisting of N, O and S and their oxides. The point of attachment to the original fragment is located at any available ring carbon atom or ring heteroatom. Non-limiting examples of monocyclic heteroaryl moieties

- 40 043752 include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (for example, 1,2,4- thiadiazolyl), imidazolyl and triazinyl (for example, 1,2,4triazinyl) and their oxides.

Cycloalkyl means a non-aromatic, fully saturated monocyclic or polycyclic ring system containing from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms. The cycloalkyl may be optionally substituted with one or more substituents, which may be the same or different, as described in the present invention. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described in the present invention. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of polycyclic cycloalkyls include [1,1.1]-bicyclopentane, 1-decalinyl, norbornyl, adamantyl, and the like.

Heterocycloalkyl (or heterocyclyl) means a non-aromatic, saturated monocyclic or polycyclic ring system containing from 3 to 10 ring atoms, preferably from 5 to 10 ring atoms, in which one or more atoms in the ring system is an element other than carbon, e.g. nitrogen, oxygen or sulfur, alone or in combination. The ring system lacks adjacent oxygen and/or sulfur atoms. Preferred heterocycloalkyl groups contain 4, 5 or 6 ring atoms. The prefix aza, oxa or thia before the root name heterocyclyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. Any -NH on the heterocyclyl ring may be protected, such as -N(Boc), -N(CBz), -N(Tos) group, etc.; such protections are also contemplated as part of the present invention. The heterocyclyl may optionally be substituted with one or more substituents, which may be the same or different as described in the present invention. The nitrogen or sulfur atom of the heterocyclyl may optionally be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term oxide, when found in the definition of a variable in the general structure described in the present invention, refers to the corresponding N-oxide, S-oxide or S,S-dioxide. Heterocyclyl also includes rings where =O replaces two available hydrogen atoms on the same carbon atom (ie, heterocyclyl includes rings containing a carbonyl group on the ring). Such =O groups may be referred to herein as oxo. An example of such ^a moiety is pyrrolidinone (or pyrrolidone): As used herein, the term monocyclic heterocycloalkyl refers to the monocyclic versions of the heterocycloalkyl moieties described herein and includes 4- to 7-membered monocyclic heterocycloalkyl groups containing from 1 to 4 ring heteroatoms, said ring heteroatoms independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O) and S(O) ₂ . The point of attachment to the original fragment is located at any available ring carbon atom or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1-1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone and pyrrolidinone and their oxides. Unlimited

Common examples of lower alkyl-substituted oxetanyl include the moiety:

It is noted that in the heteroatom-containing ring systems of the present invention there are no hydroxyl groups on carbon atoms adjacent to N, O or S, and there are no N or S groups on carbon atoms adjacent to another heteroatom. related to the carbon atoms marked 2 and 5.

, missing -OH, attachedLine as a bond usually means a mixture of, or any of, the possible isomers, for example containing (R)- and (S)- stereochemistry. For example:

means containing both

As used herein, the wavy line vwc denotes the point of attachment to the remainder of the connection. Lines drawn inside ring systems such as

connected to any of the replaceable ring atoms.

’ means that the specified line (communication) can be used 41 043752

Oxo is defined as an oxygen atom that is double bonded to a ring carbon atom on a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl or other ring,

described in the present invention, for example,

As is well known in the art, a bond drawn from a particular atom, where no moiety is depicted at the end of the bond, indicates the methyl group associated through such a bond with the atom, unless otherwise noted. For example:

represents

One or more compounds of the present invention may also exist as, or optionally be converted into, a solvate. The preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of solvates of the antifungal fluconazole in ethyl acetate, as well as from water. Similar preparations of solvates and hemisolvates, including hydrates (if the solvent is water or are water-based) and the like, are described in E. S. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004 ); and A. L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting process involves dissolving a compound of the present invention in required amounts of a desired solvent (e.g., an organic solvent, an aqueous solvent, water, or mixtures of two or more of these) at a temperature higher than ambient temperature and cooling the solution, with or without antisolvent present, at a rate sufficient to form crystals, which were then isolated by standard methods. Analytical techniques, such as IR spectroscopy, indicate the presence of solvent (including water) in the crystals, as a solvate (or hydrate in the case of water included in the crystalline form).

The term purified, purified form, or isolated and purified form for a compound refers to the physical state of said compound after isolation from a synthesis process, or a natural source, or a combination thereof. Thus, the term purified, in a purified form, or in an isolated and purified form for a compound refers to the physical state of said compound after being obtained from a purification process, or processes described in the present invention, or well known to one skilled in the art and in sufficient purity to characterize standard analytical techniques described in the present invention, or well known to those skilled in the art.

The present invention also includes the compounds of the present invention in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of the present invention and their salts, solvates and prodrugs are intended to be included in the present invention. Certain compounds of the present invention may exist in various isomeric forms (eg, enantiomers, diastereoisomers, atropoisomers). The compounds of the present invention include all of their isomeric forms, both in pure form and mixtures of two or more, including racemic mixtures.

Likewise, unless otherwise noted, the description of the structural representation of any tautomeric form of a compound that exhibits tautomerism is intended to include all such tautomeric forms of the compound. Accordingly, while the compounds of the present invention, their salts and solvates and prodrugs may exist in various tautomeric forms or in equilibrium among such forms, all such forms of the compound are embraced and included within the scope of the present invention. Examples of such tautomers include, but are not limited to, ketone/enol tautomeric forms, imine-enamine tautomeric forms, and, for example, heteroaromatic forms such as the following moieties:

If a compound containing one or more stereocenters was used in the reaction scheme shown in the example, the stereocenters are marked with an asterisk as shown below:

- 42 043752

Accordingly, the above description consists of the following pairs of isomers: (i) trans isomers ((2R,7aR)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (compound ABC-1) and ((2S,7aR)-2methylhexahydro- Sh-pyrrolizin-7a-yl)methanamine (compound ABC-2); and (ii) cis-isomers ((2R,7aR)-2methylhexahydro-1H-pyrrolizin-7a-yl)methanamine (compound ABC-3) and ((2S,7aS)-2-methylhexahydro1H-pyrrolizin-7a-yl)methanamine (ABC-4 connection).

All stereoisomers of the compounds of the present invention (including salts and solvates of the compounds of the present invention and their prodrugs), such as may exist due to the asymmetric carbon atoms that are present in the compound of the present invention, and include enantiomeric forms (which may exist , even in the absence of asymmetric carbon atoms), rotameric forms, atropoisomers and diastereoisomeric forms are contemplated within the scope of the present invention.

The individual stereoisomers of the compounds of the present invention may be isolated in pure form, for example substantially pure from other isomers, or may be isolated as a mixture of two or more stereoisomers or as a racemate. The chiral centers of the present invention may be characterized by the S or R configuration, as defined in IUPAC 1974 guidelines. It is intended that the use of the terms salt, solvate, prodrug, and the like. equally refers to salts, solvates and prodrugs of isolated enantiomers, stereoisomeric pairs or groups, rotamers, tautomers or racemates of the compounds of the present invention.

If diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by known methods, for example, chiral chromatography and/or fractional crystallization, a simple structural representation of a compound assumes all diastereomers of the compound. As is known, enantiomers can also be separated by converting an enantiomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (eg, a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (eg, hydrolyzing) separately isolated diastereomers into the corresponding pure enantiomers.

As used herein, salts of the compounds of the present invention are any of acid salts formed with inorganic and/or organic acids, basic salts formed with inorganic and/or organic bases, salts formed which include the zwitterionic feature for example, where the compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to, a carboxylic acid, are included within the scope of the compounds of the present invention as described herein. The formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds has been discussed, for example, in S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and R. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, p. 330-331. Such disclosures are incorporated herein by reference.

The present invention contemplates all available salts, including salts that are generally accepted as safe for use in the preparation of pharmaceutical compositions, and those that can be formed at the present time within the scope of one skilled in the art, and later classified as generally assessed as safe for use. in the preparation of pharmaceutical compositions referred to in the present invention as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentane propionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, iodohydrates, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methylsulfates, 2-naphthalene sulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (which are mentioned herein), tartrates, thiocyanates, toluenesulfonates (also known as tosylates), undecanoates and the like.

Examples of pharmaceutically acceptable base salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases. ions (e.g. organic amines) such as benzathines, diethylamines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabiethyl)ethylenediamine), N-methyl-D-glucamines, Nmethyl-D-glucamides, tert-butylamines, piperazine , phenylcyclohexylamine, choline, tromethamine and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups can be converted to ammonium ion or quaternized by means such as lower alkyl halides (e.g. methyl, ethyl, propyl and butyl chlorides, -bromides and -iodides), dialkyl sulfates (e.g. dimethyl-, diethyl-, dibutyl- and diamyl sulfates), long-chain halides (for example, decyl-, lauryl-, myristyl- and stearyl chlorides, -bromides and -iodides), arylalkyl halides (for example, benzyl and phenethyl bromides) and others.

All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acid and base salts are intended to be equivalent to the free forms of the corresponding compounds within the scope of the present invention.

A functional group in a compound called protected means that the group is in a modified form to prevent unwanted side reactions at the protected site if the protected compound was subjected to specific reaction conditions designed to modify another site of the molecule. Suitable protecting groups are known, for example, by reference to standard textbooks, for example T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.

In the compounds of the present invention, the atoms may exhibit their natural isotopic abundance or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variants of the compounds of the present invention. For example, the various isotopic forms of hydrogen (H) include protium (1H) and deuterium ( ^2H ). Protium is the dominant isotope of hydrogen found in nature. Deuterium enrichment may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or may provide a compound useful as a standard for characterizing biological samples. The isotopically enriched compounds of the present invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein using appropriate isotopically enriched reagents and/or intermediates.

The present invention also covers isotopically labeled compounds of the present invention that are structurally identical to the compounds listed in the present invention, except for the fact that a statistically significant percentage of one or more atoms in such form of the compound has been replaced by an atom with an atomic mass or mass number, different from the atomic mass or mass number of the most abundant isotope commonly found in nature, thereby altering the abundance of naturally occurring isotope present in the compound of the present invention. Examples of isotopes that may advantageously be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: ^2H , ^3H , 11C, ^13C , ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, ¹²³ I and ¹²⁵ I. It will be noted that other isotopes may also be included known ways.

Certain isotopically labeled compounds of the present invention (eg, ³ H, 11 C and ¹⁴ C labeled) are found to be particularly useful in compound and/or substrate tissue distribution assays using various known techniques. Tritiated (i.e. ^3H ) and carbon-14 (i.e.

¹⁴ C) isotopes are particularly preferred for their ease of production and detectability. In addition, substituting a naturally occurring isotope in excess with a heavier isotope, such as substituting deuterium for protium (i.e., ^2H ), may provide certain therapeutic benefits resulting from greater metabolic stability (eg, increased in vivo half-life or requirement for more low dosage) and thus may be preferable in some cases. The isotopically labeled compounds of the present invention can generally be prepared by the following procedures similar to those disclosed in the reaction schemes and/or in the examples set forth below, substitution of the appropriate isotopically labeled reagent with a non-isotopically labeled reagent, or well known reactions of an appropriately prepared precursor with a compound of the present invention. invention, which was specially prepared for such a labeling reaction. Such compounds are also included in the present invention.

The term composition is intended to cover a product containing specific ingredients in specific amounts, and any product that is derived from, directly or indirectly, a combination of specific ingredients in specific amounts.

As used herein, the term pharmaceutical composition covers both

- 44 043752 a total composition and individual dosage units containing one or more than one (for example two) pharmaceutically acceptable agents, such as, for example, a compound of the present invention (optionally together with an additional agent as described in the present invention), together with any pharmaceutically inactive excipients. As will be appreciated by those skilled in the art, excipients are any component that adapts the composition to a particular route of administration or assists in converting the composition into a dosage form without exerting an active pharmaceutical effect. The total composition and each individual dosage unit may contain a constant amount of the above one or more than one pharmaceutically active agent. The total composition is a substance that has not yet been formed into individual dosage units.

It will be noted that the pharmaceutical compositions of the present invention may contain more than one compound of the present invention (or a pharmaceutically acceptable salt thereof), for example, a combination of two or three compounds of the present invention, each present in such composition by adding to the composition the required amount of the compound in a pharmaceutically acceptable pure form. It will also be noted that in formulating the compositions of the present invention, the composition may contain, in addition to one or more compounds of the present invention, one or more other agents that also have pharmacological activity as described in the present invention.

Although the compositions of the present invention may be used in bulk form, it will be noted that for most applications, the compositions of the present invention will be included in a dosage form suitable for administration to a patient, each dosage form containing an amount of the selected composition that contains an effective amount of one or more compounds of the present invention. Examples of suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, for example, a liquid, gel, powder, solid or semi-solid pharmaceutical composition that has been added to a capsule or compressed into a tablet, and may contain additionally one or more coatings that modify their release properties, for example, coatings that impart delayed release, or formulations that have delayed release properties; (ii) a dosage form adapted for intramuscular (IM) administration, for example, an injectable solution or suspension, and which can be adapted to form a depot preparation with sustained release properties; (iii) a dosage form adapted for intravenous administration (IV), for example, a solution or suspension, for example, as an IV solution or concentrate administered into an IV drip; (iv) a dosage form adapted for administration through oral tissues, for example, a rapidly dissolving tablet, lozenge, solution, gel, sachet or needle array suitable for providing intramucosal administration; (v) a dosage form adapted for administration through the mucous membrane of the nasal or upper respiratory cavity, for example, a solution, suspension or emulsion composition for dispersion in the nose or respiratory tract; (vi) a dosage form adapted for transdermal administration, for example a patch, cream or gel; (vii) a dosage form adapted for intradermal administration, for example, a group of microneedles; and (viii) a dosage form adapted for delivery through the rectal or vaginal mucosa, for example, a suppository.

To prepare pharmaceutical compositions containing the compounds of the present invention, typically the compounds of the present invention will be combined with one or more pharmaceutically acceptable excipients. Such excipients impart properties to the composition that facilitate handling or processing, for example, lubricants or compression aids in powdered medicaments intended for tableting, or adapt the composition to the required route of administration, for example, excipients that provide the composition for oral administration, e.g. , absorption from the gastrointestinal tract, transdermal or transmucosal administration, for example, by an adhesive patch to the skin, or buccal administration or injection, for example, by intramuscular or intravenous routes of administration. Such excipients are collectively referred to herein as a carrier. Typically, formulations may contain up to about 95 percent active ingredient, although formulations with higher amounts can be prepared.

Pharmaceutical compositions may be solid, semi-solid or liquid. Solid form formulations can be adapted to various modes of administration, examples of which include, but are not limited to, powders, dispersible granules, microtablets, granules, which can be used, for example, for tableting, encapsulation or direct administration. Formulations in liquid form include, without limitation, solutions, suspensions and emulsions, which, for example, but not exclusively, can be used in the preparation of formulations intended for parenteral administration, for intranasal administration, or for administration to some other mucosal membrane. Formulations prepared for administration into various mucous membranes may also include additional components that adapt them for such administration, for example, modifiers

- 45 043752 viscosity.

Aerosol preparations, for example, suitable for administration by inhalation or through the nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, for example nitrogen. Also included are preparations in solid form which are intended to be converted, immediately before use, into a suspension or solution, for example for oral or parenteral administration. Examples of such solid forms include, but are not limited to, freeze-dried formulations and liquid formulations adsorbed into a solid absorbent medium.

The compounds of the present invention may also be delivered transdermally or transmucosally, for example, from a liquid, suppository, cream, foam, gel or rapidly dissolving solid form. It will be noted that transdermal compositions can also take the form of creams, lotions, aerosols and/or emulsions and can be provided in unit dosage form, which includes any transdermal patch known in the art, for example, a patch that includes or matrix containing a pharmaceutically active compound, or a container that contains a pharmaceutically active compound in solid or liquid form.

Examples of pharmaceutically acceptable carriers and methods for preparing the various compositions mentioned above can be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, ^20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD .

Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparations are divided into unit doses of suitable size containing suitable amounts of the active ingredient, for example, an effective amount to achieve the desired purpose.

The exact dosage used may vary depending on the patient's requirements and the severity of the condition being treated. Determining the correct dosage regimen for a particular situation is within the skill of one skilled in the art. For convenience, the total daily dosage can be divided and administered in portions throughout the day as needed.

According to the present invention, antagonism of adenosine A2a and/or A2b receptors is accomplished by administering to a patient in need of such therapy an effective amount of one or more compounds of the present invention or a pharmaceutically acceptable salt thereof.

In some embodiments, it is preferred for the compound to be administered in the form of a pharmaceutical composition comprising a compound of the present invention or a salt thereof and at least one pharmaceutically acceptable carrier (described herein). It will be noted that the pharmaceutical compositions of the present invention may contain more than one compound of the present invention or a salt thereof, for example, a combination of two or three compounds of the present invention, or, additionally or alternatively, another active agent such as described in the present invention each is present by adding to the formulation a required amount of a compound or a salt thereof (or agent, where applicable) that has been isolated in a pharmaceutically acceptable pure form.

As mentioned above, administration of a compound of the present invention to antagonize A2a and/or A2b receptors is preferably accomplished by incorporating the compound into a pharmaceutical composition included in a dosage form, for example, one of the dosage forms described above containing an effective amount of at least one compound of the present invention. invention (eg, 1, 2 or 3, or 1 or 2, or 1 and usually 1 compound of the present invention) or a pharmaceutically acceptable salt thereof. Methods for determining the safe and effective administration of compounds that are pharmaceutically active, for example, the compounds of the present invention are known to those skilled in the art, for example, as described in the standard literature, for example, as described in Physicians' Desk Reference (PDR), for example, 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), the Physician's Desk Reference, ^56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742) or Physician's Desk Reference, ^57th Edition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742); the disclosure of which is incorporated herein by reference. The amount and frequency of administration of the compounds of the present invention and/or their pharmaceutically acceptable salts will be adjusted according to the judgment of the attending physician, who takes into account factors such as the age, condition and size of the patient, as well as the severity of the symptoms being treated. The compounds of the present invention may be administered in a total daily dosage of up to 1000 mg, which may be administered as a single daily dose or may be divided into multiple doses over a 24 hour period, such as two to four doses per day.

As will be appreciated by those skilled in the art, an appropriate dosage level for the compound (or compounds) of the present invention will generally be from about 0.01 to 500 mg per kg of patient body weight per day, which can be administered in one or more doses. A suitable dose level may be from about 0.01 to 250 mg/kg per day, from about

- 46 043752

0.05 to 100 mg/kg per day or approximately 0.1 to 50 mg/kg per day. Within this range, the dosage may be from 0.05 to 0.5, from 0.5 to 5, or from 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing from 1.0 to 1000 milligrams of active ingredient, in particular 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50. 0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of active ingredient for symptomatic dosage adjustment in a patient being treated. The compounds may be administered in a 1 to 4 times daily regimen or may be administered once or twice daily.

Those skilled in the art will appreciate that treatment protocols using at least one compound of the present invention may vary according to the needs of the patient. Thus, the compounds of the present invention used in the methods of the present invention can be administered by various protocols described above. For example, the compounds of the present invention may be administered intermittently rather than continuously during a treatment cycle.

In general, in any administered form, the administered dosage form will contain an amount of at least one compound of the present invention or a salt thereof that will provide a therapeutically effective serum titer of the compound in some form for a suitable period of time, for example, at least 2 hours, more preferably at least four hours or longer. In general, as is known in the art, dosages of a pharmaceutical composition to provide a therapeutically effective serum titer of a compound of the present invention can be divided over time to provide a serum titer equal to or greater than the minimum therapeutically effective serum titer in a continuous manner for the entire period, for which was treated. As will be noted, the administered dosage form may also be in a form that provides a sustained release period for the pharmaceutically active compound, which will provide a therapeutic serum titer over a longer period, requiring less frequent dosing intervals. As mentioned above, the composition of the present invention may include additional pharmaceutically active ingredients, or it may be co-administered, concurrently, or sequentially with other pharmaceutically active agents, as may be further needed or required during treatment. As will be noted, the administered dosage form may also be in a form that provides a sustained release period for the pharmaceutically active compound, which will provide a therapeutic serum titer over a longer period, requiring less frequent dosing intervals.

Examples of receiving.

The compounds of the present invention can be prepared readily according to the following schemes and specific examples or modifications thereof using readily available starting materials, reagents and traditional synthetic techniques. In such reactions it is also possible to use variants which are themselves known to those skilled in the art but are not mentioned in detail. The general procedures for preparing the compounds claimed in the present invention can be readily understood and noted by one skilled in the art by studying the following diagrams and descriptions.

General scheme 1

One general strategy for the synthesis of G1.6 type compounds is the four-step procedure shown in General Scheme 1, where R ₄ corresponds to ring A in formula (I) and where R ¹ , R ² and ring A are defined in formula (I). In the first step, aminobenzonitriles G1.1 can be treated with 1(isocyanatomethyl)-2,4-dimethoxybenzene in solvents such as a combination of dichloromethane and pi

- 47 043752 ridin, with the formation of intermediate urea compounds G1.2. In a second step, such ureas can be dehydrogenated to the corresponding G1.3 carbodiimides in the presence of triphenylphosphine, tetrabromomethane and triethylamine in a solvent such as dichloromethane. In a third step, treatment of the G1.3 carbodiimides with a G1.4 type hydrazide in the presence of acetic acid in a solvent such as dichloromethane or dioxane gave the G1.5 type products. In the fourth step, the 2,4-dimethoxybenzyl group of G1.4 was removed under acidic conditions to yield G1.6 type products, which can be purified by silica gel chromatography, preparative reverse phase HPLC and/or chiral SFC.

General scheme 2

R ¹

G2.5

One general strategy for the synthesis of G2.5 type compounds is the three-step procedure shown in General Scheme 2, where R ^A(n) corresponds to R ^A1 , RA ² , RA ³ and RA ⁵ in formula (I) and where R ¹ , R ² , R ³ and RA ⁽ⁿ⁾ (as RA ¹ , RA ² , RA ³ and RA ⁵ ) are defined in formula (I). In the first step, protected G2.1 cyclic amines can be converted to unprotected G2.2 amines by careful, controlled acid treatment. Acids such as formic acid in the absence of solvent or hydrochloric acid in the presence of MeOH or DCM can be used. In a second step, G2.2 type intermediates can be converted to G2.4 type intermediates by a CN transition metal catalyzed coupling reaction with G2.3 aryl bromides. The reaction was carried out under reduction conditions with palladium catalysts such as third generation precatalyst tert-butyl-X-Fhos, a base such as sodium tert-butoxide and a solvent such as THF at an appropriate temperature. In a third step, the 2,4-dimethoxybenzyl group of G2.4 was removed under acidic conditions to yield G2.5-type products, which can be purified by silica gel chromatography, preparative reverse phase HPLC, and/or chiral SFC.

General scheme 3

^{G3 4} G3.5

One general strategy for the synthesis of G3.6 type compounds is the four-step procedure shown in General Scheme 3, where R4 corresponds to ring A in formula (I) and where R ¹ , R ² and ring A are defined in formula (I). In a first step, G3.1 aminobenzoic acids can be converted to G3.2 aminoquinazolines by treatment with cyanamide in the presence of aqueous HCl in a solvent such as EtOH. In a second step, G3.2 type intermediates can be converted to G3.3 type intermediates by coupling with 1,2,4-triazole followed by treatment of G3.2 with phosphorus(V) oxychloride in a solvent such as acetonitrile. In a third step, G3.3 type intermediates can be treated with G3.4 hydrazides in a solvent such as THF to produce G3.5 type products. In the fourth step, G3.5 intermediates can undergo redistribution upon heating in pure N,O-bis(trimethylsilyl)acetamide (BSA) to form the products

- 48 043752 type G3.6. Type G3.6 products can be purified by silica gel chromatography, preparative reverse phase HPLC and/or chiral SFC.

General scheme 4

One general strategy for the synthesis of compounds of type G4.5 is the three-step procedure outlined in General Scheme 4, where R ¹ , R ² , R ³ , R ^{A 1} , R ^{A 2} and R ^{A 3} are defined in formula (I). Heteroarylcyclohexanol G4.1 can be converted to the corresponding cyclohexanone G4.2 by Dess-Martin periodinane oxidation. In a second step, G4.2 type intermediates can be treated with R ³ -Li G4.3 at low temperature to produce G4.4 type products. In a third step, the 2,4dimethoxybenzyl group of compound G2.4 can be removed by DDQ to give products like G4.5, which can be purified by silica gel chromatography, preparative reverse phase HPLC and/or chiral SFC.

Experimental part.

Abbreviations used in the experimental portion may include, without limitation, the following:

18-crown-6 1,4,7,10,13,16-Hexaoxacyclooctadecane °C Degrees Celcius AcOH Acetic acid aq. Water atm. Atmospheres Vos ₂ O Di-tert-butyl dicarbonate B.S.A. N, C)-Bis(tr and methylsil and l) acetamide CD ₃ OD Deuterated methanol-<74 DCM Dichloromethane DDQ 2,3 -Dichlor -5,6 -d icyano -1,4 -benzoquinone D.E.A. Diethyl amine DIAD Diisopropyldiazene-1,2-dicarboxylate DIBAL Diisobutyl aluminum hydride DIPEA A, A-Diisopropylethylamine DMAP 4-(Dimethylamino)-pyridine DMF Dimethylformamide

- 49 043752

DMP Dess-Martin periodinan DMSO Dimethyl sulfoxide DMSO-J6 Deuterated dimethyl sulfoxide dppf Bis(diphenylphosphino)ferrocene ES Electrospray ionization Et ₂ O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol 4 Watch HPLC High performance liquid chromatography M Molar MeCN Acetonitrile MeOD-J4 Deuterated methanol MeOH Deuterated methanol MHz Megahertz MIN minutes ml Milliliters MS Mass spectroscopy MsCl CCRT-Toluenesulfonyl chloride NaH Sodium hydride N.B.S. A-Bromosuccinimide H.M. Nanometers NMR Nuclear magnetic resonance Pd/C Carbon-supported palladium catalyst PPTS Pyridinium para-toluenesulfonate p-TsOH 4-Methylbenzenesulfonic acid Py Pyridine rac. Racemic SFC Supercritical liquid chromatography (CO2) T3P Tripropylphosphonic anhydride tBuXPhos-Pd G3 /'у \=( y=J O H ₂ N-Pd-OS-CH ₃ 1 ° f-Bu-P—f-Bu / i-Pr Qgh , _Pr ί-Pr [(2-Di-tert-butylphosphino -2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1, Gbiphenyl)] palladium (II) methanesulfonate CAS No. 1447963-75-8

- 50 043752

tBuXPhos-Pd G3 \=( 0 H ₂ N-Pd-OS-CH ₃ 1 θ f-Bu-Pf-Bu / i-Pr Qjy , _Pr i-Pr [(2-Di-tert-butylphosphino-2',4',6 '- triisopropyl-1,1 '-biphenyl)-2-(2'-amino-1, Gbiphenyl)] palladium (II) methanesulfonate CAS No. 1447963-75-8

General experimental data.

Unless otherwise noted, all reactions were carried out with a magnetic stirrer and carried out under an inert atmosphere such as nitrogen or argon.

Unless otherwise noted, the diethyl ether used in the experiments described below was Fisher ACS certified material and stabilized BHT.

Unless otherwise noted, degassed refers to a solvent from which oxygen has been removed, usually by bubbling an inert gas such as nitrogen or argon through the solution for 1015 minutes with a needle at the outlet to normalize the pressure.

Unless otherwise noted, concentrated means the evaporation of a solvent from a solution or mixture using a rotary evaporator or vacuum pump.

Unless otherwise noted, evaporated means evaporation using a rotary evaporator or vacuum pump.

Unless otherwise noted, silica gel chromatography was performed on an ISCO®, Analogix®, or Biotage® automated chromatography system using a commercially available cartridge as a column. The columns were usually filled with silica gel as the stationary phase. Reverse phase preparative HPLC conditions can be found at the end of the experimental section. Aqueous solutions were concentrated using a Genevac® evaporation unit or lyophilized.

Unless otherwise noted, proton nuclear magnetic resonance ( ^1H NMR) spectra and proton-decoupled carbon nuclear magnetic resonance spectra (¾)^} NMR) were recorded on Bruker or Varian NMR spectrometers at 400, 500, or 600 MHz at ambient temperature . All chemical shifts (δ) are described in parts per million (ppm). Proton resonances are referred to in relation to the residual protium in the NMR solvent, which may include, but is not limited to, CDCl ₃ , DMSO-d ₆ and MeOD-d4. Carbon resonances are referred to in relation to solvent NMR carbon resonances. Data are presented as follows: chemical shift, multiplicity (br = broadened, br s = broadened singlet, s = singlet, d = doublet, dd = doublet doublet, ddd = doublet doublet, t = triplet, q = quartet, m = multiplet ), coupling constants (J) in hertz (Hz), integration.

Intermediate 1: rac-3-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol

Intermediate 1

To a stirred solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol) in DMF (3.40 mL), cesium carbonate (2.22 g, 6.80 mmol) and 2,2,3- trimethyloxirane (820 mg, 9.52 mmol). The mixture was stirred and heated at 90°C for 4 hours. The mixture was cooled to room temperature, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 5-100% EtOAc in hexanes to give rac-3-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C ₈ H ₁₃ BrN ₂ O) (ES, m/z) [M+H]+: 233, 235.

Intermediates in the following table. 1 was prepared in a manner similar to that described for intermediate 1 from the appropriate pyrazole and epoxide.

- 51 043752

Table 1

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 2 HE G.N H Br 220, 222 1 -(3-bromo-IH-1,2,4-triazol-1-yl)-2-methylpropan-2-ol 3 HE X-N Ιγ Br 234, 236 1 -(3 -bromo-5 -methyl-1H-1,2,4-triazol-1 -yl)-2-methylpropan-2ol 4 HE N'\V Br 219, 221 1 -(4-bromo-1 //-pyrazol-1 -yl)-2-methylpropan-2-ol 5 ^P^on jkn Br^^ ⁷ 231,233 2-(4-bromo-177-pyrazol-1-yl)cyclopentan-1-ol 6 ^< U^on |Qn Br^^ ⁷ 245, 247 2-(4-bromo-1 //-pyrazol-1 -yl)-1 -methylcyclopentan-1 -ol 7 OH OH 1 z- ^N d /'O' bg \ Br \ ND mixture of 1-(4-bromo-3-methyl-1 //-pyrazol-1 -yl)-2-methylpropan2-ol and 1-(4-bromo-5-mestil-1//-pyrazol-1-yl) -2-mstilpropan2-ol 8 he he N'\N'N Al* Br Br 247, 249 mixture of rac-3 -(4-bromo-3-methyl-177-pyrazol-1-yl)-2- methylbutan-2-ol and rac-3-(4-bromo-5 -methyl- 1//-pyrazol-1yl)-2-methylbutan-2-ol 9 \Loh N, O Br 247.249 3-(4-bromo-177-pyrazol-1-yl)-2,3-dimethylbutan-2-ol 10 HE G ,Ν Br 234, 236 rac-3 -(3 -bromo-\H-1,2,4-triazol-1 -yl)-2-methylbutan-2-ol

- 52 043752

Intermediate 11: 1-((4-bromo-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol.

Step 1: (1-hydroxycyclobutyl)methylmethanesulfonate

To a stirred solution of 1-(hydroxymethyl)cyclobutan-1-ol (9.00 g, 88.0 mmol) in DCM (260 mL) at 0°C was added triethylamine (17.2 mL, 123 mmol), followed by methanesulfonyl chloride ( 7.0 ml, 90 mmol). The mixture was stirred at 0°C for 10 minutes. The mixture was then warmed to room temperature and stirred for 15 minutes. The mixture was then separated with water. The layers were separated and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and evaporated to give (1-hydroxycyclobutyl)methylmethanesulfonate.

Step 2: 1-((4-bromo-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol

To a solution of 4-bromo-1H-pyrazole (7.70 g, 52.4 mmol) in DMF (60 ml) at 0° C., NaH (60% in mineral oil, 2.30 g, 57.6 mmol) was added portionwise. . The mixture was stirred at 0°C under nitrogen atmosphere for 30 minutes. A solution of (1-hydroxycyclobutyl)methylmethanesulfonate (13.1 g, 72.8 mmol) in DMF (20 ml) was added to the mixture. The mixture was stirred and heated at 90°C for 16 hours. The mixture was quenched with water (70 ml), then extracted three times with EtOAc. The organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-30% EtOAc in petroleum ether as eluent to give 1-((4-bromo-1H-pyrazol-1yl)methyl)cyclobutan-1-ol. LCMS (C ₈ H ₁₁ BrN ₂ O) (ES, m/z): 231, 233 [M+H]+.

Intermediate 12: 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole.

Step 1: (3-methyloxetan-3-yl)methylmethanesulfonate

О MsCI, Et ₃ N, DCM О ^but 5< ” Ms' ⁰ ' +

Step 1 of the synthesis of intermediate 12 was carried out similar to step 1 of the synthesis of intermediate 11 from the corresponding starting materials to obtain (3-methyloxetan-3yl)methylmethanesulfonate.

Step 2: 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole

Intermediate 12

To a solution of 4-bromo-1H-pyrazole (5.04 g, 34.3 mmol) in DMF (114 ml) was added (3-methyloxetan-3yl)methylmethanesulfonate (6.18 g, 34.3 mmol) and cesium carbonate ( 15.6 g, 48.0 mmol). The mixture was stirred and heated at 60°C for 6 hours. The solvents were evaporated. DCM (100 ml) was added to the residue and the mixture was filtered. The solvents in the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexane to give 4-bromo-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole. LCMS (C ₈ HnBrN ₂ O) (ES, m/z): 231, 233 [M+H] ⁺ .

Intermediate 13 shown in the following table. 2 was prepared in a manner similar to that described for intermediate 12 from the corresponding starting materials.

table 2

Intermediate connection Structure Observ. m/z [M + H] ⁺ Name 13 JO ^N 249, 251 4-bromo-1-((3-(fluoromethyl)oxetan-3-yl)methyl)-1H-pyrazole

Intermediate 14: (1s,3s)-3-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol.

Step 1: 4-bromo-1-(5.8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazole

- 53 043752

To a solution of 2-bromo-5,8-dioxaspiro[3,4]octane (0.500 g, 2.59 mmol) and 4-bromo-III-pyrazole (0.761 g, 5.18 mmol) in DMF (2.6 ml ) Potassium carbonate (1.07 g, 7.77 mmol) and 18-crown-6 (0.137 g, 0.518 mmol) were added to an 8 mL vessel. The mixture was stirred and heated at 90°C. After 5 minutes, the mixture was cooled to room temperature and additional 4-bromo-III-pyrazole (400 mg, 2.72 mmol) was added to the mixture. The mixture was stirred and heated at 90°C for 48 hours. The mixture was then cooled to room temperature and partitioned between EtOAc (25 ml) and water (25 ml). The layers were separated and the organic layer was washed with brine. The two aqueous layers were combined and extracted with EtOAc (15 ml). The organic layers were combined, washed with brine twice, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-50% EtOAc in hexanes to give 4-bromo-1-(5,8-dioxaspiro[3,4]octan-2-yl)-1H-pyrazole. LCMS (C9H12B1N2O2) (ES, m/z): 259, 261 [M+H]+.

Step 2: 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone

To a solution of 4-bromo-1-(5,8-dioxaspiro[3,4]octan-2-yl)-III-pyrazole (270 mg, 1.042 mmol) and PPTS (131 mg, 0.521 mmol) in dioxane (2, 6 ml) water (2.6 ml) was added. The mixture was stirred and heated at 85°C for 95 hours. The mixture was cooled to room temperature. The mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexane to give 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone. LCMS (C ₇ H ₈ BrN ₂ O) (ES, m/z): 215, 217 [M+H] ⁺ .

Step 3: (1S,3S)-3-(4-6pom-1H-pyrazol-1-yl)-1-methylcyclobutanol

Intermediate 14

A solution of 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (129 mg, 0.600 mmol) in diethyl ether (3.5 ml) was cooled to 0°C. Methylmagnesium bromide (3 M in diethyl ether, 0.240 ml, 0.720 mmol) was added dropwise to the stirred mixture. The mixture was stirred for 16 hours, leaving the ice bath to complete its action. The mixture was partitioned between EtOAc and 20% aqueous citric acid and stirred for 2 hours. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-60% EtOAc in hexanes to give (1s, 3s)-3-(4-bromo-1H-nirazol-1-yl)-1-methylcyclobutanol. LCMS (C ₈ H ₁₂ BrN ₂ O) (ES, m/z): 231, 233 [M+H] ⁺ .

Intermediate 15: 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

Br

Intermediate 15

4-Bromo-1H-pyrazole (1.50 g, 10.2 mmol), 4-iodotetrahydro-2Hpyran (2.16 g, 10.2 mmol), potassium carbonate (1.41 g, 10. 2 mmol) and DMF (15 ml). The mixture was stirred and heated at 100°C for 16 hours. The mixture was obtained by chromatography on silica gel with 0-50% EtOAc in petroleum ether as eluent to give 4-bromo-1-(tetrahydro-2H-pyran-4-yl) -1Hpyrazole. LCMS (C ₈ HnBrN ₂ O) (ES, m/z): 231.233 [M+H] ⁺ .

Intermediate 16: mixture of 4-bromo-5-methyl-1-trityl-1H-pyrazole and 4-bromo-3-methyl-1trityl-1H-pyrazole

Ph ₃ CCI ^Me NaH

THF, 0-23 °C

Intermediate 16

Add 4-bromo-3-methyl-1H-pyrazole (1.00 g, 6.21 mmol) to a 200 mL round bottom flask.

Vg

- 54 043752 and THF (62.1 ml). The mixture was stirred under nitrogen atmosphere. The mixture was cooled at 0°C. NaH (0.311 g, 7.76 mmol) was added to the mixture in portions. The mixture was slowly warmed to room temperature over 30 minutes. The mixture was then cooled at 0°C and trityl chloride (1.90 g, 6.83 mmol) was added to the mixture. The mixture was stirred for 16 hours at room temperature. The mixture was quenched with water (60 ml) and diluted with EtOAc (60 ml). The layers were separated and the aqueous layer was further extracted with EtOAc (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by chromatography on silica gel with 0-25% EtOAc in hexanes as eluent to give 4-bromo-3-methyl-1-trityl-1H-pyrazole and 4-bromo-5-methyl-1-trityl-1H-pyrazole as a mixture of regioisomers. LCMS (C ₂₃ H ₁₉ BrN ₂ ) (ES, m/z): 425, 427 [M+Na]+.

Intermediate 17: 4-bromo-3-(difluoromethyl)-1-trityl-1H-pyrazole

N Trt

N'\ TrtCI, Ru, DMAP _N -N ί ? -----------------eleven /

F ₂ HC^\ ^DCM ' ^κ · ^τ · f ₂ hc^\

Br Br

Intermediate 17

To a stirred mixture of 4-bromo-5-(difluoromethyl)-1H-pyrazole (250 mg, 1.27 mmol), trityl chloride (460 mg, 1.65 mmol) and pyridine (201 mg, 2.54 mmol) in DCM ( 4 ml) DMAP (15.5 mg, 0.127 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was washed with water (5 ml) and aqueous saturated NH ₄ Cl (5 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-50% EtOAc in petroleum ether as eluent to give 4-bromo-5-(difluoromethyl)-1-trityl-1Hpyrazole. LCMS (C ₂₃ H ₁₇ BrF ₂ N ₂ ) (ES, m/z): 461, 463 [M+Na] ⁺ .

Intermediate 18: mixture of 4-bromo-3-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1Hpyrazole and 4-bromo-5-(difluoromethyl)-1-(tetrahydro-2H-pyran- 4-yl)-1H-pyrazole

Intermediate 18

Cesium carbonate (595 mg, 1.828 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate ( 329 mg, 1.828 mmol). The mixture was stirred and heated at 80°C under nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and diluted with water (100 ml). The mixture was extracted three times with EtOAc. The organic layer was washed with water and then with brine, dried over anhydrous MgSO ₄ and filtered. The solvents in the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-90% EtOAc in hexanes as eluent to obtain a mixture of 4-bromo-3-(difluoromethyl)-1(tetrahydro-2H-pyran-4-yl)-1 H-pyrazole and 4 -bromo-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H pyrazole.

Intermediate 19: 2-(4-bromo-1H-πyrazol-1-yl)-2-methylpropan-1-ol.

Stage 1: Methyl-2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate /

O.

\=O o

ABOUT

Cs ₂ CO ₃ (DMF, 80 °C Br

Vg

To a solution of 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol) in DMF (20 ml) was added methyl 2-bromo-2methylpropanoate (1.76 ml, 13.6 mmol), followed by cesium carbonate (8.87 g, 27.2 mmol). The mixture was heated at 80°C for 18 hours. The mixture was filtered and the filter cake was washed with DCM. The combined filtrates were evaporated. The resulting residue was purified by silica gel chromatography with 10% EtOAc in hexanes as eluent to give methyl 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropanoate. LCMS (C ₈ H ₁₁ BrN ₂ O ₂ ) (ES, m/z): 247, 249 [M+H] ⁺ .

Step 2: 2-(4-bromo-1H-pyrazol-1-ul)-2-methylpropan-1-ol

Sodium borohydride (0.799 g, 21.1 mmol) at 0°C. The mixture was stirred at room

- 55 043752 temperature for 2 hours. The mixture was diluted in DCM (50 ml), washed with water and saline.

The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to obtain 2-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-1-ol. LCMS (C ₇ H11BrN ₂ O) (ES, m/z): 219, 221

[M+N]+.

Intermediate 20 in the following table. 3 was prepared in a manner similar to that described for the synthesis of intermediate 19 from the appropriate starting materials.

Table 3

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 20 He V- on Br 2-(4-bromo-3-methyl-172-pyrazol-1-yl)-2-methylpropan-1-ol 233.235

Intermediate 21: 1-(4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol.

Step 1: 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol

Step 1 of the synthesis of intermediate 21 was carried out in a manner similar to that used for the synthesis of intermediate 1 from the corresponding starting materials to obtain 1-(3cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol.

Step 2: 1-(4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol

Vg

Intermediate 21

To a solution of 1-(3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (1.55 g, 8.60 mmol) in DCM (86 ml) was added 1,3-dibromo-5 ,5-dimethylhydantoin (1.23 g, 4.30 mmol). The mixture was stirred at room temperature for 30 minutes. The solvents were evaporated and the resulting residue was purified by silica gel chromatography with 10-90% EtOAc in hexanes to give 1-(4-bromo-3-cyclopropyl1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C ₁₀ H ₁₅ BrN ₂ O) (ES, m/z): 259, 261 [M+H] ⁺ .

Intermediate 22: 4-bromo-1-ethyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1Hpyrazole.

Step 1: (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol

Vg

Step 1 of the synthesis of intermediate 22 was carried out in a manner similar to step 2 of the synthesis of intermediate 21 from the corresponding starting materials to obtain (4-bromo-1ethyl-1P-pyrazol-3-yl)methanol. LCMS (C ₆ H ₉ BrN ₂ O) (ES, m/z): 205, 207 [M+H] ⁺ .

Step 2: rac-4-bromo-1-ethyl-3-(((tetraαhydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole

Intermediate 22

To a stirred solution of (4-bromo-1-ethyl-1H-pyrazol-3-yl)methanol (570 mg, 2.78 mmol) in DCM (27 ml), 3,4-dihydro-2H-pyran (468 mg, 5.56 mmol) and then 4methylbenzenesulfonic acid (polymer supported) (239 mg, 1.39 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was loaded directly onto a silica gel column, then purified with 0-60% EtOAc in hexane as eluent to give rac-4-bromo-1ethyl-3-(((tetrahydro -2H-pyran-2-yl)oxy)methyl)-1H-pyrazole. LCMS (C11H ₁₇ BrN ₂ O ₂ ) (ES, m/z): 289, 291

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[M+N]+.

Intermediate 23: rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2yl)oxy)cyclobutyl)methyl)-1H-pyrazole.

Step 1: rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methylmethanesulfonate

Triethylamine (8 .38 ml, 60.1 mmol), and then methanesulfonyl chloride (4.02 ml, 51.5 mmol). The mixture was stirred at 0°C for 10 minutes and then warmed to room temperature and stirred for 40 minutes. The mixture was then separated with water. The layers were separated and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and evaporated to give rac-{1-((tetrahydro-2H-pyran-2yl)oxy)cyclobutyl)methylmethanesulfonate, LCMS (C11H20O5S) (ES, m/z): 287 [M+ Na] ⁺ .

Step 2: rac-4-bromo-1-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole

To a solution of 4-bromo-1H-pyrazole (5.40 g, 36.7 mmol) in DMF (60 ml) at 0° C., NaH (60% in mineral oil, 1.62 g, 40.4 mmol) was added portionwise. . The mixture was stirred at 0°C under a nitrogen atmosphere for 1 hour. Rat-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methylmethanesulfonate (10.7 g, 40.4 mmol) was added to the mixture. . The mixture was stirred and heated at 90°C under nitrogen atmosphere for 16 hours. The mixture was quenched with water (200 ml) and extracted with EtOAc three times. The combined organic layers were washed with water and then brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and evaporated. The resulting residue was purified by silica gel chromatography with 030% EtOAc in petroleum ether as eluent to give rac-4-bromo-1-((1-((tetrahydro-2Hpyran-2-yl)oxy)cyclobutyl)methyl)-1H- pyrazole (intermediate 23). LCMS (C ₁₃ H ₁₉ BrN ₂ O ₂ ) (ES, m/z): 315, 317 [M+H] ⁺ .

Intermediate 24 and Intermediate 25: 1-(4-bromo-3-methyl-1H-pyrazol-1yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1 -yl)-2-methylpropan-2-ol

A mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol1-yl)-2-methylpropane -2-ol (intermediate 7) was separated by SFC (Chiral Technologies

IG 21x250mm column with 15% (MeOH modifier 0.1% NH4OH) as co-solvent) to produce 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 24, first eluting peak) and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 25, second eluting peak).

For intermediate 24: LCMS (C ₁₃ H ₁₉ BrN ₂ O ₂ ) (ES, m/z): 233, 235 [M+H] ⁺ .

For intermediate 25: LCMS (C ₈ H ₁₃ BrN ₂ O) (ES, m/z): 233, 235 [M+H] ⁺ .

Intermediate 26 and intermediate 27 in the following table. 4 was prepared in a manner similar to the preparation of Intermediate 24 and Intermediate 25 by SFC resolution of the racemic mixture of Intermediate 1.

- 57 043752

Table 4

Intermediate connection Structure SFC terms Observ. m/z [M + N] ⁺ Name 26 He N'\ % Br Peak 1; Chiral Technologies AD-H 50 x 250 mm column with 35% MeOH in as a co-solvent 233.235 (S or 7?)-3-(4-bromo-1R-pyrazol-1-yl)-2methylbutan-2-ol 27 HE N'\ % Br Peak 2; Chiral Technologies AD-H 50 x 250 mm column with 35% MeOH in as a co-solvent 233.235 (R or 5)-3-(4-bromo-1H-pyrazol-1-yl)-2methylbutan-2-ol

Intermediate 28: rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutan-1-one

To a solution of 2-bromocyclobutanone (16.2 g, 109 mmol) in MeCN (30 ml) was added 4-bromo-1H-pyrazole (8.00 g, 54.4 mmol) and potassium carbonate (30.1 g, 218 mmol ). The mixture was stirred at 20°C for 10 hours. The mixture was filtered and the solvents of the filtrate were evaporated. The residue was purified by reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mmx100 mm MeCN/water (with 0.1% TFA modifier) as eluent) to obtain rac-2-(4-bromo-1H-pyrazole-1 -yl)cyclobutanone. LCMS (C7H7BrN2O) (ES, m/z) [M+H]+: 215, 217.

Intermediate 29: 2-(4-bromo-1H-pyrazol-7-yl)-1-methylcyclobutan-1-ol

Methylmagnesium bromide (0.248 mL, 0.744 mmol, 3 M in diethyl ether) was added to a stirred mixture of rac-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanone (intermediate 28) (80.0 mg, 0.372 mmol ) in THF (2 ml) at -78°C and the mixture was stirred at this temperature for 3 hours. The reaction was quenched with aqueous saturated NH ₄ Cl (2 ml) and the desired layer was extracted from the mixture with EtOAc (2x20 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The resulting residue was purified by preparative TLC on silica gel with 30% EtOAc in petroleum ether as eluent to give 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclobutanol. LCMS (C ₈ H ₁₁ BrN ₂ O) (ES, m/z) [M+H]+: 231, 233.

Intermediate 30: rac-4-bromo-1-(2.2-dimethoxycyclobutyl)-1H-pyrazole

To a stirred mixture of trimethoxymethane (592 mg, 5.58 mmol) and rac-2-(4-bromo-1H-pyrazol-1yl)cyclobutanone (intermediate 28) (600 mg, 2.79 mmol) in MeOH (5 ml) 4-methylbenzenesulfonic acid hydrate (53.1 mg, 0.279 mmol) was added. The mixture was stirred at 28°C for 12 hours. The mixture was diluted with EtOAc (50 ml) and washed with water (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% EtOAc in petroleum ether as eluent to give rac-4-bromo-1-(2,2-dimethoxycyclobutyl)-1H-pyrazole.

- 58 043752

LCMS (C9H13B1N2O2) (ES, m/z) [M+H]+: 261, 263.

Intermediate 31: mixture of yl)oxy)cyclobutyl)methyl)-1H-pyrazole and yl)oxy)cyclobutyl)methyl)-1H-pyrazole

Gd n /(3 + N'\__ DIAD, PPh ₃ but g G --Λθ THF, 60 °C ( j Br rac-4-bromo-5-methyl-1-((1-((tetrahydro-2H- pyrαn-2rac-4-bromo-3 -methyl-1-((1 -((tetrahydro-2H-niran-2-

Intermediate 31

To a stirred solution of rac-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol (1.00 g, 5.37 mmol), 4-bromo-5-methyl-1H-pyrazole (0.864 g, 5.37 mmol) and triphenylphosphine (1.41 g, 5.37 mmol) in THF (10.2 ml) was added diisopropyldiazene-1,2-dicarboxylate (1.09 g, 5.37 mmol). The mixture was stirred and heated at 60°C for 16 h. The solvents were evaporated. The resulting residue was purified by chromatography on silica gel with 0-80% EtOAc in hexane to obtain a mixture of rac-4-bromo-5methyl-1 -((1 -((tetrahydro-2H-niran-2-yl)oxy)cyclobutyl)methyl) -1 H-pyrazole and rac-4-bromo-3-methyl-1 ((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole. LCMS (C ₁₄ H ₂₁ BrN ₂ O ₂ ) (ES, m/z): 329, 331 [M+H] ⁺ '

Intermediate 32: rac-4-bromo-1-(2-((tempαhydro-2H-niran-2-yl)oxy)cyclopentyl)1 H-pyrazole

3,4-Dihydro-2H- pyran (2.4 ml, 26 mmol) and then 4-methylbenzenesulfonic acid (polymer bound, 2.0 g). The mixture was stirred at room temperature for 16 hours. The mixture was filtered and the solvents of the filtrate were evaporated. The residue was purified by C18 reverse phase chromatography with 0-100% MeCN in water as eluent to give rac-4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H -pyrazole. LCMS (C ₁₃ H ₁₉ BrN ₂ O ₂ ) (ES, m/z): 315, 317 [M+H] ⁺ .

Intermediate 33: 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol.

Step 1: 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-olone and CS2CO3

X? ’ -------- £%

O2N / DMF, 80 °C _p

4-nitro-1H-nirazole (15.0 g, 133 mmol), cesium carbonate (64.8 g, 199 mmol) and DMF (195 mL) were added to a 500 mL round bottom flask. 2,2-Dimethyloxirane (23.6 mL, 265 mmol) was added to the mixture. The mixture was heated at 80°C for 16 hours. The mixture was cooled to room temperature. The mixture was filtered and washed with EtOAc. The solvents in the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-80% EtOAc in hexanes to give 2-methyl-1-(4-nitro-1Hpyrazol-1-yl)propan-2-ol. LCMS (C ₇ H11N ₃ O ₃ ) (ES, m/z): 186 [M+H] ⁺ .

Step 2: 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol

2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (18.8 g, 102 mmol), 10% palladium catalyst on a carbon support (1, 08 g, 1.01 mmol) and EtOAc (300 ml). The mixture was degassed under vacuum and refilled with nitrogen three times. The mixture was degassed and refilled with hydrogen from a cylinder. The mixture was stirred under a hydrogen atmosphere for 21 hours. The mixture was filtered through Celite® (diatomaceous earth). The solvents in the filtrate were evaporated to give 1(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C ₇ H ₁₃ N ₃ O) (ES, m/z): 156 [M+H] ⁺ .

Intermediate 34: 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol.

Step 1: Ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propanoate

- 59 043752

K2CO3 (11 .00 g, 80.00 mmol). The mixture was stirred and heated at 80°C for 10 hours. The mixture was cooled, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 5-20% EtOAc in petroleum ether as eluent to give ethyl 2-methyl-2-(4-nitro-1H-pyrazol-1yl)propanoate. LCMS (C ₉ H ₁₃ N ₃ O ₄ ) (ES, m/z): 228 [M+H]+.

Step 2: 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propan-1-ol

no ₂ no ₂

NaBH ₄ (0.999 g, 26 .4 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (40 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated to give 2-methyl-2-(4-nitro-1 H-pyrazol-1 -yl)propan-1 -ol.

Step 3: 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-1-ol

Intermediate 34

Step 3 of the synthesis of intermediate 34 was carried out in a manner similar to that described in step 2 of the synthesis of intermediate 33 using 2-methyl-2-(4-nitro-1H-pyrazol-1yl)propan-1-ol as the starting material to obtain 2- (4-amino-1H-pyrazol-1-yl)-2-methylpropan1-ol. LCMS (C ₇ H ₁₃ N ₃ O) (ES, m/z): 156 [M+H] ⁺ .

Intermediate 35: 2-amino-5-fluoro-4-methoxybenzonitrile.

Step 1: 2-bromo-4-fluoro-5-methoxyaniline

A solution of 4-fluoro-3-methoxyaniline (350.0 g, 2.48 mol) in EtOAc (3.5 L) was cooled at 0-5°C. Tetra-n-butylammonium tribromide (14.0 kg, 2.90 mol) was added to the mixture in portions. The mixture was heated to 15°C and stirred at this temperature for 1 hour. The mixture was adjusted to pH 8 with saturated aqueous Na ₂ CO ₃ . The mixture was extracted with EtOAc and the combined organic layers were washed with water (2 x 1.5 L) and dried with anhydrous Na ₂ SO ₄ . Solids were removed by filtration and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to give 2-bromo-4-fluoro-5-methoxyaniline. LCMS (C ₇ H ₇ BrFNO) (ES, m/z): 220, 222 [M+H] ⁺ .

Step 2: 2-amino-5-fluoro-4-methoxybenzonitrile

F

Intermediate 35

To a solution of 2-bromo-4-fluoro-5-methoxyaniline (300 g, 1.36 mol) in DMF (2.1 L) was added Zn(CN) ₂ (327 g, 2.78 mol) and Pd(PPh ₃ ) ₄ (90.0 g, 0.0778 mol). The mixture was degassed in vacuo and purged with nitrogen. The mixture was stirred and heated at 130°C for 1 hour under a nitrogen atmosphere. The mixture was poured into ice water (4 L). The mixture was extracted with EtOAc (3 L, 2 L, 1 L) and the combined organic layers were washed with brine (2 L, 1.5 L). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to give 2-amino-5-fluoro-4methoxybenzonitrile. LCMS (C ₈ H ₇ FN ₂ O) (ES, m/z): 167 [M+H] ⁺ .

Intermediate 36: 2-amino-4-chloro-5-fluorobenzonitrile

- 60 043752

2-bromo-5-chloro-4-fluoroaniline (1.00 g, 4.46 mmol), copper(I) cyanide (0.472 g, 4.90 mmol) and NMP (8 ml). The mixture was stirred and heated at 180°C under microwave irradiation for 1 hour. The mixture was diluted in diethyl ether (100

ml) and filtered through Celite® (diatomaceous earth). The filtrate was washed with water (3x100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvents of the filtrate were evaporated to give 2-amino-4-chloro-5-fluorobenzonitrile (LCMS (C ₇ H ₄ ClFN ₂ ) (ES, m/z): 171 [M+H ]+.

Intermediate 37: 2-((((2.4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4methoxybenzonitrile.

Step 1: 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea

2-Amino-5-fluoro-4-methoxybenzonitrile (intermediate 35) (817 mg, 4.92 mmol), DCM (6 mL) and pyridine (1 mL) were added to a 20 mL vessel. The mixture was stirred. 1-(isocyanatomethyl)-2,4-dimethoxybenzene (1425 mg, 7.380 mmol) was added to the mixture. The mixture was stirred and heated at

40°C for 16 hours. Solids were collected by filtration and washed with MeOH (3 x 3 ml) to give 1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4-dimethoxybenzyl)urea.

Step 2: 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile

1-(2-cyano-4-fluoro-5-methoxyphenyl)-3-(2,4dimethoxybenzyl)urea (1.16 g, 3.22 mmol), triphenylphosphine (1.69 g, 6.44 mmol), triethylamine (1.80 ml, 12.9 mmol) and DCM (25 ml). The mixture was stirred and cooled at 0°C. A solution of tetrabromomethane (2.14 g, 6.44 mmol) in DCM (5 ml) was added dropwise to the mixture. After 30 minutes the mixture was concentrated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc in hexanes as eluent to give 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4methoxybenzonitrile. LCMS (C ₁₈ H ₁₆ FN ₃ O ₃ ) (ES, m/z) [M+Na]+: 364.

Intermediates in the following table. 5 was prepared in a manner similar to that described for intermediate 37 from the appropriate intermediates and starting materials.

- 61 043752

Table 5

Intermediate connection Structure Observ. m/z [M + Na] ⁺ Name 38 Z o T—/ ^- C—Z 'o, o ζ o / 364 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5fluoro-3-methoxybenzonitrile 39 Z o -l—/ ^- C—Z o ^z o / 368 4-chloro-2-((((2,4- dimethoxybenzyl)imino)methylene)amino)-5fluorobenzonitrile 40 Z o -P—S— Z //=/ h /Z O / 348 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5fluoro-4-methylbenzonitrile 41 i _F that F 352 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)- 3,5-difluorobenzonitrile 42 Z o h )=\o Z 384 3,5 -dichloro-2-((((2,4- dimethoxybenzyl)imino)methylene)amino)benzonitrile

Intermediate 43: 1-(tert-butyl)-3-ethyl-(R)-piperidine-1,3-dicarboxylate Boc ₂ O ¹ t ₃ , DMAP DCM ..

ABOUT

Intermediate 43

A solution of (R)-ethylpiperidine-3-carboxylate (200.0 g, 1270 mmol), triethylamine (257.5 g, 2540 mmol) and DMAP (15.5 g, 130 mmol) in DCM (2 L) was cooled at 0 °C. Di-tert-butyl dicarbonate (305.4 g, 1400 mmol) was added to the mixture in portions. The mixture was stirred at room temperature for

- 62 043752

h. The organic layer was then washed with aqueous saturated sodium bicarbonate (3x1 L). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated to give 1-(tert-butyl)-3-ethyl-(R)-piperudine-1,3-dicarboxylate.

Intermediate 44 in the following table. 6 was prepared in a manner similar to that described for intermediate 43 from the corresponding starting materials.

Table 6

Intermediate connection Structure Observ. m/z [M + Na] ⁺ Name 44 Vos no. 280 1 -(/u/A't-butyl)-3-methylazepane-1,3-dicarboxylate

Intermediate 45: 1-(tert-butyl)-3-methyl-5-methylpiperidine-1,3-dicarboxylate.

Step 1: 5-methylpiperidine-3-carboxylic acid o ^pt ° ²

H ₂ 50 lbs. per sq. inch O

OH HC1, MeO^ ni^Aon

To a stirred mixture of 5-methylnicotinic acid (10 g, 72.9 mmol) and concentrated aqueous HCl (0.599 ml, 7.29 mmol) in MeOH (100 ml) at 20°C was added platinum (IV) oxide (1.67 g , 7.29 mmol). The mixture was degassed and purged with nitrogen, then the pressure was increased to 50 psi with hydrogen. The mixture was stirred for 10 hours. The mixture was filtered and the solvents of the filtrate were evaporated to give 5-methylpiperidine-3-carboxylic acid.

Step 2: 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid

ABOUT

Vos ₂ O

HE ----------i

MeCN/water

oh he

To a stirred mixture of di-tert-butyl dicarbonate (5.84 ml, 25.1 mmol) and 5-methylpiperidine-3carboxylic acid (3.00 g, 21.0 mmol) in MeCN (20 ml) and water (20 ml) at Sodium bicarbonate (7.04 g, 84.0 mmol) was added at 20°C. The mixture was stirred at 20°C for 5 hours. The mixture was diluted with water (20 ml), adjusted to pH 5 with concentrated aqueous HCl and extracted with EtOAc (3x30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated to give 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid. LCMS (C ₁₂ H ₂₁ NO ₄ ) (ES, m/z) [M+H]+: 244.

Step 3: 1-(tert-butyl)-3-methyl-5-methylpiperidine-1,3-dicarboxylate o

it

TMSCHN2

DCM/MeOH

Intermediate 45

Trimethylsilyldiazomethane (15 .4 ml, 30.8 mmol). The mixture was stirred at room temperature for 2 hours. The solvents were evaporated to give 1-tert-butyl-3-methyl-5-methylpiperidine-1,3-dicarboxylate. LCMS (C ₁₃ H ₂₃ NO ₄ ) (ES, m/z) [M+H]+: 258.

Intermediate 46: 1-(tert-butyl)-3-methyl-4-methylpiperidine-1,3-dicarboxylate.

Step 1: Methyl 4-methylpiperidine-3-carboxylate

Step 1 of the synthesis of intermediate 46 was carried out in a manner similar to that described in Step 1 of the synthesis of intermediate 45 from the corresponding starting materials to obtain methyl 4-methylpiperidine-3-carboxylate. LCMS (C ₈ H ₁₅ NO ₂ ) (ES, m/z) [M+H]+: 158.

Step 2: 1-(tert-butyl)-3-methyl-4-methylpiperidine-1,4-dicarboxylate

O

Vos ₂ O o^-----MeCN/water o

ABOUT'

Intermediate 46

Step 2 of the synthesis of intermediate 46 was carried out in a manner similar to that described in

- 63 043752 step 2 of the synthesis of intermediate 45 from the corresponding starting materials, except that the crude material was obtained by chromatography on silica gel with 0-30% EtOAc in petroleum ether as eluent to obtain 1-(tert-butyl)-3- methyl 4-methylpiperidine-1,4dicarboxylate.

Intermediate 47: mixture of rac, cis-1-(tert-butyl)-3-ethyl-5-fluoropiperidine-1,3dicarboxylate and rac, trans-1-(tert-butyl)-3-ethyl-5-fluoropiperidine-1 ,3-dicarboxylate

EtOH (73 mL) was added to a 250 mL round bottom flask containing rac, cis-1-(tert-butyl)-3-ethyl-5 fluoropiperidine-1,3-dicarboxylate (2.00 g, 7.26 mmol). . Sodium tert-butoxide (7.26 mL, 14.5 mmol) (2 M solution in THF) was added dropwise to the mixture with stirring. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated to approximately 10 ml by volume. EtOAc (10 ml) was added to the mixture. The solvents were evaporated. The residue was dissolved in EtOAc (60 ml) and washed with water (3x20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated from fluoropiperidine-1,3-dicarboxylate and dicarboxylate.

to give a mixture of rac, cis-1-(tert-butyl)-3-ethyl-5rac, trans-1-(tert-butyl)-3-ethyl-5-fluoropiperidine-1,3 Intermediate 48 and 49: methyl(3S ,6R)-1-(1-(2-hydroxy-2-methylpropyl)-1H-nirazol-4yl)-6-methylpiperidin-3-carboxylate yl)-6-methylpiperidin-3-carboxylate and methyl(3R,6S) -1-(1 -(2-hydroxy-2-methylpropyl)-1 H-pyrazole-4-

A 100 ml flask was filled with 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (4.66 g, 30.0 mmol), methyl 2-methylene-5-oxohexanoate ¹ [ ¹ Bizet, V.; Lefebvre, V.; Baudoux, J.; Lasne, M.; Boulange, A.; Leleu, S.; Frank, X.; Rouden, J. Eur. J. Org. Chem. 2011, 4170] (3.12 g, 20.0 mmol) and LiBF ₄ (1.88 g, 20.0 mmol). TFE (31.2 ml) was added to the flask. The flask was equipped with a reflux condenser, which had a nitrogen inlet. The mixture was refluxed for 48 hours. The mixture was cooled to room temperature and a 10% carbon supported palladium catalyst (0.639 g, 6.00 mmol) was added to the mixture. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 6 hours. The mixture was filtered and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-4% MeOH in DCM as eluent to give a racemate with cis-relative stereochemistry. The racemic mixture was resolved by chiral SFC (Chiral Technologies AD-H 21x250 mm column with 15% (MeOH modifier 0.1% NH4OH) as co-solvent), yielding methyl(3S,6R)-1-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6methylpiperidin-3-carboxylate (intermediate 48, first peak eluted) and methyl(3R,6S)-1-(1-(2-hydroxy-2- methylpropyl)-1H-πyrazol-4-yl)-6-methylpiperidin-3-carboxylate (intermediate 49, second peak eluted).

For intermediate 48: LCMS (C ₁₅ H ₂₅ N ₃ O ₃ ) (ES, m/z): 296 [M+H]+.

For intermediate 49: LCMS (C ₁₅ H ₂₅ N ₃ O ₃ ) (ES, m/z): 296 [M+H] ⁺ .

Intermediates in the following table. 7 was prepared in a manner similar to that described for Intermediate 48 and Intermediate 49 from the corresponding intermediates and starting materials, except that such compounds were isolated as racemic mixtures of diastereomers that were not resolved by SFC resolution.

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Table 7

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 50 ui ^{he is} NN 310 ethyl-1-(1-(1 -hydroxy-2-methylpropan-2-yl)-\H- pyrazol-4-yl)-6-methylpiperidin-3-carboxylate 51 He N-N\ 310 methyl 1-(1 -(2-hydroxy-2-methylpropyl)-3 -methyl-1Hpyrazol-4-yl)-6-methylpiperidin-3-carboxylate

Intermediate 52: Ethyl 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2oxopiperidin-3-carboxylate.

Step 1: Diethyl 2-(3-oxopentyl)malonate

A mixture of diethyl malonate (10.0 g, 62.4 mmol), pent-1-en-3-one (5.78 g, 68.7 mmol) and potassium carbonate (0.863 g, 6.24 mmol) was stirred at room temperature in a sealed tube for 3 days. The resulting mixture was filtered to obtain a filtrate, which was pure diethyl 2-(3-oxopentyl) malonate. LCMS (C ₁₂ H ₂₀ O ₅ ) (ES, m/z): 245 [M+H]+. The crude substance was used without further purification.

Step 2: rac-diethyl 2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)pentyl)malonate

To a stirred solution of 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 33) (2.00 g, 12.9 mmol) in DCM (129 mL) was added diethyl -2-(3-oxopentyl)malonate (6.93 g, 28.4 mmol) and AcOH (0.077 ml, 1.3 mmol). The mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (1.62 g, 25.8 mmol) was added to the mixture in portions. The mixture was stirred at room temperature for an additional 30 minutes. The mixture was quenched with 1 M aqueous HCl (150 ml). The organic layer was separated and the aqueous layer was extracted with DCM twice more. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate solvents were evaporated to give racdiethyl-2-(3-((1-(2-hydroxy-2-methylpropyl)-1H-nirazol-4-yl)amino )pentyl)malonate. LCMS (C19H33N3O5) (ES, m/z): 384 [M+H] ⁺ .

Step 3: Ethyl 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidine-3carboxylate

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To a solution of rac-diethyl 2-(3-(( 1 -(2-hydroxy-2-methylpropyl)-1 H-pyrazol-4yl)amino)pentyl)malonate (1.70 g, 4.43 mmol) in toluene (22 ml) AcOH (0.530 ml, 8.87 mmol) was added. The mixture was stirred at 90°C for 2 days. The mixture was cooled to room temperature and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes to give ethyl-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4yl)-2-oxopiperidine -3-carboxylate. LCMS (C ₁₇ H ₂₇ N ₃ O ₄ ) (ES, m/z): 338 [M+H]+.

Intermediate 53: Ethyl 3-hydroxycyclohexanecarboxylate

Intermediate 53

To a solution of ethyl 3-oxocyclohexanecarboxylate (2.00 g, 11.7 mmol) in THF (20 ml) was added a solution of sodium borohydride (0.889 g, 23.5 mmol) in THF (10 ml) at 0°C. The mixture was stirred at 0°C for 2 hours. Water (10 ml) was added to the mixture and the mixture was extracted with EtOAc (3x15 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to give ethyl 3-hydroxycyclohexanecarboxylate.

Intermediate 54: tert-butyl(R)-3-(hydrazinecarbonyl)piperidine-1-carboxylate

Intermediate 43 Intermediate 54

A solution of (R)-1-tert-butyl-3-ethylpiperidine-1,3-dicarboxylate (320.0 g, 1243 mmol) and hydrazine hydrate (311.3 g, 6217 mmol) in EtOH (1.6 L) was stirred and heated at 80°C for 16 hours. The solvents were evaporated. The resulting residue was purified by silica gel chromatography eluting with DCM to give tert-butyl(R)-3-(hydrazinecarbonyl)piperidine-1-carboxylateα. LCMS (CnH ₂₁ N ₃ O ₃ ) (ES, m/z): 244 [M+H] ⁺ .

Intermediates in the following table. 8 was prepared in a manner similar to that described for intermediate 54 from appropriate intermediates and starting materials.

Table 8

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 55 Vos HN-NH ₂ 258 mpem-butyl-3 -(hydrazinecarbonyl)azepane-1 -

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carboxylate 56 Vos N II n ABOUT 258 /ire/i-butyl-3-(hydrazinecarbonyl)-5 methylpiperidine-1-carboxylate 57 Vos 258 /ire/i-butyl-3-(hydrazinecarbonyl)-4methylpiperidine-1-carboxylate 58 Vos N. II n F γ NH ₂ O 206 [M+H-C ₄ H ₈ ] ⁺ mpem-butyl-3-fluoro-5-(hydrazinecarbonyl)piperidine 1-carboxylate 59 trans GI-) o _{cis {+/} .) o ^F NY ⁿ ' ^NH2 nh ₂ IJ ⁿ *ϊ U n N ⁺ B°c Boc 206 [M+H-C ₄ H ₈ ] ⁺ a mixture of mpem-6yvwi(3R.5R and 35.55)-3-fluoro-5(hydrazinecarbonyl)piperidine-1-carboxylate and mpem-6yvwi(3S,5R and 37?,55)-3-fluoro-5- (hydrazinecarbonyl)piperidine-1-carboxylate 60 Vos L?/°F NH H ₂ N 248 tert-butyl-3 -fluoro-3 - (hydrazinecarbonyl)pyrrolidine-1-carboxylate 61 OH ,N h N—. O '—/\jh h ₂ n 296 (3R,6S)-1 -(1 -(2-hydroxy-2-methylpropyl)-177-pyrazol-

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4-yl)-6-methylpiperidin-3-carbazide 62 A NN OH H ₂ N' ^NH 296 1-(1-(1-hydroxy-2-methylpropan-2-yl)-1 R-pyrazol-4yl)-6-methylpiperide in-3-carbazide 63 OH ,Ν m N—\ O '—' \n H ₂ N 310 1-(1 -(2-hydroxy-2-methylpropyl)-3-methyl-\Hpyrazol-4-yl)-6-methylpiperidin-3-carbazide 64 it is about N-HN-NH ₂ / \/ O 324 6-ethyl-1 -(1 -(2-hydroxy-2-methylpropyl)-1 R-pyrazol- 4-yl)-2-oxopiperidine-3-carbazide 65 IT. A ,,nh ₂ T IN II n 159 3-hydroxycyclohexane-1-carbazide 66 O II n Vos 258 /ire/i-butyl-5-(hydrazinecarbonyl)-2methylpiperidine-1-carboxylate

Intermediate 67: (R)-1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-carbazide.

Step 1: Ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidine-3-carboxylate o

A 40 mL reaction vessel was filled with ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-carboxylate (1.00 g, 6.36 mmol) and THF (15 mL). 4-Bromo-1-methyl-1H-pyrazole (4.96 mL, 48.0 mmol) was added to the mixture, followed by tBuXPhos-Pd G3 (2.02 g, 2.54 mmol) and sodium tert-butoxide (4 .61 g, 48.0 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The vessel was sealed and heated at 65°C for 24 hours. The mixture was cooled to room temperature and diluted with EtOAc (40 ml). The mixture was filtered through Celite® (diatomaceous earth). The solvents in the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM to give ethyl 1-(1-methyl-1H-pyrazol-4yl)piperidine-3-carboxylate. LCMS (C ₁₂ H ₁₉ N ₃ O ₂ ) (ES, m/z): 238 [M+H]+.

Step 2: (R)-1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-carbazide

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A round bottom flask was filled with ethyl 1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-carboxylate (7.72 g, 32.5 mmol) and EtOH (77 ml). Hydrazine hydrate (31.7 mL, 651 mmol) was added to the mixture. The round bottom flask was equipped with a reflux condenser and the mixture was heated at 80°C for 16 hours. The mixture was cooled to room temperature and the solvents were evaporated to give (R and S)-1-(1-methyl-1Hpyrazol-4-yl)piperidin-3- carbazide (intermediate 67). The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AD-H 21x250 mm column with 40% (MeOH with 0.25% DEA modifier) as a cosolvent to give (R or S)-1-(1-methyl-1H-pyrazole -4yl)piperidine-3-carbazide as the first eluting peak and (S or R)-1-(1-methyl-1H-pyrazol-4yl)piperidin-3-carbazide as the second eluting peak, corresponding to intermediate 67a and intermediate 67b, respectively LCMS (C ₁₀ H ₁₇ N ₅ O) (ES, m/z): 224 [M+H]+.

Intermediate 68 in the following table. 9 was prepared in a manner similar to that described for intermediate 67, except that SFC separation was not performed. Thus, the compound was isolated as a mixture of isomers.

Table 9

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 68 OH NN V h ₂ n' ^nh 296 1-(1 -(2-hydroxy-2-methylpropyl)-177-pyrazol-4-yl)-6methylpiperide in-3-carbazide

Intermediate 69: tert-butyl(R)-3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate

CDI |Sun. , η Hydrazine hydrate _R „ „

N% // 'Ν-Ά Р

EU THF ^he HN-NH ₂

Intermediate 69

(R)-1-(tert-butoxycarbonyl)pyrrolidine-3carboxylic acid (2.00 g, 9.29 mmol) and THF (18.6 mL) were added to a 100 mL round bottom flask. 1,1'-carbonyldiimidazole (1.96 g, 12.1 mmol) was added to the mixture. The mixture was heated at 60°C for 30 minutes. The mixture was cooled to room temperature and transferred dropwise into a stirring mixture of hydrazine hydrate (0.447 g, 13.9 mmol) in THF (10 ml) over 25 min. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (50 ml) and extracted with EtOAc (2x 60 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated to give (R)-tert-butyl-3(hydrazinecarbonyl)pyrrolidine-1-carboxylate. LCMS (C ₁₀ H ₁₉ N ₃ O ₃ ) (ES, m/z): 230 [M+H] ⁺ .

Intermediates in the following table. 9A was prepared in a manner similar to that described for the preparation of intermediate 60.

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Table 9A

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 70 Vos HN nh ₂ 186 [M+H-C ₄ H ₈ ] ⁺ tert-butyl-1 -(hydrazinecarbonyl)-3 azabicyclo[3,1,0]hexane-3-carboxylate 71 O O HN^V^NH O NH ₂ 158 2-oxopiperidine-3-carbazide 72 Vos A ^hn 'nh ₂ 268 [M+Na] ⁺ (L)-(ire/i-butyl-2-(hydrazinecarbonyl)morpholine-4carboxylate 73 Vos ίν ^{0 ην} 'νη ₂ 316 [M+Na] ⁺ /ire/i-butyl-2-(hydrazinecarbonyl)thiomorpholine-4carboxylate 1,1-dioxide

Intermediate 74: benzyl 3-fluoro-3-(hydrazinecarbonyl)piperidine-1-carboxylate

Intermediate 74

To a stirred solution of hydrazine hydrate (0.155 ml, 7.11 mmol), 1-((benzyloxy)carbonyl)3-fluoropiperidine-3-carboxylic acid (2.00 g, 7.11 mmol) and DIPEA (5.02 ml, 28.4 mmol) to DCM (70 mL) was added dropwise tripropylphosphonium anhydride (50% v/v solution in EtOAc, 6.38 mL, 14.2 mmol). The mixture was stirred at room temperature for 12 hours. The racemic mixture was quenched by adding saturated aqueous sodium bicarbonate. The mixture was stirred for 5 minutes, the organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated to give benzyl 3-fluoro-3-(hydrazinecarbonyl)piperidine-1-carboxylate. LCMS (C14H18FN3O3) (ES, m/z): 296 [M+H]+.

Intermediate 75 and Intermediate 76: tert-butyl(2R,5S or 2S,5R)-5-(5((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)-2methylpiperidin-1-carboxylate and tert-butyl (2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino) -9fluoro-8-methoxy-[1,2,4]triαzolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-carboxylate

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Intermediate 76

A solution of rac, cis-tert-butyl 5-(hydrazinecarbonyl)-2-methylpiperidine-1-carboxylate (intermediate 66) (5.00 g, 19.4 mmol) in DCM (7 mL) was added with AcOH (0.556 mL, 9.72 mmol). The mixture was stirred at room temperature. 2-((((2,4dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (intermediate 37) (6.63 g, 19.4 mmol) was added to the mixture. The mixture was stirred for 60 hours. The mixture was filtered, the filtrate was loaded directly onto a silica gel column and purified with 0-100% EtOAc in hexane as eluent to give racemic tert-butyl(2R,5S and 2S,5R)-5-(5- ((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-carboxylate. The racemic mixture was resolved by chiral SFC (Chiral Technologies AD-H 50x250 mm column with 35% EtOH as co-solvent) to give tert-butyl(2R,5S or 2S,5R)-5-(5-((2,4-dimethoxybenzyl )amino)-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-carboxylate (intermediate 75, first eluted peak) and tert -butyl(2S,5R or 2R,5S)-5-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)-2-methylpiperidin-1-carboxylate (intermediate 76, second peak eluted).

Intermediates in the following table. 10 was prepared in a manner similar to Intermediate 75 and Intermediate 76 from the corresponding intermediates and starting materials.

Table 10

Intermediate connection Structure SFC terms Observ./i/z [M + N] ⁺ Name 77 О' ⁱⁿ ° ^с ' ν /L nA // n о ι Η Д X । ^N ΐό F ¹ Peak 1; Chiral Technologies AD-H 21 x 250 mm column with 50% (IPA with 565 mpem-6yTm(lR.5R or 15.55)-1-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazo lin-2-yl)-3 azabicyclo[3,1,0]hexane-3-carboxylate modifier 0.2% DIPA) as a co-solvent 78 O— ό—o— 3 o o co Peak 2; Chiral Technologies AD-H 21 x 250 mm column with 50% (IPA with 0.2% DIPA modifier) as cosolvent 565 tert-butyl(15,55 or 1Λ,5Λ)-1-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazo lin-2-yl)-3 azabicyclo[3,1,0]hexane-3-carboxylate

Intermediates 79-81: tert-butyl(3S,5R or 3R,5S)-3-(5-((2,4-71 043752 dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2, 4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1carboxylate and tert-butyl(3R,5S or 3S,5R)-3-(5-((2.4-dimethoxybenzyl)amino)- 9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidine-1-carboxylate and tert-butyl(3R,5R and 3S,5S)- 3-(5((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1.2.4]triazolo[1.5-c]quinazolin-2-yl)-5fluoropiperidin-1-carboxylate

Intermediates 79-81 were prepared from Intermediate 37 and Intermediate 58 in a manner similar to that used to prepare Intermediate 75 and Intermediate 76. The crude residue was purified by silica gel chromatography with 0-100% EtOAc in hexane as eluent to give tert -butyl(3S,5R and 3R,5S)-3-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)-5-fluoropiperidin-1carboxylate (first eluted peak, mixture of intermediate 79 and intermediate 80) and tert-butyl(3R,5R and 3S,5S)-3-(5-((2,4- dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-carboxylate (second eluting peak, intermediate 81) . For intermediate 81: LCMS (C ₂₉ H ₃₄ F ₂ N ₆ O ₅ ) (ES, m/z): 585 [M+H]+. A mixture of intermediate 79 and intermediate 80 was resolved by chiral SFC (Chiral Technologies AD-H 50x250 mm column with 35% MeOH as co-solvent) to give tert-butyl(3S,5R or 3R,5S)-3-(5-( (2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-carboxylate (intermediate 79 , first eluted peak) and tert-butyl(3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8methoxy-[1,2,4]triazolo[ 1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-carboxylate (intermediate 80, second peak eluted). For intermediate 79: LCMS (C ₂₉ H ₃₄ F ₂ N ₆ Os) (ES, m/z): 585 [M+H] ⁺ . For intermediate 80: LCMS (C ₂₉ H ₃₄ F ₂ N ₆ O ₅ ) (ES, m/z): 585 [M+H] ⁺ .

Intermediate 82: (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3yl)-[1,2,4]triazolo[1,5-c]quinazoline -5-am.

Step 1: (R)-tert-butyl-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin- 2-yl)piperidine-1-carboxylate

(R)-tert-Butyl-3-(hydrazinecarbonyl)piperidine-1-carboxylate (intermediate 54) (596 mg, 2.45 mmol), DCM (7 mL) and AcOH (0.070 mL, 1.2 mmol). 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (intermediate 37) (836 mg, 2.45 mmol) was added to the mixture. The mixture was stirred for 16 hours. The solution was loaded onto a silica gel column and purified with 0-80% EtOAc in hexane as eluent to give (R)-tert-butyl-3-(5-((2,4-dimethoxybenzyl)amino)-9 -fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidine-1-carboxylate, LCMS (C ₂₉ H ₃₅ FN ₆ O ₅ ) (ES, m/z) [M+H] ⁺ : 567.

Step 2: (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5

c]quinazoline-5-amine

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Intermediate F connection 82

(R)-tert-butyl-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c] was added to a 20 ml vessel ]quinazolin-2-yl)piperidin-1-carboxylate (1.40 g, 2.47 mmol) and formic acid (4 ml). The solution was stirred for 16 hours. The mixture was diluted with DCM (50 ml) and washed with 2 M aqueous potassium carbonate (75 ml). The mixture was extracted with additional DCM (50 ml). The combined organic layers were dried over sodium sulfate, filtered, and the solvents of the filtrate were evaporated to give (K)-Na(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3yl)-[1,2, 4]triazolo[1,5-c]quinazolin-5-amine (intermediate 82). LCMS (C ₂₄ H ₂₇ FN ₆ O ₃ ) (ES, m/z) [M+H]+: 467.

Intermediates in the following table. 11 was synthesized in a manner similar to that used for the preparation of intermediate 82, from the corresponding intermediates and starting materials. For the synthesis of intermediate 89, the formic acid deprotection step (step 2) was not necessary.

Table 11

Intermediate connection Structure Observ. WzlM + ΗΓ Name 83 n ⁿ 7 N A- F 481 2-(azepan-3-yl)-A-(2,4-dimethoxybenzyl)-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 84 \ ^HI z^z/TN. //" / O- 481 2-(azepan-3-yl)-U-(2,4-dimethoxybenzyl)-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

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85 \ o ο- ¹ 481 A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5 amine 86 ^z^z ^z \ /=/ / c> \ 481 A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(4methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5amine 87 / HN ^Η , ^Ν “Υ'ν4 N^AYx y'O''' F 469 (L)-A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2- (morpholin-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 88 ^h 0 b HN ^v %o ⁿ tS Y 0 F 517 2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-

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3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-2-one

Intermediate 90 and Intermediate 91: (S or R)-N-(2,4dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-5-amine and (R or S)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy-[ 1,2,4]triazolo[1,5

c]quinazoline-5-amine.

Step 1: rac-benzyl-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl) -3-fluoropiperidine-1-carboxylate

Intermediate 74

AcOH (0.201 mL, 3 .52 mmol). The mixture was stirred at room temperature for 10 minutes. 2-((((2,4dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (intermediate 38) (2.00 g, 5.86 mmol) was added to the mixture. The mixture was stirred and heated at 40°C for 16 hours. The mixture was cooled to room temperature. The mixture was diluted with DCM (100 ml) and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with EtOAc in isohexane as eluent to give rac-benzyl-3-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)-3-fluoropiperidine-1carboxylate. LCMS (C ₃₂ H ₃₂ F ₂ N ₆ O ₅ ) (ES, m/z): 619 [M+H]+.

Step 2: (S or R)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy[1,2,4]triazolo[1,5 -c]quinazolin-5-amine and (R or S)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3fluoropiperidin-3-yl)-7-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-5-amine

ABOUT'

A 200 ml round bottom flask was filled with rac-benzyl-3-(5-((2,4-dimethoxybenzyl)amino)-9fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2 -yl)-3-fluoropiperidine-1-carboxylate (2.00 g, 3.23 mmol), 10% Pd/C (800 mg, 3.23 mmol) and MeOH (50 ml). The mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered through Celite® (diatomaceous earth) and the solvents of the filtrate were evaporated. The residue was purified by chromatography on silica gel with 0-8% MeOH in DCM (with 0.2% NH ₄ OH) in

- 75 043752 as eluent to give a racemic mixture, which was resolved by chiral SFC separation (Chiral Technologies, IC 20x250 mm column with 50% (EtOH with 0.2% DEA modifier) as co-solvent) to give (S or R)-N -(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (first eluted peak, intermediate 90) and (R or S)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin-3-yl)-7-methoxy[1,2,4]triazolo [1,5-c]quinazoline-5-amine (second eluted peak, intermediate 91). For intermediate 90: LCMS (C ₂₄ H ₂ 6F ₂ N6O ₃ ) (ES, m/z): 485 [M+H]+. For intermediate 91: LCMS (C ₂₄ H ₂₆ F ₂ N ₆ O ₃ ) (ES, m/z): 485 [M+H] ⁺ .

Intermediate 92: (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-(piperidin-3yl)-[1,2,4]triazolo[1,5-c]quinazoline -5-am.

Step 1: tert-butyl(R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazoline-2 -yl)piperidine-1-carboxylate

To a solution of tert-butyl(R)-3-(hydrazinecarbonyl)piperidine-1-carboxylate (intermediate 54) (1.52 g, 6.25 mmol) in DCM (25 mL) was added AcOH (0.201 mL, 3.52 mmol). The mixture was stirred at room temperature for 10 minutes. To this mixture was added 2-((((2,4dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (intermediate 38) (2.00 g, 5.86 mmol). The mixture was stirred for 16 hours. The mixture was diluted with DCM (100 ml), washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous MgSO4, solids were removed by filtration and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with EtOAc in isohexane as eluent to give tert-butyl(R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2 ,4]triazolo [1,5-c]quinazolin-2 yl)piperidine-1-carboxylate. LCMS (C ₂ 9H ₃₅ FN ₆ O ₅ ) (ES, m/z): 567 [M+H] ⁺ .

Step 2: (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5c]quinazolin- 5-amine

To a solution of tert-butyl(R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5с]quinazolin-2- yl)piperidine-1-carboxylate (2.12 g, 3.74 mmol) in DCM (30 ml) was added 4 M HCl in dioxane (10 ml, 40.0 mmol). The mixture was stirred at room temperature for 2 hours. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH ₄ OH) as eluent to give (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy -2-(piperidin3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 92). LCMS (C ₂₄ H ₂₇ FN ₆ O ₃ ) (ES, m/z): 467 [M+H] ⁺ .

Intermediates in the following table. 12 was prepared in a manner similar to that used for the preparation of intermediate 92, from appropriate intermediates and starting materials.

- 76 043752

Intermediates in the following table. 12A was prepared in a manner similar to that used in step 2 of the preparation of intermediate 92, from the corresponding intermediates and starting materials.

Table 12A

Intermediate connection Structure Observ. m/z[M + H] ⁺ Name 95 I G I ° L J Г* z^z O \ 481 A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((ZL,65 or 35.6L)-6-methylpiperidin-3-yl)- [1,2,4]triazolo [1,5-c]quinazo lin-5-amine

-77043752

96 ^H o O—/ 7 H Z—G L— ¹¹ - °- n $= 481 A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((35.6L or 37?.65)-6-methylpiperidin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 97 ^0 HN ΗΝ-^/^'Ν^Ν Хъ F 465 2-((17?,57? or 15.55)-3-azabicyclo[3,1,0]hexan-1-yl)- A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo [1,5-c]quinazolin-5-amine 98 ^0 ΗΝ HNA Ν'Ν^Ν F 465 2-((15.55 or 17?.57?)-3-azabicyclo[3,1,0]hexan-1-yl)- A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 99 ^0 HN ^η , ^ν ^νΆν F cis C J1 γ'Ό F 485 A-(2,4-dimethoxybenzyl)-9-fluoro-2-((37?.55 or 35.57?)5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo [ 1.5c]quinazo lin-5-amine 100 ^0 ΗΝ F 485

- 78 043752

A-(2,4-dimethoxybenzyl)-9-fluoro-2-((35.5L or 3R,5S)5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo [1, 5c]quinazo lin-5-amine 101 ^x o HN F trans (+/-) F 485 A-(2,4-dimethoxybenzyl)-9-fluoro-2-((ZL,5L and 3S,5S)-5 fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo [1, 5c]quinazo lin-5-amine 102 ^O HN HN^N'N^N ^F cis (+/-) F 485 A-(2,4-dimethoxybenzyl)-9-fluoro-2-((3L,55 and 3S,5R)-5fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo [1,5с ]quinazo lin-5-amine 103 ^о HN ^h / ⁿ A^ ⁿ ' ⁿ ^ ⁿ •V ^m AM· ^F trans (+/-) F 485 A-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R and 35.55)-5fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo [1.5c ]quinazo lin-5-amine

Intermediate 104: rac-N'-2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1Hpyrazol-4-yl)piperidin-3-carbazide.

Stage 1: 2-amino-6-fluoro-8-methoxyquinazolin-4-ol cyanamide NH, O HCI ethanol, heating with arr. cold.

^he --------- BUT

Cyanamide (158 mg, 3.75 mmol) and hydrochloric acid (325 µl, 1.95 mmol) (6 M, aq). The mixture was refluxed for 16 hours. The mixture was cooled. The precipitate was collected by filtration and dried under high vacuum to give 2-amino-6-fluoro-8methoxyquinazolin-4-ol. LCMS (C ₉ H ₈ FN ₃ O ₂ ) (ES, m/z): 210 [M+H]+.

Step 2: 6-fluoro-8-methoxy-4-(1H-1,2,4-triazol-1-yl)quinazolin-2-amine but

ΝΗ

POCI ₃ . 1,2,4-triazole DIPEA acetonitrile, 40 °C

ΝΗ

POCl ₃ (295 μl, 3.16 mmol) was added dropwise over 15 min to a stirred mixture of 1,2,4triazole (524 mg, 7.59 mmol), 2-amino-6-fluoro-8-methoxyquinazoline-4- ol (264.7 mg, 1.265 mmol) and DIPEA (553 µl, 3.16 mmol) in acetonitrile (5 ml) at room temperature. The mixture was stirred and

- 79 043752 heated at 40°C for 3 hours and then at room temperature for 16 hours. The mixture was filtered through Celite® (diatomaceous earth), washed with acetonitrile and diethyl ether to obtain 6fluoro-8-methoxy-4-(1H -1,2,4-triazol-1-yl)quinazolin-2-amine. LCMS (CnH ₉ FN ₆ O) (ES, m/z): 261 [M+H]+.

Step 3: rac-N'-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4yl)piperidin-3-carbazide

Intermediate 67 Intermediate 104

A 20 mL reaction vessel was filled with 6-fluoro-8-methoxy-4-(1H-1,2,4-triazol-1yl)quinazolin-2-amine (41.1 mg, 0.158 mmol), (R and S)- 1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-carbazide (intermediate 67) (38.8 mg, 0.174 mmol), THF (1 mL) and DIPEA (138 μL, 0.790 mmol). The mixture was stirred and heated at 50°C for 4 hours. The mixture was diluted with ethyl acetate (10 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated to give rac-N'-(2-amino-6fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1H-pyrazol-4 -yl)piperidin-3-carbazide. LCMS (C19H23FN8O2) (ES, m/z): 415 [M+H] ⁺ .

Intermediates in the following table. 13 was prepared from the corresponding starting materials in a manner similar to intermediate 104, except that the enantiomerically pure hydrazide, intermediate 67b, was used.

Table 13

Intermediate connection Structure Observ. Wz[M + H| ⁺ Name 105 ZI IZ сГ h Z 1 403 (R or S)-N-(2-amino-6,7-difluoroquinazolin-4-yl)-1-(1methyl-1H-pyrazo l-4-yl)piperidin-3-carbazide 106 NH _{2 s} N^N AVA F 385 (R or 5)-A'-(2-amino-6-fluoroquinazolin-4-yl)-1-(1methyl-1H-pyrazo l-4-yl)piperidin-3-carbazide 107 nh ₂ O Η VJ ^no F 403 (R or 5)-A'-(2-amino-6,8-difluoroquinazolin-4-yl)-1-(1methyl-1H-pyrazo l-4-yl)piperidin-3-carbazide 108 NH ₂ O _u N^N νΑ'Ά F 403 (R or 5)-A'-(2-amino-5,6-difluoroquinazolin-4-yl)-1-(1methyl-1H-pyrazo l-4-yl)piperidin-3-carbazide 109 N Z—V E-O ZI IZ A h Z 1 401 (R or 5)A'-(2-amino-6-chloroquinazolin-4-yl)-1-(1methyl-1H-pyrazo l-4-yl)piperidin-3-carbazide

- 80 043752

(R or b)-A-(2-amino-6-chloro-8-methylquinazolin-4-yl)1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-carbazide

(R or b)-L-(2-amino-6-chloro-8-methoxyquinazolin-4yl)-1-(1-methyl-1H-pyrazol-4-yl)piperidin-3-carbazide

(R or d)-A-(2-amino-6-methoxyquinazolin-4-yl)-1-(1methyl-1H-pyrazol-4-yl)piperidin-3-carbazide

Intermediates 113-116: 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4dimethoxybethyl)amino)-9-fluoro-8-methoxy-[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5-(5-((2 ,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1 H-pyrazole -1 -yl)-2-methylpropan-2-ol and 1(4-((2R or 2S,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8 -methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol.

Step 1: 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-6-ethyl -1-(1 -(2-hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)piperidin-2-one

To a solution of 6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-oxopiperidin-3 carbazide (intermediate 64) (270 mg, 0.835 mmol) in dioxane (7 ml) was added AcOH (0.024 ml, 0.42 mmol). The mixture was stirred at room temperature for 30 minutes. To this mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (intermediate 37) (285 mg, 0.835 mmol). The mixture was stirred at room temperature for 3 days. The mixture was filtered and the filtrate was purified by silica gel chromatography with 0-100% 3:1 EtOAc:EtOH in hexanes as eluent to give 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro8-methoxy-[ 1,2,4]triazolo[1,5-c]quinazolin-2-yl)-6-ethyl-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4yl)piperidin-2- she. LCMS (C ₃₃ H ₃₉ FN ₈ O ₅ ) (ES, m/z): 647 [M+H]+.

Step 2: 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo [1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol and 1(4-((2S or 2R ,5R or 5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)- 2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5-(5-((2 ,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2ethylpiperidin-1-yl)-1H-pyrazol-1 -yl)-2-methylpropan-2-ol and 1-(4-((2R or 2S,5R or 5S)-5-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy- [ 1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1 yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

- 81 043752

Intermediate 114

To a solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-6-ethyl- 1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one (320 mg, 0.495 mmol) in THF (4.9 ml) add borane in THF (1, 0 M, 2.47 ml, 2.47 mmol). The mixture was stirred at room temperature for 24 hours. The racemic mixture was quenched with MeOH and then the solvents were evaporated. The resulting residue was purified by preparative reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/water (with 0.1% TFA) as eluent) to obtain two racemic mixtures of the corresponding diastereomers. Each racemate was resolved by chiral SFC.

The first eluting racemate was cleaved by chiral SFC cleavage (Chiral Technologies, AS-H, 21x250 mm column with 50% (IPA + 0.2% DIPA) as cosolvent) to give 1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin2-yl)-2-ethylpiperidine -1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluted peak) and 1-(4((2S or 2R,5R or 5S)-5-(5-(( 2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-2-ethylpiperidin-1 -yl)-1 H-pyrazole -1-yl)-2-methylpropan-2-ol (second eluted), corresponding to intermediate 113 and intermediate 114, respectively. For intermediate 113: LCMS (C ₃₃ H ₄₁ FN ₈ O ₄ ) (ES, m/z): 634 [M+H] ⁺ . For intermediate 114: LCMS (C ₃₃ H ₄₁ FN ₈ O ₄ ) (ES, m/z): 634 [M+H] ⁺ .

The second eluting racemate was resolved by chiral SFC cleavage (AS-H, 21 x 250 mm column with 50% (IPA + 0.2% DIPA) as cosolvent) to give 1-(4-((2S or 2R,5S or 5R) 5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2ethylpiperidin-1- yl)-1H-nirazol-1-yl)-2-methylpropan-2-olα (first eluted peak) and 1-(4-((2R or 2S,5R or 5S)-5-(5-((2, 4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-2-ethylniperidin-1-yl)-1H-nirazol-1- yl)-2-methylpropan-2-ol (second eluted peak), corresponding to intermediate 115 and intermediate 116, respectively. For intermediate 115: LCMS (C ₃₃ H ₄₁ FN ₈ O ₄ ) (ES, m/z): 634 [M+H]+. For intermediate 116: LCMS (C ₃₃ H ₄₁ FN ₈ O ₄ ) (ES, m/z): 634 [M+H] ⁺ .

Intermediate 117: mixture of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3methyl-1H-pyrazol-4-yl)piperidin-3-yl) -[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5- methyl-1H-pyrazol-4-yl)niperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine.

Step 1: mixture of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-trityl-1Hpyrazol-4-yl)piperidin-3 - yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4-dimethoxybenzyl)9-fluoro-8-methoxy-2-(1- (3-methyl-1-trityl-1H-pyrazol-4-yl)pineridin-3-yl)-[1,2,4]triazolo[1,5c]quinazolin-5-amine

- 82 043752

A 20 ml vessel was filled with (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(pineridin-3yl)-[1,2,4]triazolo[1,5-c] quinazoline-5-amine (intermediate 82) (500 mg, 1.07 mmol) and THF (6.7 ml). A mixture of 4-bromo-5-methyl-1-trityl-1H-pyrazole and 4-bromo-3-methyl-1-trityl-1H-pyrazole (intermediate 16) (865 mg, 2.14 mmol) was added to the mixture, followed by tBuXPhos-Pd G3 (412 mg, 4.29 mmol) and sodium tert-butoxide (412 mg, 4.29 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The mixture was stirred and heated at 90°C for 16 hours. The mixture was cooled to room temperature. Celite® (diatomaceous earth) and saturated aqueous NH ₄ Cl were added to the mixture. The mixture was stirred vigorously for 5 minutes. The mixture was filtered through Celite® (diatomaceous earth) overlaid with anhydrous MgSO ₄ and washed with DCM. The solvents in the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-20% MeOH in DCM to give a mixture of (R)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5-methyl-1-trityl -1 H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4-dimethoxybenzyl) -9-fluoro-8-methoxy-2-(1-(3-methyl1-trityl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c ]quinazoline-5-amine. LCMS (C ₄₇ H ₄₅ FN ₈ O ₃ ) (ES, m/z): 789 [M+H]+.

Step 2: mixture of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1H-pyrazol-4yl)piperidin-3-yl)-[ 1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8methoxy-2-( 1 -(5-methyl- 1 H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

Ome

Ome

Intermediate 117

To a stirred solution of a mixture of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl1-trityl-III-pyrazol-4-yl)piperidin-3- yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-2-( 1 -( 5-methyl-1H-pyrazol-4-yl)niperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (565 mg, 0.716 mmol) in MeOH (7 .2 ml) a 4 M solution of HCl in dioxane (1.79 ml, 7.16 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvents were evaporated and the residue was dissolved in DCM (50 ml). Saturated aqueous sodium bicarbonate (50 ml) was added to the mixture. The biphasic mixture was separated and the aqueous layer was extracted with additional DCM (50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated to give a mixture of N)-I-(2,4-dimethoxybenzyl)-9fluoro-8-methoxy-2-(1-(3-methyl -1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5amine and (R)-N-(2,4-dimethoxybenzyl)-9 -fluoro-8-methoxy-2-(1-(5-methyl-1H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazolin-5- amine. LCMS (C ₂₈ H ₃₁ FN ₈ O ₃ ) (ES, m/z): 547 [M+H]+.

Intermediates in the following table. 14 was prepared in a manner similar to that used for the preparation of intermediate 117 from the corresponding starting materials.

Table 14

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 118 ОМе ,Ν у^ОМе Ν' \ 1 ⁴ ΝΗ ^ν Ύι Y^OMe F 533 (77)-2-( 1-( 1/-pyrazol-4-yl)pipsridin-3-yl)-L'-(2.4- dimethoxybenzyl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazo lin-5-amine 119 f o f / - M I \__/ / \\ + IZ O CM X 583 (Λ)-2-( 1 -(3 -(difluoromethyl)-1 R-pyrazol-4-yl)piperide in- 3-yl)-L''-(2.4-dimstoxybsnzyl)-9-fluoro-8-mstoxy- [1,2,4]triazolo[1,5-c]quinazo lin-5-amine

Intermediate 120 and Intermediate 121: N-(2,4-dimethoxybenzyl)-9fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1R, 2R or 1S,2S)-2-((tetrahydro-2H-pyran-2yl)oxy)cyclopentyl)-1 H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo [1 ,5-c]quinazolin-5-amine and N(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1- ((1S,2S or 1R,2R)-2((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4 ]triazolo[1,5c]quinazolin-5-amine

Intermediate connection 121 F

To a reaction vessel containing a solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)-[1,2, 4]triazolo[1,5-c]quinazolin-5-amine (intermediate

- 84 043752 compound 95) (150 mg, 0.312 mmol) in THF (4 ml), 4-bromo-1-(2-((tetrahydro-2H-pyran-2yl)oxy)cyclopentyl)-1H-pyrazole (intermediate) was added compound 32) (177 mg, 0.562 mmol), followed by tBuXPhos-Pd G3 (124 mg, 0.156 mmol) and sodium tert-butoxide (105 mg, 1.09 mmol). The mixture was sprayed with nitrogen for 10 minutes. The mixture was stirred and heated at 90°C for 16 hours. An additional amount of 4-bromo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazole (intermediate) was added to the mixture compound 32) (88.5 mg, 0.281 mmol), tBuXPhos-Pd G3 (62 mg, 0.078 mmol) and sodium tert-butoxide (52.5 mg, 0.547 mmol). The mixture was stirred and heated at 90°C for 16 hours. The mixture was prepared by preparative TLC on silica gel with 4% MeOH in DCM as eluent to obtain a mixture of isomers. The mixture was resolved by chiral SFC separation (ID 21x250 mm column with 50% (MeOH with ACN 1:1 + 0.2% DIPA) as co-solvent) to give N-(2,4-dimethoxybenzyl)-9-fluoro-8methoxy- 2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1R,2R or 1S,2S)-((tetrahydro-2H-pyran-2yl)oxy)cyclopentyl)-1 H -pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (first eluted peak, intermediate 120) and N-(2,4 -dimethoxybenzyl)-9-fluoro-8-methoxy-2((3R,6S or 3S, 6R)-6-methyl-1-(1-((1S,2S or 1R,2R)-2-((tetrahydro- 2H-pyran-2-yl)oxy)cyclopentyl)1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amineα (fourth eluted peak, intermediate 121), corresponding to intermediate 120 and intermediate 121, respectively. (Note: peaks 2 and 3 are characterized by incomplete separation). For intermediate 120: LCMS (C ₃₈ H ₄₇ FN ₈ O ₅ ) (ES, m/z): 715 [M+H] ⁺ . For intermediate 121: LCMS (C ₃₈ H ₄₇ FN ₈ O ₅ ) (ES, m/z): 715 [M+H] ⁺ .

Intermediate 122 and Intermediate 123: 1-(4-((3R,5S and 3R,5S)-3-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3R ,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2methylpropan-2-ol

connection 123

To a stirred mixture of sodium tert-butoxide (300 mg, 3.12 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2methylpropan-2-ol (intermediate 4) (274 mg, 1.25 mmol) and N-(2,4-dimethoxybenzyl)-9fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5- amine (intermediate 85) (300 mg, 0.624 mmol) in THF (2 mL), tBuXPhos-Pd G3 (149 mg, 0.187 mmol) was added under nitrogen in a glove box. The mixture was stirred and heated at 100°C for 14 hours. The mixture was prepared by preparative TLC on silica gel with 10% MeOH in DCM as eluent to obtain two diastereomers: 1-(4-((3R,5S and 3R,5S)- 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylniperidin-1- yl)-1H-pyrazol-1-yl)-2methylpropan-2-ol and 1-(4-((3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)- 9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2- methylpropan-2-ol, corresponding to intermediate 122 and intermediate 123, respectively. For intermediate 122, LCMS (C ₃₂ H ₃₉ FN ₈ O ₄ ) (ES, m/z): 619 [M+H] ⁺ . For intermediate 123, LCMS (C ₃₂ H ₃₉ FN ₈ O ₄ ) (ES, m/z): 619 [M+H] ⁺ .

Intermediate 124: (R)-5-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5- c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-one

- 85 043752

To a stirred mixture of sodium tert-butoxide (66.5 mg, 0.692 mmol), (R)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1, 2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 82) (89.0 mg, 0.190 mmol), 2-(4-bromo-1H-pyrazol-1-yl)-1- methylcyclobutanol (intermediate 29) (40.0 mg, 0.173 mmol) in THF (2 ml) was added tBuXPhos-Pd G3 (41.3 mg, 0.0520 mmol). The mixture was stirred and heated at 80°C for 12 hours. The mixture was cooled, diluted with EtOAc (10 ml) and washed with water (10 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative TLC on silica gel with EtOAc as eluent to give the ring-opened product (R)-5-(4-(3-(5((2,4-dimethoxybenzyl)amino)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)1H-pyrazol-1-yl)pentαn-2-one. LCMS (C ₃₂ H ₃₇ FN ₈ O ₄ ) (ES, m/z): 617 [M+H]+.

Intermediate 125: 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin- 1 -yl)-1 H-pyrazol-1 -yl)cyclobutan-1 -one.

Step 1: N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1H-pyrazol-4yl)piperidin-3-yl)-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

To a stirred mixture of sodium tert-butoxide (177 mg, 1.84 mmol), (R)-N-(2,4-dimethoxybenzyl)9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1 ,2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 82) (236 mg, 0.506 mmol), 4-bromo-1-(2,2-dimethoxycyclobutyl)-III-pyrazole (intermediate compound 30) (120 mg, 0.460 mmol) in THF (4 ml) was added tBuXPhos-Pd G3 (110 mg, 0.138 mmol). The mixture was stirred and heated at 80°C for 12 hours under a nitrogen atmosphere. The mixture was cooled, diluted with EtOAc (10 ml) and then washed with water (10 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc in petroleum ether as eluent to give N-(2,4-dimethoxybenzyl)2-((3R)-1-(1-(2,2-dimethoxycyclobutyl)-1 P-pyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C ₃₃ H ₃₉ FN ₈ O ₅ ) (ES, m/z): 647 [M+H] ⁺ .

Step 2: 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine1 -yl)-1 H-pyrazol-1 -yl)cyclobutan-1-one

Intermediate 125

Mixture of N-(2,4-dimethoxybenzyl)-2-((3R)-1-(1 -(2,2-dimethoxycyclobutyl)-1 H-pyrazol-4yl)piperidin-3-yl)-9-fluoro-8 -methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (130 mg, 0.201 mmol) and formic acid (2 ml) were stirred and heated at 40°C for 15 hours. The mixture cooled and adjusted to pH=8 with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM (3x10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents

- 86 043752 the filtrate was evaporated. The residue was purified by preparative TLC on silica gel with EtOAc as eluent to give 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1, 5-c]quinazolin-2yl)piperidin-1-yl)-1H-pyrazol-1-yl)cyclobutan-1-one. LCMS (C ₂₂ H ₂₃ FN ₈ O ₂ ) (ES, m/z): 451 [M+H]+.

Intermediate 126 and Intermediate 127: rac-(1R or 1S,3R or 3S)-3-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline- 2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan1-ol and rac-(1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol.

Step 1: 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)cyclohexane-1 - ol

To a stirred mixture of 3-hydroxycyclohexanecarbazide (intermediate 65) (0.556 g, 3.52 mmol) in DCM (30 mL) was added AcOH (0.084 mL, 1.5 mmol). 2-((((2,4dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4-methoxybenzonitrile (intermediate 37) (1.00 g, 2.93 mmol) was added to the solution. The mixture was stirred and heated at 35°C for 10 hours. The mixture was concentrated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to give 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)cyclohexanol. LCMS (C ₂₅ H ₂₈ FN ₅ O ₄ ) (ES, m/z) [M+H] ⁺ : 482.

Step 2: 3-(5-((2,4-Dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)cyclohexane-1 - He

F

To a stirred solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanol (780 mg, 1.62 mmol) to DCM (10 ml) was added DMP (1.37 g, 3.24 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (5 ml) and the mixture was filtered. The filtrate was extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether to give 3-(5((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1 ,5-c]quinazolin-2-yl)cyclohexanone. LCMS (C ₂ 5H ₂ 6FN5O4) (ES, m/z) [M+H] ⁺ : 480.

Step 3: 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2 yl)-1 - (1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol

To a stirred solution of 4-bromo-1-ethyl-1H-pyrazole (621 mg, 3.55 mmol) in THF (3 ml) was added n-butyllithium (1.42 ml, 3.55 mmol, 2.5 M in hexane ) at -78°C. The mixture was stirred at -78°C for 20 minutes. A solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)cyclohexanone was added to the mixture ( 340 mg, 0.709 mmol) in THF (3 ml) at -78°C and the mixture was stirred at this temperature for 1 hour. The mixture was quenched with saturated aqueous NH ₄ Cl (5

- 87043752 ml) and extracted with EtOAc (3x10 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to give 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4 ]triazolo[1,5c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl). LCMS (C ₃₀ H ₃₄ FN ₇ O ₄ (ES, m/z) [M+H]+: 576.

Step 4: rac-(1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin2-yl)- 1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and rac-(1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8methoxy-[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol

To a solution of 3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-1-(1 -ethyl-1H-pyrazol-4-yl)cyclohexanol (180 mg, 0.313 mmol) in DCM (4 ml) and water (2 ml) was added portionwise to DDQ (106 mg, 0.469 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes. The mixture was diluted with DCM (10 ml) and washed with Na ₂ SO ₃ (2 M aqueous solution, 5 ml) and saline (2x10 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by reverse phase HPLC (Waters XBridge C18 OBD preparative column, 19 mm x 100 mm with MeCN/water (with 10 mM NH4HCO3 modifier) as eluent) to obtain two diastereomers rac-(1R or 1S,3R or 3S)-3 -(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-III-pyrazol-4-yl) cyclohexan-1-ol and rac-(1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline- 2-yl)-1-(1-ethyl-1H-pyrazol-4yl)cyclohexan-1-ol, corresponding to intermediate 126 and intermediate 127, respectively. For intermediate 126: LCMS (C ₂₁ H ₂₄ FN ₇ O ₂ ) (ES, m/z) [M+H] ⁺ : 426. For intermediate 127: LCMS (C ₂₁ H ₂₄ FN ₇ O ₂ ) (ES , m/z) [M+H] ⁺ : 426.

Intermediate 128: (2S,3S and 2R,3R)-3-(4-bromo-1H-pyrazol-1-yl)butan-2-ol he

Intermediate 128

To a mixture of 4-bromo-III-pyrazole (2.00 g, 13.6 mmol) and cesium carbonate (13.3 g, 40.8 mmol) in MeCN (20 ml) was added cis-2,3-dimethyloxirane (2 .38 ml, 27.2 mmol). The mixture was stirred and heated at 80°C for 16 hours. The mixture was cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated, the residue was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes to give (2S,3S and 2R,5R)-3-(4-6pom-1Hpyrazol-1-yl)butan-2-ol. LCMS (C ₇ H11BrN ₂ O) (ES, m/z) [M+H] ⁺ : 219.221.

Intermediates in the following table. 15 was prepared from the corresponding starting materials in a manner similar to intermediate 128.

- 88 043752

Table 15

Intermediate connection Structure Observ. /t?L|M + N| ⁺ Name 129 HE (+/-) anpuA 219, 221 racemic, anti-3-(4-bromo-177-pyrazol-1-yl)butan2-ol 130 OH (+/-) syn*U^ βΛ ^Ν 233.235 racemic, syn-3 -(4-bromo-3-methyl-177-pyrazole-1 - yl)butan-2-ol 131 OH (+/-) Τ/,Ν Br^ ⁷ 233.235 racemic-syn-3-(4-bromo-5-methyl-177-pyrazol-1 yl)butan-2-ol 132 OH (+/-) ο ₂ ν' 186 racemic-syn-3-(4-nitro-177-pyrazol-1-yl)butan-2ol 133 but^ jQn o ₂ n 202 rac-2-methyl-3-(4-nitro-177-pyrazol-1-yl)propan-1,2diol 134 he jQ ⁿ o ₂ n 200 2-methyl-1-(5-methyl-4-nitro-177-pyrazol-1-yl)propan-2ol 135 HE <4 Ο,Ν D 200 2-methyl-1-(3-methyl-4-nitro-177-pyrazol-1-yl)propan-2- ol

Intermediate 136: Ethyl 3-(4-bromo-1H-pyrazol-1-yl)propanoate

Intermediate 136

To a stirred mixture of 4-bromo-1H-pyrazole (0.500 g, 3.40 mmol) in DMF (10 ml) was added

- 89 043752

K ₂ CO ₃ (1.18 g, 8.50 mmol) and ethyl 3-bromopropanoate (0.924 g, 5.10 mmol). The mixture was stirred and heated at 60°C for 8 hours. The mixture was diluted with water (30 ml), filtered and the filtrate was extracted with EtOAc (2x30 ml). The organic layers were dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel column chromatography with 3-25% EtOAc in petroleum ether as eluent to give ethyl 3-(4-bromo-Spirazol-1-yl)propanoate. LCMS (C ₈ HnBrN ₂ O ₂ ) (ES, m/z) [M+H]+: 247, 249.

Intermediates in the following table. 16 was prepared from the corresponding pyrazole and an alkyl halide or mesylate in a manner similar to that used to prepare intermediate 136.

Table 16

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 137 ABOUT [Qn 231,233 3 -(4-bromo-177-pyrazol-1-yl)-3-methylbutan-2-one 138 O O ^Br \ 245, 247 3 -(4-bromo-3-methyl-177-pyrazol-1-yl)-3-methylbutan-2-one 139 ABOUT r-N O Vg D 261.263 Methyl 2-(4-bromo-3-methyl-177-pyrazol-1-yl)-2methylpropanoate 140 ABOUT X? In g 261.263 Methyl 2-(4-bromo-5 -methyl-177-pyrazol-1-yl)-2methylpropanoate 141 ABOUT In g 203.205 Methyl 2-(4-bromo-5 -methyl-177-pyrazol-1-yl)-2methylpropanoate 142 NHBoc rN |Qn o ₂ n 307 [M+Na] ⁺ /ire/i-butyl(2-methyl-1-(4-nitro-177-pyrazol-1-yl)propan2-yl)carbamate

- 90 043752

Intermediate 145: rac-1-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol

Vg vg

Intermediate 141 Intermediate 145

To a solution of 1-(4-bromo-1H-pyrazol-1-yl)propan-2-one (intermediate 141) (2.00 g, 9.85 mmol) in Et2O (22 mL) a 3 M solution was added dropwise ethylmagnesium bromide (9.85 ml, 29.6 mmol) at 0°C under nitrogen atmosphere. The solution was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 15 hours. The mixture was quenched with saturated aqueous ammonium chloride (50 ml), diluted with EtOAc (50 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (2x100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and the solvents were evaporated. The resulting residue was purified by reverse phase HPLC (MeCN/water with 0.05% TFA) to give rac-1-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C ₈ H ₁₃ BrN ₂ O) (ES, m/z) [M+H]+: 233.235.

Intermediate 146: 1-((5-methyl-2-phenyl-1,3-dioxan-5-yl)methyl)-4-nitro-1H-pyrazole

Intermediate 146

To a solution of (5-methyl-2-phenyl-1,3-dioxan-5-yl)methanol (4.00 g, 19.2 mmol) in THF (20 ml) was added 4-nitro-N-pyrazole (2, 61 g, 23.1 mmol), triphenylphosphine (10.1 g, 38.4 mmol). DIAD (5.83 g, 28.8 mmol) in DCM (20 ml) was slowly added to the mixture. The mixture was stirred at room temperature for 15 hours. The solvents were evaporated. The residue was purified by silica gel chromatography with 030% EtOAc in petroleum ether to give 1-((5-methyl-2-phenyl-1,3-dioxan-5-yl)methyl)-4-nitro1H-pyrazole. LCMS (C ₁₅ H ₁₇ N ₃ O ₄ ) (ES, m/z) [M+H] ⁺ : 304.

The intermediate in the following table. 17 was prepared from the corresponding pyrazole and alcohol in a manner similar to that described for the synthesis of intermediate 146.

Table 17

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 147 A-O. ТНР o ₂ n 558 [2M+Na] ⁺ 4-nitro-1-((1 -((tetrahydro-2R-pyran-2- yl)oxy)cyclopropyl)methyl)-1H-pyrazole

Intermediate 148: rac-3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-ol

- 91 043752

He

Br

Intermediate Intermediate connection 138 connection 148

To a suspension of 3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-one (intermediate 138) (1.27 g, 5.18 mmol) in EtOH (25, 9 ml) sodium borohydride (0.588 g, 15.5 mmol) was added. The mixture was stirred for 16 hours. The mixture was diluted with EtOAc (50 ml), washed with water (50 ml) and aqueous potassium hydroxide (1 M, 20 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvent of the filtrate was evaporated to give 3-(4-bromo-3-methyl-1H-pyrazol-1-yl)-3-methylbutan-2-ol, which was carried forward without further purification. . LCMS (C ₉ H ₁₅ BrN ₂ O) (ES, m/z) [M+H]+: 247, 249.

Intermediates in the following table. 18 was prepared from the corresponding pyrazole-containing ketone or ester in a manner similar to that described for the preparation of intermediate 148.

Table 18

Intermediate connection Structure Observation m/z [M + N] ⁺ Name 149 HE /l Vg 233.235 2-(4-bromo-3-methyl-ΙΗ-pyrazol-1-yl)-2-methylpropan-1-ol 150 HE nA Vg 233.235 2-(4-bromo-5 -methyl-1 /7-pyrazol-1 -yl)-2-methylpropan-1 -ol 151 he νο ₂ 200 rac-3-methyl-3-(4-nitro-177-pyrazol-1-yl)butan-2-ol 152 he ^U^on Ν'\ νο ₂ 202 4-nitro-1 -((1 -((tstrahydro-2//-pyran-2- yl)oxy)cyclopropyl)methyl)-177-pyrazole

Intermediate 153: 4-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol

Intermediate Intermediate connection 136 connection 153

To a solution of ethyl 3-(4-bromo-1H-pyrazol-1-yl)propanoate (100 mg, 0.405 mmol) (intermediate 136) in THF (4 mL) was added a 3 M solution of MeMgBr in diethyl ether (1.35 ml, 4.05 mmol) at 15°C in a nitrogen atmosphere. The mixture was stirred at 15°C for 1 hour. The mixture was cooled at 0°C, diluted with water (5 ml), extracted with EtOAc (2x5 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified

- 92 043752 by preparative TLC on silica gel with 25% EtOAc in petroleum ether as eluent to obtain 4-(4-bromo-1H-pyrazol-1-yl)-2-methylbutan-2-ol. LCMS (C ₈ H ₁₃ BrN ₂ O) (ES, m/z) [M+H]+: 233,

235.

Intermediate 154: 4-bromo-1-((racemic, anti)-3-((rac-tetrahydro-2H-pyran-2yl)oxy)butan-2-yl)-1H-pyrazole

Intermediate 154

Intermediate 129

To a solution of intermediate 129 (9.40 g, 42.9 mmol) in DCM (100 ml) was added 3,4dihydro-2H-pyran (19.6 ml, 215 mmol) and PPTS (10.8 g, 42.9 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM (15 ml), washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to give rac-4-bromo-1-((2S,3R)-3-((tetrahydro-2Hpyran-2-yl)oxy)butane -2-yl)-1H-pyrazole. LCMS (C ₁₂ H ₁₉ BrN ₂ O ₂ ) (ES, m/z) [M+H] ⁺ : 303, 305.

The intermediate in the following table. 19 was prepared from the corresponding starting materials in a manner similar to that described for the synthesis of intermediate 154.

Table 19

Intermediate connection Structure Observ. nt/z [M + N] ⁺ Name 155 22? ^h about JQn Br^ ⁷ 303, 305 /ha/-4-bromo-1 -(2-methyl-1 -((tstrahydro-2R-pyran-2yl)oxy)propan-2-yl)-1 /7-pyrazole

Intermediate 156: rac-3-(4-amino-1H-pyrazol-1-yl)-3-methylbutan-2-ol

Intermediate Intermediate 151 connection 156

A 100 mL round bottom flask was filled with 10% Pd/C (200 mg, 0.188 mmol), 3-methyl-3-(4nitro-1H-pyrazol-1-yl)butan-2-ol (intermediate 151) (750 mg, 3.76 mmol) and EtOH (31.4 ml). The mixture was degassed by pumping and refilling with nitrogen three times. The mixture was then pumped out and refilled with hydrogen from a cylinder. The mixture was stirred for 3 hours. The mixture was filtered through celite and the solvents of the filtrate were evaporated to give 3-(4-amino-1H-pyrazol-1-yl)-3methylbutan-2-ol. LCMS (C ₈ H ₁₅ N ₃ O) (ES, m/z) [M+H] ⁺ : 170.

Intermediates in the following table. 20 was prepared from the corresponding nitropyrazole in a manner similar to that described for the preparation of intermediate 156.

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Table 20

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 157 / P o ^c XnH XX h ₂ n 255 tert-butyl(1-(4-amino-177-pyrazol-1-yl)-2-methylpropan-2yl)carbamate 158 but HO'X% H ₂ N 2-(4-amino-177-pyrazol-1-yl)-2-methylpropan-1,3-diol 159 ^but ^pOH rN H ₂ N 172 rac-3-(4-amino-177-pyrazol-1-yl)-2-methylpropan-1,2-diol 160 _th he (+/-) * XX Η ₂ Ν 156 racemic, syn-3-(4-amino-177-pyrazol-1-yl)butan-2-ol 161 t XX ^N H ₂ N 238 rac-1 -((1 -((tetrahydro-277-pyran-2- yl)oxy)cyclopropyl)methyl)-177-pyr azol-4-amine 162 Ph y-O J) y η ₂ ν 274 1 -((5 -methyl-2-phenyl-1,3-dioxan-5 -yl)methyl)- 177-pyrazol-4amine

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Intermediate 165: tert-butyl(1-(4-((28.5 R and 2K.58)-5-(hydrazinecarbonyl)-2methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2- methylpropan-2-yl)carbamate

Intermediate 165

Step 1: methyl(3K,68 and 3S,6R)-1-(1-(2-((tert-butoxy1<arbonyl)amino)-2-methylpropyl)-!Npyrazol-4-yl)-6-methylpiperidine -3-carboxylate.

Add tert-butyl (1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2yl)carbamate (intermediate 157) (85.0 mg, 0.334 mmol), triacetoxyborohydride, to a 20 mL vessel. sodium (106 mg, 0.501 mmol) and DCE (1.5 ml). The mixture was stirred. Methyl 2-methylene-5-oxohexanoate (0.063 mL, 0.40 mmol) was added to the mixture. After 20 min, 1 M aqueous KOH (3 ml), water (3 ml) and DCM (3 ml) were added to the mixture. The organic layer was collected with a phase separator. The solvents were evaporated. The resulting residue was dissolved in MeOH (1 ml) and water (0.4 ml). The mixture was stirred at room temperature for 72 hours. Water (20 ml) was added to the mixture. The mixture was extracted with DCM (2x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by chromatography on silica gel with 0-100% EtOAc in hexanes as eluent to obtain methyl(3K,68 and 3S,6K)-1-(1-(2-((tert-butoxycarbonyl)amino)2-methylpropyl )-1H-pyrazol-4-yl)-6-methylpiperidine-3-carboxylate. LCMS (C20H34N4O4) (ES, m/z) [M+H] ⁺ : 395.

Step 2: tert-butyl(1-(4-((28.5R and 2K.58)-5-(hydrazinecarbonyl)-2-methylpiperidin-1-yl)-1Hpyrazol-1-yl)-2-methylpropan-2 -yl)carbamate.

Methyl (3R,6S and 38.6K)-1-(1-(2-((tert-butoxycarbonyl)amino)-2methylpropyl)-1H-pyrazol-4-yl)-6-methylpiperidin- 3-carboxylate (99.1 mg, 0.251 mmol), EtOH (1 ml) and hydrazine hydrate (0.175 ml, 3.77 mmol). The mixture was heated at 90°C for 16 hours. The solvents were evaporated to give tert-butyl(1-(4-((28.5R and 2K.58)-5-(hydrazinecarbonyl)-2-methylpiperidin-1-yl)1 N-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate. LCMS (С1 ₉ Нз ₄ М ₆ 0з) (ES, m/z) [М+Н] ⁺ : 395.

Intermediates in the following table. 21 was prepared from the corresponding aminopyrazole in a manner similar to that described for the preparation of intermediate 165.

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Table 21

Intermediate connection Structure Observ. m/z [M + N] ⁺ Name 166 but^^ ^he NN V h ₂ n' ^nh 312 1-(1-(1,3-dihydroxy-2-methylpropan-2-yl)-177-pyrazol- 4-yl)-6-methylpiperidin-3-carbazide 167 he A BUT - Ιχ/L^O η ₂ ν' ^ΝΗ 312 1-(1 -(2,3-dihydroxy-2-methylpropyl)-\H-pyrazol-4-yl)- 6-Methylpiperidine-3-carbazide 168 °—\/ Ph—( / .. ξ-Ν η ₂ ν' ^νη 414 6-methyl-1 -(1 -((5 -methyl-2-phenyl-1,3-dioxane-5 - yl)methyl)-17/-pyrazol-4-yl)piperidine-3-carbazide 169 OTNR Ν Υ \.Ν. η ₂ ν' ^νη 378 6-methyl-1-(1-((1 -((tetrahydro-277-pyran-2yl)oxy)cyclopropyl)methyl)-177-pyrazol-4yl)piperidin-3-carbazide 170 HN-N V 224

(3R,6S and 3S, <57?)-6-methyl-1-(177-pyrazol-4-yl)piperidine3-carbazide

Intermediate 171: 1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5methylpiperidin-3-carbazide

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Step 1: Methyl 4-methyl-2-methylene-5-oxopentanoate.

A solution of methyl 2-(bromomethyl)acrylate (6.04 mL, 50.3 mmol) and DMAP (6.76 g, 55.3 mmol) in DCM (201 mL) was stirred at room temperature for 30 min. Propionaldehyde (5.41 mL, 75 mmol) and L-proline (5.79 g, 50.3 mmol) were added to the mixture. The mixture was stirred at 23°C for 48 hours. The mixture was washed with water (200 ml), 1 M aqueous HCl (100 ml) and brine (100 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-2.5% MeOH in DCM as eluent to give methyl 4-methyl-2-methylene-5-oxopentanoate.

Step 2: methyl(3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5methylpiperidin-3-carboxylate.

1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 163) (1.43 g, 8.45 mmol) was dissolved in MeOH (25.6 ml). Sodium triacetoxyborohydride (6.51 g, 30.7 mmol) was added to the mixture, followed by methyl 4-methyl-2-methylene-5-oxopentanoate (1.20 mL, 7.68 mmol). The mixture was stirred for 5 minutes (until sodium triacetoxyborohydride went into solution). The mixture was quenched with 1 M aqueous sodium hydroxide (30.7 mL, 30.7 mmol) and left stirring for 48 hours. MeOH was evaporated and DCM (30 mL) was added to the mixture. The layers were separated and the DCM layer was dried with anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-10% MeOH in DCM to give methyl(3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1Hpyrazol-4- yl)-5-methylpiperidine-3-carboxylate. LCMS (C ₁₆ H ₂₇ N ₃ O ₃ ) (ES, m/z) [M+H]+: 310.

Step 3: mixture of methyl(3S,5R and 3R,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)5-methylpiperidin-3-carboxylate and methyl(3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1Hpyrazol-4-yl)-5-methylpiperidin-3-carboxylate.

Methyl(3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5methylpiperidin-3-carboxylate (1.39 g, 4.49 mmol) was stirred in MeOH (35.9 ml) with potassium tert-butoxide (1.01 g, 8.98 mmol) for 18 h at 60°C. The mixture was cooled to room temperature and the solvents were evaporated. The resulting residue was dissolved in DCM and quenched with saturated aqueous NH ₄ Cl. The layers were separated using a Biotage Isolute® phase separator and the DCM layer was concentrated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM to give a mixture of methyl(3S,5R and 3R,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H- pyrazol-4-yl)-5methylpiperidin-3-carboxylate and methyl(3R,5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1Hpyrazol-4-yl)- 5-methylpiperidine-3-carboxylate. LCMS (C ₁₆ H ₂₇ N ₃ O ₃ ) (ES, m/z) [M+H] ⁺ : 310.

Step 4: (3R,5S and 3S,5R)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)-5methylpiperidin-3-carbazide and (3R, 5R and 3S,5S)-1-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4yl)-5-methylpiperidine-3-carbazide.

To a solution of the product from Step 3 (1.18 g, 3.81 mmol) in ethanol (15.3 mL) was added hydrazine hydrate (1.87 mL, 38.1 mmol). The mixture was stirred and heated at 80°C for 16 hours. The mixture was cooled to room temperature and the solvents were evaporated to give (3R,5S and 3S,5R)-1-(1-(2-hydroxy-2methylpropyl)-5-methyl- 1H-pyrazol-4-yl)-5-methylpiperidin-3-carbazide and (3R,5R and 3S,5S)-1-(1-(2hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4- yl)-5-methylpiperidine-3-carbazide, LCMS (C ₁₅ H ₂₇ N ₅ O ₂ ) (ES, m/z) [M+H] ⁺ : 310.

Intermediate 172 and Intermediate 173: N-(2,4-dimethoxybenzyl)-9fluoro-8-methoxy-2-((3R,5S and 3S,5R)-5-methylpiperidin-3-yl)-[1,2 ,4]triazolo[1,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,5S and 3R,5R)-5- methylpiperidin-3-yl)-

[1,2,4]triazolo[1,5-c]quinazolin-5-amine

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N-(2,4-dimethoxybenzyl)-9-fluoro-8-memoxy-2-(5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5c]quinazolin-5-amine (intermediate compound 85) (2.52 g, 5.24 mmol) was subjected to chiral SFC separation (Phenomenex Lux-3 21x250 mm column with 20% MeOH (with 0.1% NH4OH) as co-solvent) to give rac-N-(2 ,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,5S)-5-methylpiperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazolin-5- amine (combination of peaks 2 and 3) and rac-N-(2,4-dimethoxybenzyl)-9fluoro-8-methoxy-2-((3S,5S)-5-methylpiperidin-3-yl)-[1,2, 4]triazolo[1,5-c]quinazolin-5-amine (combination of peaks 1 and 4). LCMS (C ₂₅ H ₂₉ FN6O ₃ ) (ES, m/z) [M+H]+: 481.

Intermediate 174 and Intermediate 175: N-(2,4-dimethoxybenzyl)-7.9difluoro-2-((3R,5S and 3S,5R)-5-methylpiperidin-3-yl)-[1,2,4] triazolo[1,5-c]quinazolin-5-amine and N-(2,4dimethoxybenzyl)-7,9-difluoro-2-((3S,5S and 3R,5R)-5-methylpiperidin-3-yl) -[1,2,4]triazolo[1,5c]quinazolin-5-amine

connection 174 connection 175

Step 1: tert-butyl(3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-carboxylate and tert-butyl(3S,5S and 3R,5R)-3(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro -[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1carboxylate.

Add tert-butyl 3-(hydrazinecarbonyl)-5methylpiperidine-1-carboxylate (intermediate 56) (1.56 g, 6.07 mmol), 1,4-dioxane (20 mL) and acetic acid to a 100 mL round bottom flask. acid (0.174 ml, 3.04 mmol). The mixture was stirred. To this stirred mixture was added 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-3,5-difluorobenzonitrile (intermediate 41) (2.00 g, 6.07 mmol). The mixture was stirred at 75°C for 16 hours. The mixture was obtained by chromatography on silica gel with 0-50% EtOAc in hexanes as eluent to give tert-butyl(3R,5S and 3S,5R)-3-(5-((2, 4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-5-methylpiperidine-1-carboxylate (first elution) and tert-butyl(3S ,5S and 3R,5R)-3-(5-((2,4dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 5-methylpiperidine-1carboxylate (second elution). LCMS (C ₂₉ H ₃₄ F ₂ N ₆ O ₄ ) (ES, m/z) [M+H] ⁺ : 569.

Step 2: N-(2,4-dimethoxybenzyl)-7,9-difluor-2-((3R,5S and 3S,5R)-5-methylpiperidin-3-yl)[1,2,4]triazolo[1,5 -c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-7.9-difluoro-2-((3S,5S and 3R,5R)-5methylpiperidin-3-yl)-[1,2,4] triazolo[1,5-c]quinazolin-5-amine.

tert-Butyl(3R,5S and 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro[1,2,4]triazolo[1,5c]quinazolin- 2-yl)-5-methylpiperidine-1-carboxylate and tert-butyl(3S,5S and 3R,5R)-3-(5-((2,4dimethoxybenzyl)amino)-7,9-difluoro-[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidine-1carboxylate from step 1 was converted to N-(2,4-dimethoxybenzyl)-7,9-difluoro-2-((3R, 5S and 3S,5R)-5methylpiperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 174) and N(2,4-dimethoxybenzyl)-7 ,9-difluoro-2-((3S,5S and 3R,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5c]quinazolin-5-amine (intermediate 175) (LCMS (C24H26F2N6O2) (ES, m/z) [M+H] ⁺ : 469) with formic acid in a manner similar to the synthesis of intermediate 82.

Intermediates in the following table. 22 was prepared in a manner similar to that described for the synthesis of intermediate 174 from the corresponding hydrazide and carbodiimide.

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Table 22

Intermediate connection Structure Observ. w/-|M + N| Name 176 N.H. (+/-) cis F 481 A-(2,4-dimethoxybenzyl)-9-fluoro-7-methoxy-2-((ZL,55' and 3S,5R)-5-methylpiperidin-3-yl)-[1,2,4]triazolo[1,5c]quinazolin-5-amine 177 ⁿ Q % (+/-) cis F 547 A-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((ZL,65' and 3S, 6/?)-6-mestil-1 -(1 R-pyrazol-4-yl)pipsridin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine

Intermediate 178: (R)-8-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)-9-fluoro-2(piperidin-3-yl)-[1,2,4]triazolo[1,5 - c]quinazoline-5-amine.

Step 1: 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile

To a mixture of 2-bromo-5-(difluoromethoxy)-4-fluoroaniline (1.40 g, 5.47 mmol) and zinc cyanide (1.28 g, 10.9 mmol) in NMP (4 ml) was added bis(tri -tert-butylphosphine)palladium (0) (0.699 g, 1.37 mmol). The mixture was stirred and heated at 160°C under nitrogen atmosphere for 1 hour in a microwave reactor. The mixture was cooled to room temperature. Brine (60 ml) was added to the mixture and the mixture was extracted with petroleum ether:ethyl acetate (3:1) (3x25 ml), the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 25% EtOAc in petroleum ether to give 2-amino-4(difluoromethoxy)-5-fluorobenzonitrile.

Step 2: Methyl(2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate

A solution of 2-amino-4-(difluoromethoxy)-5-fluorobenzonitrile (500 mg, 2.47 mmol) in methyl chloroformate (3.04 g, 32.2 mmol) was stirred and heated at 75 °C under nitrogen for 15 h The mixture was cooled, diluted with water (10 ml), extracted with EtOAc (3x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography to give methyl (2-cyano-5-(difluoromethoxy)-4-fluorophenyl)carbamate.

Step 3: (R)-tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin2-yl)piperidin-1 -carboxylate

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(R)-tert-Butyl-3-(hydrazinecarbonyl)piperidine-1- carboxylate (411 mg, 1.691 mmol) (intermediate 54). The mixture was stirred and heated at 170°C for 30 minutes. The mixture was cooled, diluted with water (30 ml) and extracted with EtOAc (3x 30 ml). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in hexanes as eluent to give (R)-tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2, 4]triazolo[1,5c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C ₂₀ H ₂₂ F ₃ N ₅ O ₄ ) (ES, m/z) [M+H]+: 454.

Step 4: tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-

[ 1,2,4]tr iazolo[1,5-c]quinazolin-2-yl)piperidin-1-carboxylate he NHDMB

To a solution of tert-butyl-3-(8-(difluoromethoxy)-9-fluoro-5-hydroxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidine-1-carboxylate (1, 00 g, 2.21 mmol) in MeCN (10 ml) was added DBU (0.831 ml, 5.51 mmol), PyBroP (1.34 g, 2.87 mmol) and (2,4-dimethoxyphenyl)methanamine (0.553 g , 3.31 mmol) at 90°C in a nitrogen atmosphere. The mixture was stirred at 90°C for 12 hours. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-50% EtOAc in hexanes as eluent to give tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro-

[1,2,4]tri azolo[1,5-c]quinazolin-2-yl)piperidine-1-carboxylate. LCMS (C ₂₉ H ₃₃ F ₃ N ₆ O ₅ ) (ES, m/z) [M+H]+: 603.

Step 5: (R)-8-(difluoromethoxy)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(piperidin-3-yl)-

[1,2,4]tr iazolo[1,5-c]quinazolin-5-amine

NHDMB NHDMB

Intermediate 178

To a solution of tert-butyl-3-(8-(difluoromethoxy)-5-((2,4-dimethoxybenzyl)amino)-9-fluoro[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidine-1-carboxylate (700 mg, 1.16 mmol) in DCM (7 ml) was added TFA (0.7 ml) at 15°C under nitrogen atmosphere. The mixture was stirred at 15°C for 2 hours. The mixture was cooled, diluted with NaHCO ₃ (15 ml), extracted with DCM (3x20 ml), dried over anhydrous Na ₂ SO ₄ and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 050% EtOAc in petroleum ether as eluent to give (R)-8-(difluoromethoxy)-N-(2,4dimethoxybenzyl)-9-fluoro-2-(piperidin-3-yl) -[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C24H25F3N6O3) (ES, m/z) [M+H]+: 503.

Example 1: (R)-1-(3-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine1 -yl)-1H-1,2,4-triazol-1 -yl)-2-methylpropan-2-ol

Intermediate 82

A 5 ml microwave irradiation vessel was filled with (R)-N-(2,4-dimethoxybenzyl)-9fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4]triazolo[1,5 -c]quinazoline-5-amine (intermediate 82) (100 mg, 0.214 mmol), tBuXPhos-Pd G3 (68.1 mg, 0.086 mmol) and sodium tert-butoxide (82 mg, 0.86 mmol). To the mixture was added 1-(3-bromo-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol (intermediate 2) (94 mg, 0.429 mmol) in THF (1.4 ml). The mixture was sprayed with nitrogen for 10 minutes. Mixture

- 100 043752 was stirred and heated at 90°C for 16 hours. The mixture was cooled to room temperature, the solids were removed by filtration and washed with DCM. The solvents in the filtrate were evaporated. TFA (0.5 ml) was added to the resulting residue. The mixture was stirred and heated at 50°C for 3 hours. The mixture was cooled to room temperature and the solvents were evaporated. The residue was purified by reverse phase preparative HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm MeCN/H ₂ O with 0.1% TFA as eluent) to give (R)-1-(3-(3-(5 -amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1 -yl)-1H-1,2,4-triazol-1 - yl)-2-methylpropan-2-ol.

LCMS (C21H26FN9O2) (ES, m/z): 458 [M+H]+. 1H NMR (499 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.89 (d, J=10.9 Hz, 1H), 7.81 (s, 2H), 7.19 (d , J=7.9 Hz, 1H), 4.31 (d, J=12.8 Hz, 1H), 3.97 (s, 4H), 3.91 (s, 2H), 3.15 (ddt , J=10.9, 6.7, 3.4 Hz, 1H), 3.11-3.04 (m, 1H), 2.86 (td, J=12.5, 2.7 Hz, 1H ), 2.23 (d, J=12.1 Hz, 1H), 1.92 - 1.77 (m, 2H), 1.75 - 1.63 (m, 1H), 1.10 (d, J=2.4 Hz, 6H).

Compounds of examples of the present invention in the following table. 15 was prepared in a manner similar to that described in Example 1 from the corresponding starting aryl halide and amine intermediates.

Table 15

Example Structure Observ. m/z [M + N] ⁺ Name 2 \ l Ύ / 397 (L)-9-fluoro-8-methoxy-2-(1 -(1 -methyl-1 R-pyrazol-4-yl) piperid in3 -yl)-[1,2,4]triazolo[1,5 - c]quinazo lin-5-amine 3 Yes c=( nh ₂ / ^N— <__/K'N^N Ά F 439 (L)-2-(1-(1-(tert-butyl)-1R-pyrazol-4-yl)piperidin-3-yl)-9fluoro-8-methoxy-[1,2,4]triazolo[1, 5-c]quinazoline-5-amine 4 Al \==/ nh ₂ / ^N— g__ Ά F 425 (Λ)-9-φτορ-2-(1-(1-isopropyl-1R-pyrazol-4-yl)piperidin-3-yl)- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 5 A-A \=/ nh ₂ F 465 (L)-9-fluoro-8-methoxy-2-( 1 -(1 -(2,2,2-trifluoroethyl)-1R-pyrazol-4yl)piperidin-3-yl)-[1,2,4] triazolo[1,5-c]quinazolin-5-amine 6 / ^z G /g g O \ 398 (D)-9-fluoro-8-methoxy-2-( 1 -(1 -methyl-1H-1,2,3-triazol-4-

- 101 043752

yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 7 BUT m ν- n^ _n A _n % F 455 (L)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl) -1R-pyrazol-1-yl)-2methylpropan-2-ol 8 ^Н0 N TU Г' _Ν _ Ν- _Ν Λ _Ν f F 469 (L)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl) -5-methyl-1R-pyrazol-1-yl)-2methylpropan-2-ol 9 ^Ch o 1 469 (7?)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )-3-methyl-1R-pyrazol-1-yl)-2methylpropan-2-ol 10 I N'\ nh ₂ , ^N— _λ ^Ν Άν F 467 (I)-1-((4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )- 1R-pyrazol-1 yl)methyl)cyclobutane-1 -o l

- 102 043752

eleven I o k kk o \ 469 (7?)-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )-3-methyl-1R-pyrazol-1-yl)-2methylpropan-1-ol 12 >A _N ' ^N <s but | \=/ NH ₂ -Χν (from intermediate 26) p 469 (S or L)-3-(4-((L)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1-Pyrazol-1-yl)-2-methylbutan-2-ol 13 Χ^ν'% but | \==/ νη ₂ / ^Ν Α ° Ά (from intermediate 27) 469 {R or 5)-3-(4-((D)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1-Pyrazol-1-yl)-2-methylbutan-2-ol 14 urn O nh ₂ / ^Ν Α // ^Ν Άν F 467 (15.35)-3-(4-((L)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl) piperidin-1-yl)-1R-pyrazol-1-yl)-1 methylcyclobutan-1-ol

- 103 043752

15 Λ nh ₂ , ^N— g Λ ^Ν 'Ν^Ν % F 467 (L)-9-fluoro-8-methoxy-2-( 1-(1 -((3-methyloxetan-3-yl)methyl)- 1-Pyrazol-4-yl)piperidin-3-yl) -[1,2 ,4]triazolo [1,5-c]quinazo lin-5 amine 16 Q N'V nh ₂ / ^N— g /Ζ ^Ν ΆΝ Ά F 481 (L)-9-fluoro-8-methoxy-2-( 1 -(5 -methyl-1 -(tetratidro-2R-pyran-4yl)-1R-pyrazol-4-yl)piperidin-3-yl)-[ 1,2,4]triazolo[1,5 c]quinazolin-5-amine 17 o l Ll T ² / ^Ν- Ι // ^Ν 'Ν^Ν Ά F 481 (L)-9-fluoro-8-methoxy-2-( 1 -(3 -methyl-1 -(tetrahydro-2H-pyran-4yl)-1H-pyrazol-4-yl)piperidin-3-yl)-[ 1,2,4]triazolo[1,5 c]quinazolin-5-amine 18 O ^/ % chAl )=/ NH ₂ ^F A / ^Ν ^ /ζ ^ν Άν F 517 (Λ)-2-( 1 -(5 -(difluoromethyl)-1 -(tstrahydro-2R-pyran-4-yl)- 1Hpyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy - [1,2,4]triazolo[1,5-c]quinazolin-5-amine

- 104 043752

19 F <An'V< F NH ₂ / ^N A °-Х F 517 (77)-2-(1 -(3 -(difluoromethyl)-1 -(tetrahydro-2R-pyran-4-yl)-1Hpyrazol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy - [1,2,4]triazolo[1,5-c]quinazolin-5-amine 20 λ NH, ^H0 ~O-O0 ^Ν ιό ψΌ F 441 (77)-(4-(3 -(5 -amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl)-1 -ethyl-1 R-pyrazol-3 yl)methanol 21 X ^ΝΗ * V Ν—<Ν~ _ν Α _ν ^νΛ 0. F 495 (7?)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )-3-cyclopropyl-1 R-pyrazole-1 - yl)-2-methylpropan-2-ol 22 όχ ^F ъ nh ₂ / ^Ν Α Λν^ν 460 (D)-2-(1-(6-(difluoromethoxy)pyridin-3-yl)piperidin-3-yl)-9fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -5-amine

- 105 043752

23 A -O 452 (A)-9-fluoro-2-(1-(6-isopropoxypyridin-3-yl)piperidin-3-yl)-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5 - amine 24 z £ Y ζ^ζ -O 474 (A)-2-(1-(6-(difluoromethoxy)-5-methylpyridin-3-yl)piperidin-3yl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5- c]quinazoline-5-amine 25 F \=( NH ₂ , ^N— H__ Ά F 474 (R)-5 -(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1-yl)-1 - (difluoromethyl)-3 methylpyridin-2(1 R)-one 26 A A J Ο Z 1 424 (A)-9-fluoro-8-methoxy-2-(1 -(6-methoxypyridin-3-yl)piperidin-3 yl)-[1,2,4]triazolo[1,5-c]quinazolin-5 -amine 27 but | nh ₂ / ^N A // ^N 'N^n °Ά 470

- 106 043752

(7?)-1-(3-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )-5 -methyl-III-1,2,4-triazole-1 - yl)-2-methylpropan-2-ol 28 / O 455 (7?)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )-177-pyrazol-1-yl)-2methylpropan-2-ol 29 OH ⁿ ' ⁿ v^ \L_y nh ₂ / ^N— F 469 (7?)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )-5-methyl-177-pyrazol-1-yl)-2methylpropan-2-ol thirty ^ОН Λ ΝΗ ₂ / ^n- W' ⁿ ^ ⁿ ^А^ф^ F 469 (R)-1 -(4-(3 -(5 -amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl) -3-methyl-177-pyrazol-1-yl)-2methylpropan-2-ol 31 I nh ₂ F 467

- 107 043752

(R)-1 -((4-(3-(5 -amino-9-fluoro-7-methoxy-[1,2,4]triazolo [1,5c]quinazolin-2-yl)piperidin-1 -yl )-1 R-pyrazol-1 yl)methyl)cyclobutan-1-ol 32 \==/ νη ₂ / ^N A Λν^ν oluu.. F 455 (Λ)-2-(4-(3 -(5 -amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl) - 1R-pyrazol-1-yl)-2methylpropan-1-ol 33 £ T O / 460 (Λ)-2-( 1 -(b-(difluoromethoxy)pyridin-3-yl)piperidin-3-yl)-9fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazo lin-5-amine 34 / ^Z C ^Z Λ J ο z 1 424 (Λ)-9-φτορ-7-methoxy-2-(1 -(6-methoxypyridin-3-yl)piperidin-3 yl)-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine 35 νη ₂ F 452 (Λ)-9-φτορ-2-( 1 -(6-isopropoxypyridin-3 -yl)piperidin-3 -yl)-7 methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5 -amine

- 108 043752

36 I \° ςΝ z^z at And—and y—o yu O / 456 (R)-1 -(3-(3 -(5 -amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl) - 1H-1,2,4-triazol-1-yl)-2methylpropan-2-ol 37 ^but ^ WN У nh ₂ z ^N A // ^N 'n^n F 470 (R)-1 -(3-(3 -(5 -amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl) -5 -methyl-1H-1,2,4-triazole-1 - yl)-2-methylpropan-2-ol 38 CV ^0H N D G ² F 453 (D)-1-((4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)pyrrolidin-1 -yl ) -1 R-pyrazol-1 yl)methyl)cyclobutan-1-ol 39 —^on N'N Q nh ₂ F 469 rac-1 -(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)azepan-1-yl)-1R -pyrazol-1-yl)-2-methylpropan2-ol

Example 40: 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)methyl)cyclobutan-1 -ol.

Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1-((( RS)tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1 H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazoline -5-amine

To a reaction vessel containing a solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2((3R,6S or 3S,6R)-6-methylpiperidin-3-yl)-[1,2, 4]triazolo[1,5-c]quinazolin-5-amine (intermediate 95) (600 mg, 1.25 mmol) in THF (12 ml), add rac-4-bromo-1-((1-( (tetrahydro-2H-pyran-2yl)oxy)cyclobutyl)methyl)-1H-pyrazole (intermediate 23) (590 mg, 1.87 mmol) followed by tBuXPhos-Pd G3 (298 mg, 0.375 mmol) and tert- sodium butoxide (420 mg, 4.37 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The mixture was stirred and heated at 90°C for 4 hours. The mixture was cooled

- 109 043752 to room temperature. Additional tBuXPhos-Pd G3 (149 mg, 0.188 mmol) was added to the mixture, followed by sodium tert-butoxide (210 mg, 2.19 mmol). Nitrogen was bubbled through the mixture for an additional 10 minutes. The mixture was stirred and heated at 90°C for 18 hours. The mixture was cooled to room temperature and then the solvents were evaporated. The residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and the solids were removed by filtration. The filtrate was concentrated. The resulting residue was purified by chromatography on silica gel with 0-40% EtOAc:EtOH (3:1) in hexane as eluent. The resulting residue was further purified by preparative TLC on silica gel with 4% MeOH in DCM as eluent to give N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R) -6-methyl-1-(1-((1(((RS)-tetrahydro-2H-niran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl) [1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C ₃₈ H ₄₇ FN ₈ O ₅ ) (ES, m/z): 715 [M+H]+.

Step 2: 1-((4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triαzolo[1,5-c] quinazolin-2yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)methyl)cyclobutan-1 -ol

N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3 S,6R)-6-methyl-1-(1 -((1 -( ((RS)-tetraαhydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1 H-pyrazol-4yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c ]quinazoline-5-amine (1.40 g, 2.22 mmol) and TFA (1.65 ml, 22.2 mmol). The mixture was stirred and heated at 60°C for 1 hour. The mixture was cooled to room temperature and then the solvents were evaporated. The residue was purified by silica gel chromatography with 6% (7 M ammonia in MeOH) in DCM as eluent to give 1-((4-((2S,5R or 2R,5S)-5(5-amino-9-fluoro -8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-III-pyrazol1-yl)methyl)cyclobutan-1-ol ( example 40). LCMS (C24H29FN8O2) (ES, m/z): 481 [M+H]+. 1H NMR (500

MHz, methanol^) δ 7.87 (d, J=10.9 Hz, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 7.15 (d, J=7, 6 Hz, 1H), 4.14 (s, 2H), 3.99 (s, 3H), 3.73 (d, J=4.9 Hz, 1H), 3.47 (d, J=9, 2 Hz, 1H), 3.36 - 3.20 (m, 3H), 2.11 (d, J=7.9 Hz, 3H), 2.02 (p, J=10.7, 9.6 Hz, 2H), 1.89-1.69 (t, 2H), 1.55 (dq, J=19.0, 9.6 Hz, 1H), 1.37-1.20 (m, 2H) , 1.12 (d, J=6.6 Hz, 3H), 0.96-0.82 (m, 2H).

Compounds of examples of the present invention in the following table. 16 was prepared in a manner similar to that described for the preparation of Example 40, from the corresponding starting aryl halide and intermediate 95.

Table 16

Example

Structure

Name

1-(4-((25.5Λ or 2L.55)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2-methylpiperidin-1 -yl)5-methyl- I R-pyrazol-1 -yl)-2-methylpropan-2-ol

1-(4-((25.5Λ or 2L.55)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-2-methylpiperidin-1 -yl)3-methyl- I R-pyrazol-1 -yl)-2-methylpropan-2-ol

Observ. m/z

- 110 043752

43 \L-OH N' ^N \nh ₂ _Α^'ιΛν cis F 497 3-(4-((25.5R or 2L.55)-5-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)1 R-pyrazol-1 -yl)-2,3-dimethylbutan-2-ol 44 \ , ^: th 481 9-fluoro-8-methoxy-2-((3L,65 or 38.6R)-6-methyl-1-(1- (tstrahydro-2R-pyran-4-yl)-1R-pyrazol-4-yl)pipsridin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 45 1 ύ 495 9-fluoro-8-methoxy-2-((37?.65 or 38.6A)-6-methyl-1-(5-methyl-1- (tstrahydro-2R-pyran-4-yl)-1R-pyrazol-4-yl)pipsridin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 46 0 τι—е у—z m ABOUT \ 495 9-fluoro-8-methoxy-2-((37?.65 or 38.6A)-6-methyl-1-(3-methyl-1- (tstrahydro-2R-pyran-4-yl)-1R-pyrazol-4-yl)pipsridin-3-yl)- [1,2,4]triazolo[1,5-c]quinazolin-5-amine 47 V N'% nh ₂ _/ ^N A « z+n^N ' cis F 499 9-fluoro-2-((3.65 or 38.6A)-1-(1-((3-(fluoromethyl)oxetan-3yl)methyl)-1R-pyrazol-4-yl)-6-methylpiperidin-3 -yl)-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

Example 48 and Example 49: (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo [1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylbutan-2-ol and (S or R)-3-( 4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 2methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylbutan-2-ol.

Step 1: (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1 ,2,4]triazolo [1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylbutan-2-ol

- 111 043752 o

Step 1 of the synthesis of Example 48 and Example 49 was carried out with Intermediate 95 and Intermediate 1 in a manner similar to that described in Step 1 of Example 40. The resulting diastereomeric mixture was prepared by SFC (Chiral Technologies AD-H 21x250 mm column with 55% ( IPA + 0.2% DIPA) as co-solvent), yielding peak 1 and peak 2, corresponding to (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5- ((2,4-dimethoxybenzyl)amino)-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H- pyrazol-1-yl)-2-methylbutan2-ol and (S or R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4-dimethoxybenzyl)amino) -9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2- methylbutan-2-ol. For peak 1, LCMS (C ₃₃ H ₄₁ FN ₈ O ₄ ) (ES, m/z): 633 [M+H] ⁺ . For peak 2, LCMS (C ₃₃ P ₄₁ FN ₈ O ₄ ) (ES, m/z): 633 [M+H] ⁺ .

Step 2: (R or S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1 ,5c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S or R)-3-(4-((2S ,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)1 H-pyrazol-1 -yl)-2-methylbutan-2-ol

Example 48 F '0

Example 49F

Step 2 of the synthesis of the compound of Example 48 and the compound of Example 49 was carried out in a manner similar to that described in Step 2 of Example 40, where peak 1 was converted to (R or S)-3-(4-((2S,5R or 2R,5S)-5- (5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1yl)-2 -methylbutan-2-ol (compound of Example 48) and peak 2 were converted to (S or R)-3-(4-((2S,5R or 2R,5S)5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1Hpyrazol-1-yl)-2-methylbutan-2-ol (example compound 49).

For compound example 48: LCMS (C ₂₄ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 483 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform-d) δ 7.99 (d, J=10.7 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.01 (s, 1H), 5.74 (s, 2H), 4.14 (s, 1H), 4.02 (m, 1H), 4.00 (s, 3H), 3, 74 (m, 1H), 3.49 (s, 1H), 3.45 (dd, J=11.6, 3.8 Hz, 1H), 3.32 (dd, J=11.3, 4, 0 Hz, 1H), 3.20 (t, J=11.3 Hz, 1H), 2.18 - 2.00 (m, 3H), 1.78 (d, J=9.9 Hz, 1H), 1 .52 (d, J=6.9 Hz, 3H), 1.14 (s, 3H), 1.11 (d, J=6.7 Hz, 2H), 1.01 (s, 3H).

For compound example 49: LCMS (C ₂₄ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 483 [M+H] ⁺ . ¹ H NMR (400 MHz, chloro- 112 043752 form-d) δ 7.99 (d, J=10.8 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=7 .6 Hz, 1H), 7.01 (s, 1H), 5.78 (s, 2H), 4.18 (s, 1H),

4.03 (m, 1H), 4.00 (s, 4H), 3.74 (m, 1H), 3.49 (s, 1H), 3.44 (dd, J=11.6, 3 ,9 Hz, 1H), 3.33 (dd, J=11.0, 4.2 Hz,

1H), 3.21 (t, J=11.3 Hz, 1H), 2.18 - 2.00 (m, 3H), 1.78 (d, J=9.7 Hz, 1H), 1, 52 (d, J=6.9 Hz, 3H), 1.14 (s, 3H),

1.11(m, J=6.9 Hz, 3H), 1.02 (s, 3H).

Example 50 and Example 51: 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c ]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-3-methyl-1 H-pyrazol-1 -yl)methyl)cyclobutan-1 -ol and 1 -((4((2R,5S or 2S ,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2methylpiperidin-1 -yl)-5- methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol.

Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl-1((1 - (((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1 H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5 -c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(5-methyl -1 -((1 -(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1 H-pyrazol4-yl)piperidin-3-yl)-[1,2,4 ]triazolo[1,5-c]quinazolin-5-amine

N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methylpiperidin-3-yl)-[1,2,4 ]triazolo[1,5-c]quinazolin-5-amine (intermediate 96) (240 mg, 0.499 mmol, tBuXPhos-Pd G3 (119 mg, 0.150 mmol), rac-4-bromo-3-methyl-1- ((1-((tetrahydro-2Hpyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (intermediate 31) (329 mg, 0.999 mmol), sodium tert-butoxide (288 mg, 3.00 mmol) and THF (5 ml).The mixture was sprayed with nitrogen for 5 minutes. The mixture was stirred and heated at 100°C for 19 hours. The solvents were evaporated and the residue was purified by preparative TLC on silica gel with 4% (7 M ammonia in MeOH) in DCM as an eluent to obtain a mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl1 -(( 1 -(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1 H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1 ,5-c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(5 -methyl-1-((1-(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1H-pyrazol4-yl)piperidin-3-yl)-[1,2, 4]triazolo[1,5-c]quinazolin-5-amine.

Step 2: 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2yl)-2-methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol and 1-((4-((2R,5S or 2S,5R) -5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5methyl-1 H-pyrazol-1-yl)methyl)cyclobutan-1-ol

To a mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3S,6R or 3R,6S)-6-methyl-1-(3-methyl-1-((1( ((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1 H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5- c]quinazolin-5-amine and N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3 S,6R or 3 R,6S)-6-methyl-1 -(5- methyl-1 -((1 -(((RS)-tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)-1 H-pyrazole

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4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (12.0 mg, 0.0186 mmol) was added to TFA (2 ml). The mixture was stirred and heated at 60°C for 1 hour. The mixture was cooled to room temperature. The mixture was concentrated and the residue was purified by preparative TLC on silica gel with 4% (7 M ammonia in MeOH) in DCM as eluent, followed by reverse phase HPLC (Waters SunFire

C18 OBD preparative column, 19 mmx100 mm MeCN/water with 0.1% TFA modifier as eluent) to obtain 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-3-methyl-1 H-pyrazol-1 -yl)methyl) cyclobutan-1-ol (compound of Example 50) and 1-((4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5-methyl-1 H-pyrazol-1 -yl)methyl)cyclobutan-1-ol (compound of Example 51).

For compound example 50: LCMS (C ₂₅ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 495 [M+H]+. 1H NMR (500 MHz, meta nol-b ₄ ) δ 8.02 (s, 1H), 7.95 (d, J=10.8 Hz, 1H), 7.26 (d, J=7.7 Hz , 1H), 4.22 (s, 2H), 4.18 (d, J=12.9 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 2H), 3.74 (s, 1H), 3.57 - 3.43 (m, 1H), 2.46 (s, 3H), 2.36-2.26 (m, 1H), 2.22 - 2.12 (m , 3H), 2.04 (q, J=9.7 Hz, 3H), 1.84-1.73 (m, 1H), 1.68-1.58 (m, 1H), 1.27 ( d, J=6.5 Hz, 3H).

For compound example 51: LCMS (C ₂₅ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 495 [M+H] ⁺ . 1H NMR (500 MHz, methanol-d ₄ ) δ 7.98-7.91 (m, 1H), 7.82 (s, 1H), 7.26 (d, J=7.7 Hz, 1H) , 4.27 (s, 2H), 4.03 (s, 3H), 3.96 (d, J=11.8 Hz, 2H), 3.76 (d, J=20.2 Hz, 1H) , 2.61 (s, 2H), 2.45 (d, J=15.4 Hz, 2H), 2.40-2.29 (m, 2H), 2.26 (s, 1H), 2, 15 (d,J=10.4 Hz, 3H), 2.11-1.97 (m, 3H), 1.89-1.74 (m, 1H), 1.75-1.58 (m, 1H), 1.28 (d, J=6.6 Hz, 3H).

Compounds of examples of the present invention in the following table. 17 was prepared in a manner similar to that described for the compound of Example 50 and the compound of Example 51, from the corresponding starting aryl halide and intermediate 96.

Table 17

Observ. m/z

[M+H]

Example

Structure

Name

1-(4-((2Λ,55,

2\5l)-5-(5-amino-9-fluoro-8-methoxyor

[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-5 methyl-177-pyrazol-1-yl)-2-methylpropan-2- ol

1-(4-((2I,55,

2\5l)-5-(5-amino-9-fluoro-8-methoxyor

[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)-2-methylpropan-2- ol

Example 54: 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin2-yl)-5-fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)methyl)cyclobutan-1 -ol.

Step 1: N-2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2Hpyran-2- yl)oxy)cyclobutyl)methyl)-1 H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-5-amine

Intermediate 99

To a reaction vessel containing a solution of N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or

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3S,5R)-5-fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 99) (80.0 mg, 0.165 mmol) in THF (1.5 ml), 4-bromo-1-((1-((tetrahydro-2H-pyran-2yl)oxy)cyclobutyl)methyl)-1H-pyrazole (intermediate 23) (83, 0 mg, 0.260 mmol), followed by tBuXPhos-Pd G3 (39.3 mg, 0.0500 mmol) and sodium tert-butoxide (47.6 mg, 0.495 mmol). The mixture was washed with nitrogen for 10 minutes. The mixture was stirred and heated at 90°C for 2 hours. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-40% EtOAc:EtOH (3:1) in hexanes as eluent to give N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S ,5R)-5fluoro-1-(1-((1 -((tetrahydro-2H-pyran-2 -yl)oxy)cyclobutyl)methyl)-1 H-pyrazol-4-yl)piperidin-3 -yl)- 8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C ₃₇ H ₄₄ F ₂ N ₈ O ₅ ) (ES, m/z): 719 [M+H]+.

Step 2: 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2yl)-5 -fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)methyl)cyclobutan-1 -ol

A mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5-fluoro-1-(1-((1-((tetrahydro-2Hpyran-2-yl )oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-5-amine (105 mg, 0.146 mmol) in TFA (1.2 ml) was stirred and heated at 60°C for 1 hour. The mixture was concentrated. The residue was purified by preparative TLC on silica gel with 5% (7 M ammonia in MeOH) in DCM as eluent to give 1-((4-((3R,5S or 3S,5R)-3-(5-amino-9- fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1 H-pyrazol-1 yl)methyl)cyclobutan-1-ol . LCMS (C ₂₃ H ₂₆ F ₂ N ₈ O ₂ ) (ES, m/z): 485 [M+H] ⁺ . 1H NMR (400 MHz, chloroformd) δ 7.96 (d, J=10.7 Hz, 1H), 7.26 (s, 1H), 7.15 (t, J=3.8 Hz, 2H), 5.91 (s, 2H), 4.90 (dtt, J=48.1, 9.9, 4.7 Hz, 1H), 4.13 (s, 2H), 4.00 (s, 3H), 3.74 - 3.64 (m, 2H), 3.42 (d, J=12.6 Hz, 1H), 2.86 (t, J=11.4 Hz, 1H), 2.71 (dq, J= 10.3, 7.2, 5.2 Hz, 2H), 2.17-1.92 (m, 3H), 1.88-1.73 (m, 2H), 1.57 (dq, J= 18.2, 9.1 Hz, 2H).

Compounds of examples of the present invention in the following table. 18 was prepared in a manner similar to that described for the preparation of Example 54, from the corresponding starting aryl halide and intermediate 99.

Table 18

Example Structure Observ. m/z [M + H] ⁺ Name 55 y-A but I C=/ Ν- F* νη ₂ -γΝ-Ν^Ν nYYx cis to Η . About F 473 1-(4-((3^.55 or 35.5L)-3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)- 1R-pyrazole-1- yl)-2-methylpropan-2-ol 56 ¹ *ό nh ₂ γΥ'Ν'^Ν ^νΛ Α cis A A. / γ^ο F 485 9-φτορ-2-((3Λ.55 or 35.5L)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4- yl)-1R-pyrazol-4-yl)piperidin-3-yl)-8-methoxy- [1,2,4]triazolo[1,5-c]quinazo lin-5-amine

Example 57: 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-ol.

Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro2H-pyran-2 -yl)oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)- 115 043752

[1,2,4]triazolo[1,5-c]quinazolin-5-amine

To a reaction vessel containing a solution of 2-((1R,5R or 1S,5S)-3-α3αbicyclo[3,1,0]hexan-1yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 97) (60.0 mg, 0.129 mmol) in THF (1.5 mL), add 4-bromo- 1-((1-((tetrahydro-2H-pyran2-yl)oxy)cyclobutyl)methyl)-1H-pyrazole (intermediate 23) (61.1 mg, 0.194 mmol) followed by tBuXPhos-Pd G3 (30, 8 mg, 0.039 mmol) and sodium tert-butoxide (43.4 mg, 0.452 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The mixture was stirred and heated at 90°C for 18 hours. The mixture was cooled to room temperature. The solvents were evaporated and the resulting residue was purified by preparative TLC on silica gel with 5% MeOH in DCM as eluent to give N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S) -3-( 1 -((1 -((tetrahydro-2H-pyran-2yl)oxy)cyclobutyl)methyl)-III-pyrazol-4-yl)-3-azabicyclo[3,1,0]hexane-1- yl)-[1,2,4]triazolo[1,5

c]quinazoline-5-amine. LCMS (C ₃₇ H ₄₃ FN ₈ O ₅ ) (ES, m/z): 699 [M+H]+.

Step 2: 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1 H-pyrazol-1 -yl)methyl)cyclobutan-1-ol 2.2.2-trifluoroacetate

A mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((1R,5R or 1S,5S)-3-(1-((1-((tetrahydro-2Hpyran-2-yl )oxy)cyclobutyl)methyl)-1H-pyrazol-4-yl)-3-azabicyclo[3,1,0]hexan-1-yl)[1,2,4]triazolo[1,5-c]quinazolin- 5-amine (59 mg, 0.084 mmol) and TFA (1.0 ml) were stirred and heated at 60°C for 1 hour. The mixture was cooled to room temperature. The solvents were evaporated. The resulting residue was purified by preparative TLC on silica gel with 8% (7 M ammonia in MeOH) in DCM as eluent. The resulting residue was further purified by reverse phase preparative HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm MeCN/HgO with 0.1% TFA modifier as eluent) to obtain 1-((4-((1R,5R or 1S,5S)-1-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-azabicyclo[3,1,0] hexan-3-yl)-1H-pyrazol-1yl)methyl)cyclobutan-1-ol 2,2,2-trifluoroacetate). LCMS (C ₂₃ H ₂₅ FN ₈ O ₂ ) (ES, m/z): 465 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=10.0 Hz, 1H), 7.27 (s, 1H), 7.21 (s, 1H), 7.06 (s , 1H), 4.18 (s, 2H), 4.08 (s, 3H), 3.79 (d, J=8.6 Hz, 1H), 3.69 (d, J=8.7 Hz , 1H), 3.54 (d,J=8.6 Hz, 2H), 3.35 (s, 2H), 3.20 (dd, J=8.8, 3.8 Hz, 2H), 2 .32 (s, 1H), 2.13-2.04 (m, 3H), 1.75 (d, J=3.8 Hz, 2H), 1.58 (d, J=4.9 Hz, 1H).

The compound of example 58 in the following table. 19 was prepared in a manner similar to that described for the preparation of Example 57 from intermediate 97 and the corresponding starting aryl halide.

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Table 19

Example Structure Observ. m/z [M + N] ⁺ Name 58 1\ _νη2 453 1-(4-((1Λ.5Λ or 15.55)-1-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3 - azabicyclo[3,1,0]hexan-3-yl)-1 R-pyrazol-1-yl)-2- methylpropan-2-ol

Example 59: 9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4yl)piperidin-3 -yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine.

Step 1: N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran4-yl)-1H -pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

Intermediate connection 100

N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5fluoropiperidin-3-yl)-8-methoxy-[1,2,4]triazolo was added to the reaction vessel [ 1,5-c]quinazoline-5-amine (intermediate 1θθ) (50.0 mg, 0.103 mmol), tBuXPhos-Pd G3 (24.6 mg, 0.0310 mmol), 4-bromo-1-( tetrahydro-2H-pyran-4yl)-1H-pyrazole (intermediate 15) (23.9 mg, 0.103 mmol), sodium tert-butoxide (59.5 mg, 0.619 mmol) and THF (1 ml). The mixture was purged with nitrogen for 5 minutes. The mixture was stirred and heated at 100°C for 4 hours. The solvents were evaporated and the resulting residue was purified by silica gel chromatography with 0-100% (30% MeOH in EtOAc) in hexanes to give N-(2,4-dimethoxybenzyl)9- fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidin-3-yl) 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine.

Step 2: 9-fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4yl)piperidin-3 -yl)-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

To the reaction vessel containing N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3S,5R or 3R,5S)-5fluoro-1-(1-(tetrahydro-2H-pyran-4-yl) -1 H-pyrazol-4-yl)piperidin-3-yl)-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-5-amine (85.0 mg, 0.130 mmol), added TFA (2 ml). The mixture was stirred and heated at 60°C for 1 hour. The solvents were evaporated and the residue was purified by reverse phase preparative HPLC (Waters SunFire C18 OBD preparative column, 19 mmx100 mm McCN/H ₂ Q with 0.1% TFA modifier as eluent ) to give 9-(fluoro-2-((3S,5R or 3R,5S)-5-fluoro-1-(1(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)piperidine -3-yl)-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-5-amine LCMS (C23H26F2N8O2) (ES, m/z): 485 [M+H]+ 1H NMR (500 MHz, methanol^) δ 7.93 (d, J=10.7 Hz, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.23 (d, J =7.5 Hz, 1H), 4.95 (dt, J=10.3, 5.4 Hz, 1H), 4.32 (dq, J=11.0, 6.1, 5.6 Hz, 1H), 4.13-3.95 (m, 4H), 3.78 (d,J=11.1 Hz, 2H), 3.65-3.52 (m, 2H), 3.46 (t ,J=11.2 Hz, 1H), 2.89 (t, J=11.4 Hz, 1H), 2.82-2.59 (m, 2H), 2.12-1.92 (m, 4H).

Example 60 and Example 61: (R or S)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2- yl)azepan-1-yl)-III-pyrazol-1-yl)-2-methylpropan-2-ol and (S or R)-1-(4-(3-(5-amino-9fluoro-8-methoxy -[1,2,4]triazolo[1,5-c]quinazolin-2-yl)azepan-1-yl)-III-pyrazol-1-yl)-2-methylpropan-2-ol

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Example 61

A vessel with a volume of ml under microwave irradiation was filled with rac-2-(azepan-3-yl)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c] quinazoline-5-amine (intermediate 83) (100 mg, 0.208 mmol) and THF (1.3 ml). 1-(4-bromo-1H-pyrazol-1-yl)-2methylpropan-2-ol (intermediate 4) (91.0 mg, 0.420 mmol) was added to the mixture followed by tBuXPhos-Pd G3 (66.1 mg , 0.0830 mmol) and sodium tert-butoxide (80.0 mg, 0.832 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The mixture was stirred and heated at 90°C for 12 hours. The mixture was cooled to room temperature and then the solids were removed by filtration and washed with DCM. The solvents in the filtrate were evaporated. The resulting residue was dissolved in TFA (802 μl, 10.4 mmol) and heated at 50°C for 3 hours. The mixture was cooled to room temperature and the solvents were evaporated. The resulting residue was purified by preparative reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mmx100 mm MeCN/ _H2O with 0.1% TFA modifier as eluent) to obtain the racemic product. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies OJ-H 21 x 250 mm column with 25% (isopropanol with 0.1% NH4OH modifier) as co-solvent) to give (R or S)-1-(4-(3- (5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)azepan-1-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (compound of Example 60, first eluted peak) and (S or R)-1-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)azepan-1-yl)1H-pyrazol-1-yl)-2-methylpropan-2-ol (compound of Example 61, second eluted peak).

For compound example 60: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H]+. Ή NMR (499 MHz, DMSO d ₆ ) δ 7.88 (d, J=11.0 Hz, 1H), 7.72 (d, J=26.0 Hz, 2H), 7.18 (d, J =7.9 Hz, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 4.63 (s, 1H), 3.97 (s, 3H), 3.87 (s , 2H), 3.75 (dd, J=14.3, 3.9 Hz, 1H), 3.53 (dd, J=14.3, 10.0 Hz, 1H), 3.45 (dq, J=9.7, 5.0, 4.6 Hz, 1H), 3.37 (dd, J=14.0, 6.1 Hz, 1H), 3.23 (ddd, J=13.3, 7.6, 5.1 Hz, 1H), 2.07 - 1.82 (m, 3H), 1.71 (s, 1H), 1.58 - 1.45 (m, 2H), 1.03 (d, J=3.5 Hz, 6H).

For compound example 61: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H] ⁺ . ¹ H NMR (499 MHz, DMSOd ₆ ) δ 7.88 (d, J=11.0 Hz, 1H), 7.70 (s, 2H), 7.18 (d, J=7.7 Hz, 1H ), 7.13 (s, 1H), 7.07 (s, 1H), 4.62 (s, 1H), 3.97 (s, 3H), 3.87 (s, 2H), 3.75 (dd, J=14.4, 3.8 Hz, 1H), 3.53 (dd, J=14.2, 10.2 Hz, 1H), 3.45 (dt, J=9.5, 4 ,9 Hz, 1H), 3.38 (s, 1H), 3.24 (dd, J=13.6, 5.5 Hz, 2H), 2.08 - 1.84 (m, 3H), 1 .71 (s, 1H), 1.50 (d, J=12.7 Hz, 2H), 1.03 (d, J=3.4 Hz, 6H).

Compounds of examples of the present invention in the following table. 20 was prepared in a manner similar to that described for the preparation of the compound of Example 60 and the compound of Example 61, from the corresponding starting amine and aryl halide, wherein the resulting isomeric mixture of the respective final compounds was separated by SFC.

- 118 043752

Table 20

Example Structure SFC terms Observ. m/z [M + N] ⁺ Name 62 he Ha 'λ nh ₂ ^F 4jL F Peak 1; Chiral Technologies ADH 21 x 250 mm column with 50% (IPA with modifier 0.2% DIP A) as a co-solvent 459 (R or 5)-1-(4-(3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3 fluoropyrrolidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-2-ol 63 OH Ha NH ₂ m JL An^N ^{F n} 4jl γΌ' F Peak 2; Chiral Technologies ADH 21 x 250 mm column with 50% (IPA with modifier 0.2% DIP A) as a co-solvent 459 (S or 7?)-1-(4-(3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 3 fluoropyrrolidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-2-ol

- 119 043752

64 BUT | N=( nh ₂ οαΛ F ¹ Peak 1; Chiral Technologies IC 21 x 250 mm column with 35% (MeOH modifier 0.1% NH ₄ OH) as co-solvent 470 (R or 5)-3-(3-((7?)-3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-с]quinazolin-2 -yl)piperidin-1 yl)-1H-1,2,4-triazol-1 -yl)-2-methylbutan-2-ol 65 but | νη ₂ о+хУ V^o F ¹ Peak 2; Chiral Technologies IC 21 x 250 mm column with 35% (MeOH modifier 0.1% NH4OH) as co-solvent 470 (5 or 7?)-3-(3-((7?)-3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)piperidin-1 yl)-177-1,2,4-triazol-1 -yl)-2-methylbutan-2-ol 66 BUT 1 \=/ nh ₂ γ^ο^ F Peak 1; Chiralcel OJ-H 4.6 x 150 mm column with 40% (MeOH with modifier 0.05% DEA) as a co-solvent 469 1-(4-((35 or 37?,45 or 47?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-с]quinazolin-2 -yl)-4methylpiperidin-1 -yl)- 177-pyrazol-1 -yl)-2- methylpropan-2-ol 67 BUT 1 \=J nh ₂ / ^N ^\ Y^O^ F Peak 2; Chiralcel OJ-H 4.6 x 150 mm column with 40% (MeOH with modifier 0.05% DEA) as a co-solvent 469 l-(4-((37? or 35.47? or 45)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-с]quinazolin-2 -yl)-4methylpiperidin-1 -yl)- 177-pyrazol-1 -yl)-2- methylpropan-2-ol

Example 68 and Example 69: 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c] quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3 -(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1Hpyrazol-1 -yl )-2-methylpropan-2-ol.

Step 1: rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

- 120 043752

rac-N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5S or 3S,5R)-5fluoropiperidin-3-yl)-7-methoxy-[1,2 ,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 102) (736 mg, 1.52 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropane -2-ol (intermediate 4) (998 mg, 4.56 mmol), tBuXPhos-Pd G3 (965 mg, 1.22 mmol), sodium tert-butoxide (876 mg, 9.11 mmol) and THF (15 ,0 ml). The mixture was purged with nitrogen for 5 minutes. The mixture was stirred and heated at 80°C for 6 hours. The mixture was cooled to room temperature. The solvents were evaporated and the resulting residue was purified by chromatography on silica gel with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to give rac-1-(4-((3R,5S or 3S,5R)-3- (5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl )-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C3iH3 ₆ F2N8O4) (ES, m/z): 623 [M+H] ⁺ .

Step 2: 1-(4-((3R,5S or 3S5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl )-5-fluoropiperidin-1-yl)-III-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S)-3-(5-amino9 -fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2methylpropan- 2 -ol

rac-1-(4-((3R,5S or 3S,5R)-3-(5-((2,4-dimethoxybenzyl)amino)9-fluoro-7-methoxy-[ 1, was added to a 20 ml vessel 2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2methylpropan-2-ol (550 mg, 0.883 mmol) and TFA (8.83 ml, 115 mmol). The mixture was stirred and heated at 50°C for 2 hours. The solvents were evaporated. MeOH was added to the resulting residue and the mixture was filtered. The solvents in the filtrate were evaporated. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AS-H 21 x 250 mm column with 15% (MeOH modifier 0.1% NH4OH) as cosolvent) to give 1-(4-((3R,5S or 3S,5R )-3-(5-amino-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazole -1-yl)-2-methylpropan-2-ol (compound of Example 68, first eluted peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro- 7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2methylpropan-2-ol (compound example 69, second eluted peak).

For compound example 68: LCMS (C ₂₂ H ₂₆ F ₂ N ₈ O ₂ ) (ES, m/z): 473 [M+H]+. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.82 (s, 2H), 7.43 (dd, J=8.3, 2.6 Hz, 1H), 7.37 (s, 1H) , 7.28 (s, 1H), 7.18 (dd, J=11.0, 2.6 Hz, 1H), 4.94 (dtt, J=48.3, 10.3, 4.8 Hz , 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.89 (s, 2H), 3.78-3.71 (m, 1H), 3.66 (d, J=11.5 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 2.75 (t, J=11.5 Hz, W), 2.66 (d, J= 6.1 Hz, 1H), 2.58 (td, J=10.4, 5.2 Hz, 1H), 1.92 (p, J=11.3 Hz, 1H), 1.04 (s, 6H).

For compound example 69: LCMS (C ₂₂ H ₂₆ F ₂ N ₈ O ₂ ) (ES, m/z): 473 [M+H] ⁺ . 1H NMR (600 MHz, DMSO-d ₆ ) δ 7.82 (s, 1H), 7.44 (dd, J=8.3, 2.7 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.19 (dd, J=11.1, 2.7 Hz, 1H), 4.95 (ddt, J=48.3, 10.4, 5.2 Hz, 1H), 4.64 (s, 1H), 3.94 (s, 2H), 3.89 (s, 1H), 3.74 (d, J=10.6 Hz, 1H), 3.66 ( d, J=11.9 Hz, 1H), 3.40 (t, J=11.8 Hz, 1H), 2.74 (d, J=11.5 Hz, 1H), 2.65 (s, 1H), 2.58 (dt, J=10.3, 5.2 Hz, 1H), 1.97-1.89 (m, 1H), 1.04 (s, 6H).

Compounds of examples of the present invention in the following table. 21 was prepared in a manner similar to that described for the preparation of Example 68 and Example 69 from Intermediate 102 and the corresponding starting aryl halide, wherein the resulting isomeric mixture of the respective final compounds was separated by SFC.

- 121 043752

Table 21

Example Structure SFC terms Observ. m/z, [M + N] ⁺ Name 70 BUT X'V \=/ nh ₂ ^F * L JJ CIS Ap F Peak 1; Phenomenex Lux-2 21 × 250 mm column with 40% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 487 l-(4-((3/?,55 or 35.5L)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-с]quinazolin-2- yl)-5 fluoropiperidin-1 -yl)-3 -methyl-177-pyrazol-1 -yl)-2methylpropan-2-ol 71 BUT XrV L=/ nh ₂ / ^N A* z^nA ^-^νΑΑ,ο^ cis F Peak 2; Phenomenex Lux-2 21 x 250 mm column with 40% (MeOH with modifier 0.1% NH4OH) as a co-solvent 487 1-(4-((35.5R or 3/?.55)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 fluoropiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)-2methylpropan-2-ol 72 ^but \l \=/ nh ₂ / ^Ν ^\* Λ>Λν ^F L JJ cis F Peak 1; ES Industries CCA 21 x 250 mm column with 20% (MeOH modifier 0.1% NH4OH) as co-solvent 485 l-((4-((37?.55 or 35.57?)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-с]quinazoline-2 -yl)-5 fluoropiperidin-1 -yl)-1 /7-p irazo l-1 - yl)methyl)cyclobutan-1-ol 73 ^but \l \=/ nh ₂ / ^N ^\* FL JJ CIS F Peak 2; ES Industries CCA 21 x 250 mm column with 20% (MeOH modifier 0.1% NH4OH) as co-solvent 485 1-((4-((35.5R or 3/?.55)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2 -yl)-5 fluoropiperidin-1 -yl)-1 /7-p irazo l-1 yl)methyl)cyclobutan-1 -ol

Example 74 and Example 75: 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c] quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or

- 122 043752

3R,5R)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl) -1Hpyrazol-1-yl)-2-methylpropan-2-ol.

Step 1: rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

rac-N-(2,4-dimethoxybenzyl)-9-fluoro-2-((3R,5R or 3S,5S)-5fluoropiperidin-3-yl)-7-methoxy-[1,2 ,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 102) (434 mg, 0.896 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2 -ol (intermediate 4) (589 mg, 2.69 mmol), tBuXPhos-Pd G3 (569 mg, 0.717 mmol), sodium tert-butoxide (517 mg, 5.37 mmol) and THF (9.0 mL) . The mixture was purged with nitrogen for 5 minutes. The mixture was stirred and heated at 80°C for 6 hours. The mixture was cooled to room temperature. The solvents were evaporated. The resulting residue was purified by chromatography on silica gel with 30-50% EtOAc:EtOH (3:1) in hexane as eluent to obtain rac-1-(4-((3R,5R or 3S,5S)-3-(5- ((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H -pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C ₃₁ H ₃₆ F ₂ N ₈ O ₄ ) (ES, m/z): 623 [M+H]+.

Step 2: 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or 3R,5R)-3-(5 -amino9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-III-pyrazol-1-yl)-2methylpropane -2-ol

In a 20 ml vessel containing rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1, 2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (439 mg, 0.705 mmol), TFA (7.05 mL, 92.0 mmol) was added. The mixture was stirred and heated at 50°C for 2 hours. The solvents were evaporated. MeOH was added to the residue. The mixture was filtered and then the solvents of the filtrate were evaporated. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies AS-H 21x250 mm column with 15% (MeOH modifier 0.1% NH4OH) as cosolvent) to obtain 1-(4-((3R,5R or 3S,5S )-3-(5amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol- 1yl)-2-methylpropan-2-ol (compound of Example 74, first eluted peak) and 1-(4-((3R,5R or 3S,5S)-3(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1 H-pyrazol-1 yl)-2-methylpropan-2-ol (example compound 75, second eluted peak).

For compound example 74: LCMS (C ₂₂ H ₂₆ F ₂ N ₈ O ₂ ) (ES, m/z): 473 [M+H] ⁺ . ¹ H NMR (499 MHz, DMSO-d ₆ ) δ 7.83 (s, 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.32 (s, 1H) , 7.24 (s, 1H), 7.19 (d, J=10.0 Hz, 1H), 5.11 (d, J=46.5 Hz, 1H), 4.64 (s, 1H) , 3.94 (s, 3H), 3.89 (s, 2H), 3.69 - 3.48 (m, 3H), 2.97-2.89 (m, 1H), 2.90 - 2 .79 (m, 1H), 2.40 (s, 1H), 2.14 (dt, J=40.9, 11.8 Hz, 1H), 1.04 (s, 6H).

For compound example 75: LCMS (C ₂₂ H ₂₆ F ₂ N ₈ O ₂ ) (ES, m/z): 473 [M+H] ⁺ . 1H NMR (499 MHz,

DMSO-d ₆ ) δ 7.83 (s, 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.19 (d, J=8.9 Hz, 1H), 5.11 (d, J=47.5 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 2H) , 3.67 - 3.50 (m, 3H), 2.97 - 2.90 (m, 1H), 2.90-2.79 (m, 1H), 2.41

- 123 043752 (s, 1H), 2.14 (dt, J=40.8, 12.8 Hz, 1H), 1.04 (s, 6H).

Compounds of examples of the present invention in the following table. 22 was prepared in a manner similar to that described for the preparation of Example 74 and Example 75 from Intermediate 103 and the corresponding starting aryl halide, wherein the resulting isomeric mixture of the respective final compounds was separated by SFC.

Table 22

Example Structure SFC terms Observ. m/z, [M + N] ⁺ Name 76 HO X'V \=/ nh ₂ / ^N ^\ * /Nn^N pCAХOX FLJ trans F Peak 1; Phenomenex Lux-3 21 × 250 mm column with 15% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 487 1-(4-((377.577 or 35.55)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 fluoropiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)-2methylpropan-2- ol 77 but ^N'V /=/ nh ₂ / ^N ^\*_// ^N 'n^n ^F * kJ trans F Peak 2; Phenomenex Lux-2 21 x 250 mm column with 15% (MeOH with modifier 0.1% NH4OH) as a co-solvent 487 1-(4-((35.55 or 377.577)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 fluoropiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)-2methylpropan-2- ol 78 / o 7 K ^z y ^z g AT ^sh o t Peak 1; Chiral Technologies OJ-H 21 x 250 mm column with 20% (MeOH with modifier 0.1% NH4OH) as a co-solvent 485 1-((4-((377.577 or 35.55)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 - fluoropiperidin-1-yl) -177-pyrazo l-1 - yl)methyl)cyclobutan-1-ol

- 124 043752

79 ^ΗΟ %·\ νη ₂ / ^Ν ^\* trans F Peak 2; Chiral Technologies OJ-H 21 x 250 mm column with 20% (MeOH modifier 0.1% NH ₄ OH) as co-solvent 485 1-((4-((35.55 or 3A.57?)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-с]quinazolin-2- yl)-5fluoropiperidin-1 -yl) - 177-pyrazol-1 yl)methyl)cyclobutan-1 -ol

Example 80 and Example 81: 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c] quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or 3R,5R)-3 -(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-1Hpyrazol-1 -yl )-2-methylpropan-2-ol.

Step 1: rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4 ]triazolo[1,5-c]quinazolin-2-ul)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

Step 1 of Example 80 and Example 81 was carried out in a manner similar to Step 1 of Example 74 and Example 75, with intermediate 101 and intermediate 4 to give rac-1-(4-((3R,5R or 3S,5S)-3 -(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-5-fluoropiperidin-1-yl )-1H-pyrazol-1-yl)-2-methylpropan-2-ol. LCMS (C ₃₁ H ₃₆ F ₂ N ₈ O ₄ ) (ES, m/z): 623 [M+H]+.

Step 2: 1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2yl)-5-fluoropiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((3S,5S or 3R,5R)-3-(5 -amino9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)- 2methylpropan-2-ol no^/

Step 2 of Example 80 and Example 81 was carried out in a manner similar to that described in Step 2 of Example 74 and Example 75, where rac-1-(4-((3R,5R or 3S,5S)-3-(5-((2,4 -dimethoxybenzyl)amino)-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)-III-pyrazol-1-yl )-2methylpropan-2-ol was converted into a racemic mixture of the corresponding final compounds. The racemic mixture was resolved by chiral SFC separation (Chiral Technologies OJ-H 21 x 250 mm column with 25% (MeOH modifier 0.2% DIPA) as cosolvent) to give 1-(4-((3R,5R or 3S, 5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl)1H- pyrazol-1-yl)-2-methylpropan-2-ol (compound of Example 80, first eluted peak) and 1-(4-((3S,5S or 3R,5R)-3-(5-amino-9-fluoro -8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-fluoropiperidin-1-yl) - 125 043752

1H-pyrazol-1-yl)-2-methylpropan-2-ol (compound of Example 81, second eluted peak).

For compound example 80: LCMS (C ₂₂ H ₂₆ F ₂ N8O ₂ ) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, methanol-d ₄ ) δ 7.94 (d, J=10.8 Hz, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.24 ( d, J=7.5 Hz, 1H), 5.12 (d, J=46.8 Hz, 1H),

4.02 (d,J=3.8 Hz, 3H), 3.84 (d, J=12.4 Hz, 1H), 3.82 - 3.74 (m, 1H), 3.74-3 .62 (m, 1H), 3.11 (t,J=11.0 Hz, 1H),

3.08 - 2.95 (m, 1H), 2.67 (s, 1H), 2.59 (s, 1H), 2.31-2.12 (m, 1H), 1.16 (s, 6H).

For compound example 81: LCMS (C22H26F2AO2) (ES, m/z): 473 [M+H] ⁺ . 1H NMR (500 MHz, methanol-d ₄ ) δ 7.94 (d, J=10.8 Hz, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 7.24 ( d, J=7.5 Hz, 1H), 5.13 (d, J=47.0 Hz, 1H), 4.02 (d, J=4.8 Hz, 3H), 3.85 (d, J=11.0 Hz, 1H), 3.82 - 3.73 (m, 1H), 3.73 - 3.60 (m, 1H), 3.11 (t, J=11.0 Hz, 1H ), 3.04 (dd,J=36.0, 12.9 Hz, 1H), 2.59 (s, 1H), 2.30 - 2.12 (m, 1H), 1.16 (s, 6H).

Example 82 and Example 83: (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1 ,5-c]quinazolin-2-yl)piperidin-1 -yl)-1 H-pyrazol-1 -yl)-1 -methylcyclopentan-1 -ol and (1S or 1R,2S or 2R)-2-(4 -((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidin-1 -yl)-1 H- pyrazol-1-yl)-1-methylcyclopentan-1-ol.

Step 1: (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1 -yl)-1 H-pyrazol-1 -yl)-1 -methylcyclopentan-1 -ol and (1S or 1R,2S or 2R )-2-(4-((R)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazoline -2-yl)piperidin-1 -yl)-1 H-pyrazol-1 -yl)-1 -methylcyclopentan-1 -ol o

peak 2 F

To a reaction vessel containing a solution of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2(piperidin-3-yl)-[1,2,4]triazolo[1,5- c]quinazolin-5-amine (intermediate 82) (150 mg, 0.322 mmol) in THF (3.0 ml), 2-(4-bromo-1H-pyrazol-1-yl)-1-methylcyclopentanol 2 was added, 2,2trifluoroacetate (intermediate 6) (184 mg, 0.514 mmol), followed by tBuXPhos-Pd G3 (77.0 mg, 0.0960 mmol) and sodium tert-butoxide (93.0 mg, 0.965 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The mixture was stirred and heated at 90°C for 4 hours. The mixture was cooled to room temperature, and then the resulting residue was purified by chromatography on silica gel with 0-40% EtOAc:EtOH (3:1) in hexane as eluent to obtain diastereomeric products mixtures. The mixture was obtained by SFC separation (Chiral Technologies OJ-H 21x250 mm column with 30% MeOH as co-solvent) to obtain peak 1 and peak 2, which correspond to (1R or 1S,2R or 2S)-2-(4-((R )-3-(5((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1- yl)1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-((2,4dimethoxybenzyl) amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1Hpyrazol-1-yl)-1-methylcyclopentane- 1-ol. For peak 1 LCMS (C ₃₃ H ₃₉ FN ₈ O ₄ ) (ES, m/z): 631 [M+H] ⁺ . For peak 2 LCMS (C ₃₃ H ₃₉ FN ₈ O ₄ ) (ES, m/z): 631 [M+H] ⁺ .

Step 2: (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5с ]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclopentan-1-ol and (1S or 1R,2S or 2R)2-(4-((R)- 3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1Hpyrazol-1-yl)- 1-methylcyclopentan-1-ol

- 126 043752

Step 2 of Example 82 and Example 83 was carried out in a manner similar to that described in Step 2 of Example 40, where Peak 1 and Peak 2 obtained from Step 1 were converted to (1R or 1S,2R or 2S)-2-(4-((R )-3-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1 -yl)-1 H-pyrazol-1 - yl)-1 methylcyclopentan-1-ol and (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)piperidin-1 -yl)-1 H-pyrazol-1 -yl)-1-methylcyclopentan-1 -ol, which are the final compounds of Example 82 and Example 83 , respectively.

For compound example 82: LCMS (C ₂₄ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 481 [M+H]+. ¹ H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=10.7 Hz, 1H), 7.31 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 5.89 (s, 2H), 4.36 (t, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.68 ( dd, J=11.5, 3.6 Hz, 1H), 3.38 (tt, J=7.5, 3.8 Hz, 2H), 2.95 (t, J=11.1 Hz, 1H ), 2.67 (td, J=11.3, 4.4 Hz, 1H), 2.40-2.07 (m, 3H), 1.99-1.73 (m, 7H), 0, 88 (s, 3H).

For compound example 83: LCMS (C24H29FW2) (ES, m/z): 481 [M+H] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 7.97 (d, J=10.7 Hz, 1H), 7.31 (s, 1H), 7.13 (d, J=7.6 Hz, 1H ), 7.07 (s, 1H), 5.88 (s, 2H), 4.35 (t, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.74-3 .64 (m, 1H), 3.43-3.31 (m, 2H), 2.95 (t, J=11.1 Hz, 1H), 2.67 (td, J=11.2, 4 .5 Hz, 1H), 2.39-2.10 (m, 3H), 2.00-1.74 (m, 7H), 0.88 (s, 3H).

Compounds of examples of the present invention in the following table. 23 was prepared in a manner similar to that described for the preparation of the compound of Example 82 and the compound of Example 83, from the corresponding intermediates and starting materials. In each case, the SFC separation was performed on the mixture of intermediates formed in the first step. SFC conditions for the isolation of such intermediates are shown with the corresponding end products formed in the second step.

Table 23

Example Structure SFC conditions for intermediate compound from stage 1 Observ. m/z [M + N] ⁺ Name 84 but γ νη ₂ / ^Ν Α F Peak 1; Whelko-1 21 x 250 mm column with 50% (MeOH with modifier 0.2% DIPA) in the form co-solvent 467 (17? or 15,27? or 25)-2-(4-((7?)-3-(5-amino-9fluoro-8-methoxy-[1,2,4]triazolo[1,5-c ]quinazolin2-yl) piperidin-1 -yl) - 172-pyrazol-1 yl)cyclopentan-1 -ol 85 but nh ₂ οΎ γ^ο^ F Peak 2; Whelko-1 21 x 250 mm column with 50% (MeOH with modifier 0.2% DIPA) in the form co-solvent 467 (15 or 17?,25 or 27?)-2-(4-((7?)-3-(5-amino-9fluoro-8-methoxy-[1,2,4]triazolo[1,5-c ]quinazolin2-yl) piperidin-1 -yl) - 172-pyrazol-1 yl)cyclopentan-1 -ol

- 127 043752

86 ύ nh ₂ N. _n A _n F Peak 1; Chiral Technologies AD-H 21 x 250 mm column with 45% (ΙΡΑ 1:1 with modifier 0.2% DIP A) in the form co-solvent 483 (S or L)-3-(4-((L)-3-(5-amino-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazoline-2- yl)piperidin-1 -yl)-3 -methyl-1 R-pyrazol-1 -yl)- 2-methylbutan-2-ol 87 A -P-? ABOUT / Peak 2; Chiral Technologies AD-H 21 x 250 mm column with 45% (ΙΡΑ 1:1 with modifier 0.2% DIP A) in the form co-solvent 483 (R or X)-3-(4-((L)-3-(5-amino-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidine -1 -yl)-3-methyl-1R-pyrazol-1 -yl)2-methylbutan-2-ol

Example 88: (1R or 1S,2R or 2S)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)cyclopentan-1 -ol

A mixture of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S or 3S,6R)-6-methyl-1-(1-((1R or 1 S,2R or 2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)-1H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5-c ]quinazoline-5-amine (intermediate 120) (5.0 mg, 7.0 µmol) in TFA (0.3 ml) was heated at 60°C for 25 min. The mixture was concentrated. The residue was purified by preparative TLC on silica gel eluting with 5% (7 M ammonia in MeOH) in DCM to give (1R or 1S,2R or 2S)-2-(4-((2S,5R or 2R,5S)-5- (5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl) cyclopentan-1-ol. LCMS (C ₂₄ H ₂₉ FN8O ₂ ) (ES, m/z): 481 [M+H]+. ¹ H NMR (400 MHz, chloroform-d) δ 7.99 (d, J=10.7 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 5.87 (s, 2H), 4.35 (d,J=7.5 Hz, 1H), 4.21 (d, J=8.7 Hz, 1H), 4.01 (s, 3H), 3.74 (d, J=6.5 Hz, 1H), 3.473.41 (m, 1H), 3.32 (d, J=11.0 Hz, 1H), 3.23 (d, J=11.3 Hz, 1H), 2.26 (m, 1H), 2.16 - 2.08 (m, 3H), 2.08 - 2.00 (m , 2H), 1.90-1.71 (m, 4H), 1.13 (d, J=6.7 Hz, 3H).

Example 89: (1S or 1R,2S or 2R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)cyclopentan-1 -ol

Example 89 was prepared from intermediate 121 in a manner similar to Example 88 to give (1S or 1R,2S or 2R)-2-(4-((2S,5R or 2R,5S)-5-(5-amino- 9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclopentan-1- ola. LCMS (C ₂₄ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 481 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 7.99 (d,J=10.7 Hz, 1H), 7.25 (s, 1H), 7.15 (d,J=7.6 Hz, 1H ), 7.01 (s, 1H), 5.81 (s, 2H), 4.36 (q, J=7.1 Hz, 1H), 4.27 - 4.15 (m, 1H), 4 .00 (s, 3H), 3.79 - 3.67 (m, 1H), 3.44 (dd, J=11.5, 4.2 Hz, 1H), 3.37-3.28 (m , 1H), 3.22 (t, J=11.1 Hz, 1H), 2.34-2.21

- 128 043752 (m, 1H), 2.19 - 1.96 (m, 4H), 1.94-1.62 (m, 6H), 1.12 (d, J=6.7 Hz, 3H) .

Example 90 and 91: 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazoline -2-yl)-5-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol and 1 -(4-((3 S,5R or

3R,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl) -1Hpyrazol-1-yl)-2-methylpropan-2-ol

To a solution of rac-1-(4-((3S,5R or 3R,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 122) (150 mg, 0.242 mmol) in DCM (2 ml) was added TFA (2 ml). The mixture was stirred at 50°C for 10 hours. The mixture was concentrated. The racemic mixture was prepared and resolved by chiral SFC (Phenomenex Lux-2 4.6x150 mm column with 0-40% (EtOH with 0.05% DEA) as co-solvent) to give 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)- 1H-pyrazol-1-yl)-2-methylpropan-2-ol (first eluted peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8 -methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (second eluting peak), corresponding to the compound of Example 90 and the compound of Example 91, respectively.

For compound example 90: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, methanol-d4) δ = 7.66 (d , J=10.8 Hz, 1H), 7.32 (d, J=10.0 Hz, 2H), 6.94 (d, J=7.8 Hz, 1H), 3.98 (s, 2H ), 3.91 (s, 3H), 3.81 - 3.71 (m, 1H), 3.38 (br d, J=9.0 Hz, 1H), 3.32-3.22 (m , 2H), 2.69 (t, J=11.6 Hz, 1H), 2.32-2.13 (m, 2H), 2.02-1.89 (m, 1H), 1.36 ( q, J=12.5 Hz, 1H), 1.14 (s, 6H), 1.00 (d, J=6.6 Hz, 3H).

For compound example 91: LCMS (C ₂ 3H ₂₉ FN8O ₂ ) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, methanol-d4) δ = 7.68 (d, J =10.8 Hz, 1H), 7.37 (d, J=19.1 Hz, 2H), 6.98 (d, J=7.8 Hz, 1H), 3.99 (s, 2H), 3.93 (s, 3H), 3.84-3.76 (m, 1H), 3.42 (br d, J=10.3 Hz, 1H), 3.34-3.26 (m, 2H ), 2.77 (t, J=11.6 Hz, 1H), 2.32-2.20 (m, 2H), 1.99 (br d, J=6.6 Hz, 1H), 1, 40 (q, J=12.5 Hz, 1H), 1.19-1.09 (m, 7H), 1.02 (d, J=6.6 Hz, 3H).

Example 92: rac-1-(4-((3R,5R or 3S,5S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazoline -2-yl)-5-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

connection 123

To a solution of 1-(4-((3R,5R and 3S,5S)-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[ 1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 123) (20 mg, 0.032 mmol) TFA (2 ml) was added to DCM (2 ml). The mixture was stirred and heated at 45°C for 5 hours. The mixture was concentrated. The residue was purified by reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/water (with 0.1% TFA as modifier) as eluent) to give 1-(4-((3R,5R and 3S,5S)-3-(5-amino9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-III -pyrazol-1-yl)-2methylpropan-2-ol. LCMS (C ₂ 3H ₂₉ FN8O ₂ ) (ES, m/z) [M+H]+: 469. ¹ H NMR (400 MHz, methanol^) δ = 8.027.90 (m, 2H), 7.73 ( s, 1H), 7.27-7.15 (m, 1H), 4.22 (br d, J=11.2 Hz, 1H), 4.13-4.07 (m, 2H), 4, 00 (s, 4H), 3.783.65 (m, 2H), 3.57-3.47 (m, 1H), 3.11 (t, J=11.0 Hz, 1H), 2.54 (brd , J=13.7 Hz, 1H), 2.27-2.14 (m, 1H), 1.901.80 (m, 1H), 1.17 (s, 6H), 1.11 (d, J= 6.8 Hz, 3H).

Example 93: (R)-5-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidin-1 -yl)-1 H-pyrazol-1 -yl)pentan-2-one

- 129 043752

To a stirred mixture of TFA (0.5 ml) in DCM (0.5 ml) was added (R)-5-(4-(3-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy -[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1Hpyrazol-1-yl)pentan-2-one (intermediate 124) (28.0 mg , 0.0450 mmol). The mixture was stirred and heated at 50°C for 15 hours. The mixture was cooled and the solvents were evaporated. The resulting residue was purified by preparative reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/water (with 0.1% TFA as a modifier) as eluent) to obtain (R)-5-(4 -(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1yl)-1H-pyrazol-1-yl )pentan-2-one. LCMS (C ₂₃ H ₂₇ FN ₈ O ₂ ) (ES, m/z) [M+H]+: 467. ¹ H NMR (400 MHz,

CD3OD) δ: 7.90 (d, J=10.96 Hz, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.19 (d, J=7.45 Hz , 1H), 4.62 (br s, 1H), 4.05 (t, J=6.80 Hz, 2H), 3.99 (s, 3H), 3.67-3.78 (m, 1H), 3.39 (br d, J=11.84 Hz, 1H), 2.95 (t, J=11.18 Hz, 1H), 2.60-2.74 (m, 1H), 2 .44 (t, J=7.02 Hz, 2H), 2.28 (br d, J=9.21 Hz, 1H), 2.10 (s, 3H), 2.02 (quint., J= 7.02 Hz, 2H), 1.81 1.95 (m, 3H).

Example 94 and 95: (S or R)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c ]quinazolin2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol and (R or S)-5-(4-((R)-3-(5-amino-9 -fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1 -yl)-1 H-pyrazol-1 -yl)pentan-2-ol

To the stirred mixture of (R)-5-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidin-1 -yl)-1H-pyrazol-1-yl)pentan-2-one (compound of Example 93) (15.0 mg, 0.0320 mmol) in THF (2 ml) was added NaBH ₄ (2.4 mg, 0.064 mmol ). The mixture was stirred at 25°C for 3 hours. The racemic mixture was quenched with 1 M aqueous HCl (2 ml). The mixture was extracted with EtOAc (2x30 ml) and the organic layer was dried over sodium sulfate, filtered and then the solvents of the filtrate were evaporated. The residue was purified by reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/water (with 0.1% TFA as modifier) as eluent) to obtain (S or R)-5-(4- ((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1Hpyrazol- 1-yl)pentan-2-ol and (R or S)-5-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[ 1,5c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)pentan-2-ol, corresponding to the compound of Example 94 and the compound of Example 95, respectively.

For compound example 94: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z) [M+H]+: 469. 1H NMR (400 MHz, CD3OD) δ: 7.94 (d, J= 10.83 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.25 (d, J=7.63 Hz, 1H), 4.19 (br t, J =7.10 Hz, 2H), 4.08-4.00 (m, 4H), 3.78-3.66 (m, 2H), 3.57 (br s, 2H), 3.36 (t , J=1.68 Hz, 1H), 2.40 (br s, 1H), 2.16-1.85 (m, 5H), 1.48-1.36 (m, 2H), 1.17 (d, J=6.26 Hz, 3H).

For compound example 95: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z) [M+H]+: 469. ¹ H NMR (400 MHz, CD3OD) δ: 7.95 (d, J =10.68 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.24 (d, J=7.78 Hz, 1H), 4.11 (t, J =6.87 Hz, 3H), 4.03 (s, 4H), 3.84 - 3.62 (m, 3H), 3.48 - 3.37 (m, 5H), 3.31 (br s , 1H), 3.19 (s, 1H), 2.33 (s, 1H), 2.02-1.77 (m, 5H), 1.41 (br d, J=5.80 Hz, 2H), 1.16 (d, J=6.10 Hz, 3H).

Example 96 and Example 97: rac-(1r,4s or 1r,4r)-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1 ,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-1-methylcyclohexan-1 ol and rac-(1r ,4r or 1r,4s)-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]mriazolo[1, 5c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-1 -methylcyclohexan-1 -ol.

Step 1: 4-nitro-1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazole

- 130 043752

no ₂

To a stirred mixture of 1,4-dioxaspiro[4,5]decan-8-ol (5.00 g, 31.6 mmol), PPh ₃ (12.4 g, 47.4 mmol) and 4-nitro-1H- pyrazole (4.29 g, 37.9 mmol) in DCM (80 ml), di-tert-butyldiazene-1,2dicarboxylate (18.2 g, 79.0 mmol) was added under a nitrogen atmosphere and the mixture was stirred at 25°C in for 10 hours. The mixture was concentrated and purified by chromatography on silica gel with 10-25% EtOAc in petroleum ether as eluent to obtain 4-nitro-1-(1,4-dioxaspiro[4,5]decan-8-yl)- 1H-pyrazole. LCMS (C11H15N3O4) (ES, m/z) [M+H]+: 254.

Step 2: 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-amine

no ₂ nh ₂

To a stirred mixture of 4-nitro-1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazole (5.50 g, 21.7 mmol) in MeOH (50 ml) and EtOAc ( 50 ml) 10% Pd/C (0.462 g, 4.34 mmol) was added. The mixture was purged with nitrogen twice and stirred under a hydrogen atmosphere for 6 hours. The mixture was filtered and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 20-50% EtOAc in petroleum ether as eluent to give 1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazol-4amine. LCMS (C11H17N3O2) (ES, m/z) [M+H] ⁺ : 224.

Step 3: Methyl 1-(1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidin-3carboxylate

O

To a stirred mixture of 1-(1,4-dioxaspiro[4,5]decan-8-yl)-III-pyrazol-4-amine (2.14 g, 9.60 mmol) and lithium tetrafluoroborate (0.600 g, 6. 40 mmol) to TFE (15 ml) was added ethyl 2-methylene-5oxohexanoate (1.00 g, 5.88 mmol). The mixture was stirred and heated at 80°C for 10 hours. The mixture was cooled, diluted with water (15 ml) and extracted with EtOAc (2x30 ml). The organic layer was dried (anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. MeOH (15 ml) and 10% Pd/C (0.068 g, 0.64 mmol) were added to the resulting residue. The mixture was degassed and purged with nitrogen twice, stirred under hydrogen atmosphere for 10 hours. The mixture was filtered and then the filtrate was concentrated. The residue was purified by chromatography on silica gel with 10-50% EtOAc in petroleum ether as eluent to give ethyl 1-(1-(1,4-dioxaspiro[ 4,5]decan-8-yl)-1H-pyrazol-4-yl)-6methylpiperidin-3-carboxylate LCMS (C ₂₀ H ₃₁ N ₃ O ₄ ) (ES, m/z) [M+H] ⁺ : 378.

Step 4: 1-(1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6-methylpiperidin-3-carbazide

To a stirred mixture of 1-(1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazol-4-yl)-6methylpiperidin-3-carboxylate (450 mg, 1.192 mmol) in EtOH ( 10 ml) hydrazine hydrate (382 mg, 11.92 mmol) was added. The mixture was stirred and heated at 80°C for 10 hours. The mixture was concentrated to give 1-(1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazol-4-yl)-6 -methylpiperidine-3-carbazide, which was used without further purification. LCMS (C ₁₈ H ₂₉ N ₅ O ₃ ) (ES, m/z) [M+H] ⁺ 364.

Step 5: rac-2-((3R,6S or 3S,6R)-1-(1-(1.4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-6methylpiperidin-3- yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5 amine

- 131 043752

A 40 ml vessel was filled with 1-(1-(1,4-dioxasniro[4,5]decan-8-yl)-1H-nirazol-4-yl)-6methylpiperidin-3-carbazide (351 mg, 0.967 mmol) and DCM (2 ml). To this mixture was added AcOH (0.025 mL, 0.44 mmol) followed by 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-4methoxybenzonitrile (intermediate 37) (300 mg, 0.879 mmol). The mixture was stirred and heated at 35°C for 16 hours. The mixture was then concentrated. The resulting residue was purified by silica gel chromatography with 10-50% EtOAc in petroleum ether as eluent to give the cis-diastereomer, 2-((3R,6S and 3S,6R)-1-(1-(1,4-dioxaspiro[ 4,5]decane-8-ul)-1H-pyrazol-4-yl)-6methylpineridin-3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2, 4]triαzolo[1,5-c]quinαzolin-5amine. LCMS (C3 ₆ H ₄ 3FN ₈ O ₅ ) (ES, m/z) [M+H]+ 687.

Step 6: 4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)cyclohexanone

To a stirred mixture of 2-((3R,6S and 3S,6R)-1-(1-(1,4-dioxaspiro[4,5]decan-8-yl)-1H-pyrazol-4ul)-6-methylpiperidin- 3-yl)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-5-amine (40.0 mg, 0.0580 mmol) in DCM (2 ml) was added TFA (2 ml). The mixture was stirred for 10 hours. The mixture was concentrated. Saturated aqueous sodium bicarbonate was added to the residue. The mixture was extracted with EtOAc (2x5 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative TLC on silica gel with EtOAc as eluent to give rac-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1 ,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1Hpyrazol-1-yl)cyclohexanone. LCMS (C ₂₅ H ₂₉ FN ₈ O ₂ ) (ES, m/z) [M+H]+ 493.

Step 7: (1r,4s or 1r,4r)-4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4 ]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclohexan-1-ol and (1r,4r or 1r,4s)- 4-(4-((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-1 -methylcyclohexan-1 -ol noAA

F

To the stirred mixture rac-4-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c] quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)cyclohexanone (18 mg, 0.037 mmol) in THF (5 ml) was added methylmagnesium bromide (0.122 ml, 0.365 mmol). The mixture was stirred at 0°C for 12 hours. The racemic mixture was quenched with aqueous NH ₄ Cl (5 ml) and extracted with EtOAc (2x5 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative reverse phase HPLC.

- 132 043752 zoy (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/water (with 0.1% TFA modifier) as eluent) to obtain (1r,4s or 1r,4r)-4-(4- ((2S,5R and 2R,5S)-5-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)-2-methylpiperidin- 1 -yl)-1 H-pyrazol-1 -yl)-1 methylcyclohexan-1-ol and (1r,4r or 1r,4s)-4-(4-((2S,5R and 2R,5S)-5- (5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 - yl)-1-methylcyclohexan-1 ol, which corresponds to the compound of Example 96 and the compound of Example 97.

For Example 96: 1H NMR (400 MHz, MeOD) δ 7.98 (s, 1H), 7.92 (d, J=11.2 Hz, 1H), 7.68 (s, 1H), 7. 22 (d, J=7.6 Hz, 1H), 4.18-4.29 (m, 1H), 4.01 (s, 4H), 3.85-3.97 (m, 2H), 3 .63-3.65 (m, 1H), 2.46-2.48 (m, 1H), 2.15-2.30 (m, 2H), 1.90-2.13 (m, 5H) , 1.73-1.84 (m, 2H), 1.60-1.72 (m, 2H), 1.31 (s, 3H), 1.20 (d, J=6.8 Hz, 3H ). LCMS (C26H33FN8O2) (ES, m/z) [M+H]+ 509.

For compound Example 97: 1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.91 (d, J=11.2 Hz, 1H), 7.70 (s, 1H), 7. 21 (d, J=8.0 Hz, 1H), 4.06 - 4.25 (m, 2H), 4.00 (s, 3H), 3.84 - 3.98 (m, 2H), 3 .65-3.68 (m, 1H), 2.48-2.50 (m, 1H), 2.10-2.32 (m, 3H), 2.02-2.08 (m, 2H) , 1.87-1.96 (m, 2H), 1.80-1.82 (m, 2H), 1.56-1.67 (m, 2H), 1.25 (s, 3H), 1 .21 (d, J=6.8 Hz, 3H). LCMS (C ₂₆ H ₃₃ FN ₈ O ₂ ) (ES, m/z) [M+H] ⁺ 509.

Example 98 and 99: (1S or 1R,2S or 2R)-2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1 ,5c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol and (1R or 1S,2R or 2S)2-(4-((R )-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1Hpyrazol-1 -yl )-1-methylcyclobutan-1-ol

A mixture of methylmagnesium bromide (0.318 ml, 0.955 mmol, 3 M in diethyl ether) in THF (1.00 ml) was cooled at 0°C. 2-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 was added to the mixture -yl)-1H-pyrazol-1-yl)cyclobutanone (intermediate 125) (86.0 mg, 0.191 mmol) in THF (1.0 ml) The mixture was stirred at 0°C for 5 hours. Water was added to the mixture (3 ml) and then the mixture was extracted with EtOAc (3x20 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by preparative TLC on silica gel with 10% MeOH in DCM as eluent. The isomeric mixture was prepared by the SFC method (OJ-3 100x4.6 mm column with 5-40% (MeOH with 0.05% DEA) as co-solvent) to give (1S or 1R,2S or 2R)-2-(4-( (R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1-yl)-1 H-pyrazol- 1-yl)-1-methylcyclobutan-1-ol (first eluted peak) and (1R or 1S,2R or 2S)-2-(4-((R)-3-(5-amino-9-fluoro-8 -methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidin-1-yl)-1H-pyrazol-1-yl)-1-methylcyclobutan-1-ol (second eluted peak) , which corresponds to the compound of example 98 and the compound of example 99, respectively.

For compound example 98: LCMS (C ₂₃ H ₂₇ FN ₈ O ₂ ) (ES, m/z) [M+H] ⁺ : 467. 1H NMR (400 MHz, CD3OD) δ = 7.98 (d, J= 10.68 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.48 Hz, 1H), 7.09 (s, 1H), 5.78 (br s, 2H ), 4.48 4.34 (m, 1H), 4.05 - 3.96 (m, 3H), 3.81-3.73 (m, 1H), 3.72 - 3.62 (m, 1H), 3.42-3.31 (m, 2H), 2.98 (t, J=11.06 Hz, 1H), 2.76-2.59 (m, 1H), 2.52-2 .38 (m, 1H), 2.33-2.15 (m, 3H), 2.06-1.77 (m, 5H), 1.42 (s, 3H).

For compound example 99: LCMS (C ₂₃ H ₂₇ FN ₈ O ₂ ) (ES, m/z) [M+H] ⁺ : 467. 1H NMR (400 MHz, CD3OD) δ = 7.98 (d, J= 10.68 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.48 Hz, 1H), 7.09 (s, 1H), 5.78 (br s, 2H ), 4.484.34 (m, 1H), 4.05-3.96 (m, 3H), 3.81-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.42-3.31 (m, 2H), 2.98 (t, J=11.06 Hz, 1H), 2.76-2.59 (m, 1H), 2.52-2.38 ( m, 1H), 2.33-2.15 (m, 3H), 2.06-1.77 (m, 5H), 1.42 (s, 3H).

Example 100: (R)-9-fluoro-7-methoxy-2-(1-(1 -methyl-1H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1 ,5-c]quinazoline-5-amine

- 133 043752

F F

Intermediate 104

BSA (2 mL, 8.18 mmol) was added to N-(2-amino-6-fluoro-8-methoxyquinazolin-4-yl)-1-(1-methyl-1Hpyrazol-4-yl)piperidin-3-carbazide (intermediate 104) (25.0 mg, 0.0600 mmol) and the mixture was stirred at 120°C for 2 hours. The solvents were then evaporated. The resulting residue was diluted with chloroform/isopropanol - 3:1 (5 ml), washed with aqueous sodium bicarbonate (saturated, 5 ml) and the organic layer was collected using a phase separation column (25 ml) and concentrated. The residue was purified by preparative reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm MeCN/water (modified with 0.1% TFA) as eluent). The racemic mixture was resolved by chiral SFC separation (OJ-H column 21x250 mm column with 20% (MeOH modifier 0.25% DMEA) as co-solvent) to give (R or S)-9-fluoro-7methoxy-2-(1 -(1-methyl-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (compound of Example 100, first eluting peak ). LCMS (C ₁₉ H ₂₁ FN ₈ O) (ES, m/z): 397 [M+H]+. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.79 (s, 2H), 7.42 (dd, J=8.4, 2.7 Hz, 1H), 7.30 (s, 1H) , 7.21-7.16 (m, 2H), 3.93 (s, 3H), 3.72 (s, 3H), 3.60 (dd, J=11.5, 3.7 Hz, 1H ), 3.32-3.30 (m, 1H), 3.29-3.23 (m, 1H), 2.83 (t, J=11.1 Hz, 1H), 2.582.52 (m, 2H), 2.20-2.12 (m, 1H), 1.88-1.81 (m, 1H), 1.80-1.74 (m, 2H).

Compounds of examples of the present invention in the following table. 24 was prepared from the corresponding intermediates in a manner similar to that described in Example 100, except that the starting materials were enantiomerically pure, so SFC separation was not performed for such examples.

Table 24

Example Structure Observ. m/z [Μ + n] ⁺ Name 101 -Λ \=/ νη ₂ , ^w ~\ DmA J^FF 385 (R or 5)-8,9-difluoro-2-(1-(1-methyl-1H-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

- 134 043752

102 -Λ \=/ νη ₂ F 367 (R or A)-9-fluoro-2-(1-(1-mestil-1R-pyrazol-4-yl)pipsridin-3yl)-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine 103 Ν £ \=/ NH ₂ F 385 (R or A')-7.9-difluoro-2-(1-(1-venstil-1R-pyrazole-4- yl)piperidin-3-yl)-[1,2,4]1riazolo[1,5-c]quinazolin-5-amine 104 I JT/Z Z^Z A Ο —ά h—Z M O F 413 (R or A')-9-chloro-7-mstoxy-2-(1-(1-mstyl-1L/-pyrazole-4- yl)piperidin-3-yl)-[1,2,4]1riazolo[1,5-c]quinazolin-5-amine 105 -Λ \=/ νη ₂ CI 397 (R or A')-9-chloro-7-vengerstyl-2-(1-(1-vengerstyl-1R-pyrazole-4- yl)piperidin-3-yl)-[1,2,4]1riazolo[1,5-c]quinazolin-5-amine 106 \ -Ν. Ν \=/ ΝΗ ₂ CI 383 (R or .5')-9-chloro-2-(1-(1-mestil-1/7-pyrazol-4-yl)pipsridin-3yl)-[1,2,4]triazolo[1,5- c]quinazoline-5-amine

- 135 043752

107 / ^z Z^Z -Π 385 (R or 5)-9,10-difluoro-2-(1-(1-methyl-1R-pyrazol-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 108 \ ,Ν Ν χ \==/ ΝΗ ₂ /° 379 (R or 5)-9-methoxy-2-(1-(1-methyl-1R-pyrazol-4-yl)piperidin3 -yl)-[1,2,4]triazolo[1,5-c]quinazoline -5 -amine

Example 109: 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol.

Step 1: 1 -(4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1, 5c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

(3R,6S)-1-(1-(2-hydroxy-2-methylpropyl)-1Hpyrazol-4-yl)-6-methylpiperidin-3-carbazide (intermediate 61) (1, 00 g, 3.39 mmol), 2((((2,4-dimethoxybenzyl)imino)-methylene)amino)-5-fluoro-4-methoxybenzonitrile (intermediate 37) (1.21 g, 3.55 mmol ) and DCM (10 ml). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexane as eluent to give 1-(4-((2S,5R)-5-(5- ((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 yl)-1H-pyrazole -1-yl)-2-methylpropan-2-ol. LCMS (C ₃₂ H ₃₉ FN ₈ O ₄ ) (ES, m/z): 619 [M+H]+. The absolute configuration of the step 1 product was designated as (2S,5R) using vibrational circular dichroism (VCD) spectroscopy with confidence. The analysis was carried out by comparing the experimental data with the calculated VCD and IR spectra of the product with the (2S,5R) configuration. The experimental VCD spectrum of the product agreed well with the calculated spectrum (2S,5R) over the region 1000-1500 cm ^-1 , which led to the determination of (2S,5R).

Step 2: 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

1-(4-((2S,5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8 Methoxy-[1,2,4]triazolo [1] was added to a 20 ml vessel ,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2methylpropan-2-ol (962 mg, 1.56 mmol) and TFA (7 ml ). The mixture was stirred and heated at 50°C for 1 hour. The mixture was then concentrated. To the resulting residue, 1 M aqueous HCl (50 ml) and DCM (50 ml) were added. The aqueous layer was washed with DCM (2x50 ml) then filtered. The pH of the aqueous layer was then adjusted to ~10 using 10 M aqueous NaOH. The aqueous layer was extracted with 10% MeOH in DCM (2x100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and

- 136 043752 the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM to give 1-(4-((2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4 ]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol (compound of example 109). LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H]+. ¹ H NMR (499 MHz, DMSO-d ₆ ) δ 7.90 (d, J=11.0 Hz, 1H), 7.72 (s, 2H), 7.20 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 3.69 (d, J=6.7 Hz, 1H), 3.35 (d, J=3.9 Hz , 1H), 3.20 (dt, J=11.1, 5.8 Hz, 1H), 3.10 (t, J=11.5 Hz, 1H), 2.00 (d, J=6, 1 Hz, 3H), 1.70 (d, J=9.3 Hz, 1H), 1.03 (d, J=4.4 Hz, 9H).

Compounds of examples of the present invention in the following table. 25 was prepared in a manner similar to that described for the preparation of Example 109 from the corresponding hydrazide and carbodiimide intermediates.

Table 25

Example Structure Observ. m/z [M + N] ⁺ Name BY \ \=/ nh ₂ /A_ 'x / ^- —\ II ^N γτι F 473 1 -(4-((25.5//)-5 -(5-amino-8-chloro-9-fluoro-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-2 -methylpiperidin-1 -yl)-177-pyrazol-1 -yl)- 2-methylpropan-2-ol 111 \ \=/ νη ₂ /“g_ F 457 1 -(4-((25.5R)-5 -(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-177-pyrazol-1 -yl)- 2-methylpropan-2-ol 112 \ \==/ nh ₂ , ^N— g_^'n^n ¹¹¹ \ / \ 1 1 ^ν yS F 453 1 -(4-((25.5R)-5 -(5-amino-9-fluoro-8-methyl-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidine -1 -yl)-177-pyrazol-1 -yl)2-methylpropan-2-ol 113 -A\=/ nh ₂ / ^N— VA^yCi Cl 417 (//)-7.9-dichloro-2-(1-(1-methyl-177-pyrazol-4-yl)piperidin-3 yl)-[1,2,4]triazolo[1,5-c]quinazolin- 5-amine

Examples 114-117: 1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazoline -2-yl)-2-methylpiperidin-1 -yl)-3-methyl-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol and 1 -(4-((2S or 2R,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2methylpiperidin-1-yl)-3-methyl -III-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5(5-amino-9-fluoro-7-methoxy-[1 ,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1P- 137 043752 pyrazol-1-yl)-2-methylpropan-2- ol and 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2 -yl)-2-methylpiperidin-1-yl)-3-methyl-III-pyrazol-1-yl)-2methylpropan-2-ol.

Step 1: 1-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2- yl) 2-methylpiperidin-1 -yl)-3-methyl-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

Intermediate 38

1-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)-6methylpiperidine-3-carbazide (intermediate 63) (133 mg, 0.431 mmol) was added to a 2 dram vessel ) and 2-((((2,4dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3-methoxybenzonitrile (intermediate 38) (140 mg, 0.410 mmol). Dioxane (1.6 ml) and acetic acid (24 μl, 0.41 mmol) were added to the mixture, and then the mixture was stirred and then heated at 60°C for 2 hours. The mixture was then allowed to slowly cool to room temperature. The mixture was diluted with DCM (10 ml) and washed with saturated aqueous sodium bicarbonate (2x10 ml) and brine. The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 10-100% EtOAc in hexanes to give 1-(4-(5-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a mixture of racemic diastereomers. LCMS (C ₃₃ H ₄₂ FN ₈ O ₄ ) (ES, m/z): 633 [M+H]+.

Step 2: 1-(4-((2R or 2S,5R or 5S)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5c]quinazoline-2 -yl)-2-methylpiperidin-1 -yl)-3-methyl-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol and 1 -(4-((2S or 2R,5R or 5S) -5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2methylpiperidin-1-yl)-3-methyl-1H -pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-((2S or 2R,5S or 5R)-5(5-amino-9-fluoro-7-methoxy-[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1Hpyrazol-1-yl)-2-methylpropan-2-ol and 1-(4 -((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1 -yl)-3 -methyl-1 H-pyrazol-1 -yl)-2 methylpropan-2-ol

1-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]) was added to a 20 ml vessel. quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl-1H-nirazol-1-yl)-2methylpropan-2-ol (80 mg, 0.126 mmol) followed by TFA (0.13 ml ). The mixture was stirred and heated at 50°C for 2 hours. The mixture was then concentrated. The resulting residue was purified by preparative reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/water with 0.1% TFA as eluent) to obtain the product as a mixture of diastereomers. The four re isomers were resolved by chiral SFC separation (IC, 21x250 mm column with 35% (2-propanol modifier 0.1% NH4OH) as co-solvent) to give 1-(4-((2R or 2S,5R or 5S) -5(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-3-methyl- 1Hpyrazol-1-yl)-2-methylpropan-2-ol (compound of Example 114, first eluted peak) and 1-(4-((2S or 2R,5R or 5S)-5-(5-αamino-9-fluoro -7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropane -2-ol (compound of Example 115, second eluted peak) and 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2, 4]triazolo[1,5-c]quinazolin-2-yl)-2- 138 043752 methylpiperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (compound Example 116, third eluting peak) and 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1, 5c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-3-methyl-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol (compound of Example 117, fourth eluted peak).

For compound example 114: LCMS (C ₂₄ H ₃₂ FN ₈ O ₂ ) (ES, m/z): 483 [M+H]+. ¹ H NMR (499 MHz, DMSO-d ₆ ) δ 7.70 (br s, 2H), 7.42 (dd, J=8.4, 2.7 Hz, 1H), 7.30 (s, 1H ), 7.18 (dd, J=11.1, 2.7 Hz, 1H), 4.75 (br s, 1H), 3.93 (s, 3H), 3.80 (s, 2H), 3, 37-3.31 (m, 1H), 3.23-3.16 (m, 1H), 2.18-2.15 (m, 1H), 2.01 (s, 3H), 2.09- 1.94 (m, 2H), 1.70-1.59 (m, 1H), 1.25-1.10 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H), 0.95 (d, J=12.0 Hz, 3H).

For compound example 115: LCMS (C ₂₄ H ₃₂ FN ₈ O ₂ ) (ES, m/z): 483 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d ₆ ) δ 7.61 (br s, 2H), 7.40 (dd, J=8.2, 2.4 Hz, 1H), 7.30 (s, 1H) , 7.18 (dd, J=11.0, 2.1 Hz, 1H), 4.75 (br s, 1H), 3.93 (s, 3H), 3.80 (s, 2H), 3.38 -3.30 (m, 1H), 3.19-3.12 (m, 1H), 2.15-2.10 (m, 1H), 2.07 (s, 3H), 2.09-1 .94 (m, 2H), 1.72-1.65 (m, 1H), 1.25-1.10 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H ), 0.93 (d,J=11.8 Hz, 3H).

For compound example 116: LCMS (C ₂₄ H ₃₂ FN ₈ O ₂ ) (ES, m/z): 483 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d ₆ ) δ 7.52 (br s, 2H), 7.41 (dd, J=8.4, 2.7 Hz, 1H), 7.39 (s, 1H) , 7.15-7.11 (m, 1H), 4.41 (br s, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.30 - 3.20 ( m, 1H), 3.13 - 3.09 (m, 1H), 2.18-2.11 (m, 1H), 2.00 (s, 3H), 2.00-1.84 (m, 2H), 1.75-1.66 (m, 1H), 1.24-1.10 (m, 2H), 1.04 (m, 6H), 0.91 (d, J=6.5 Hz , 3H).

For compound example 117: LCMS (C ₂₄ H ₃₂ FN ₈ O ₂ ) (ES, m/z): 483 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d ₆ ) δ 7.77 (br s, 2H), 7.43 (dd, J=8.4, 2.7 Hz, 1H), 7.33 (s, 1H) , 7.18 (dd, J=11.1, 2.7 Hz, 1H), 4.60 (br s, 1H), 3.94 (s, 3H), 3.83 (s, 2H), 3 .26-3.22 (m, 1H), 3.10-3.06 (m, 1H), 2.18-2.16 (m, 1H), 2.04 (s, 3H), 2.01 1.87 (m, 2H), 1.75-1.69 (m, 1H), 1.24-1.10 (m, 2H), 1.03 (s, 3H), 1.02 (s, 3H), 0.93(d, J=6.5 Hz, 3H).

Compounds of examples of the present invention in the following table. 26 was prepared in a manner similar to that described for the preparation of Examples 114-117 from the corresponding hydrazide and carbodiimide intermediates. The resulting isomeric mixtures were resolved using the SFC separation method.

Table 26

Example Structure SFC terms Observ. m/z [M + N] ⁺ Name 118 1 £ 0Н Х Х ^Н2 F Peak 1; Lux-4 21 x 250 mm column with 35% (MeOH with modifier 0.1% NH ₄ OH) as co-solvent 469 G(4-((27? or 2S,5R or 55)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2methylpiperidin-1-yl)-1 R-pyrazol-1-yl)-2methylpropan-2-ol 119 , ^z 1 z^z Η . Η ΤΊ—σ y—Z yu O / Peak 2; Lux-4 21 x 250 mm column with 35% (MeOH modifier 0.1% NH4OH) as co-solvent 469 1-(4-((25 or 2R,5S or 57?)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-2methylpiperidin-1 -yl)-1R-pyrazol-1 -yl)-2methylpropan-2-ol

- 139 043752

120 / o Tu -^° Peak 3; Lux-4 21 x 250 mm column with 35% (MeOH with modifier 0.1% NH ₄ OH) as co-solvent 469 1-(4-((2L or 25.55 or 5L)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-2-ol 121 o—V ,g lCh'N ΤΊ—C y—Z yu o / Peak 4; Lux-4 21 x 250 mm column with 35% (MeOH modifier 0.1% NH4OH) as co-solvent 469 1-(4-((25 or 2R,5R or 55)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-2-ol 122 / o i-Ur-Tu s o t Peak 1; IC-3 4.6 x 100 mm column with 40% (IPA with modifier 0.05% DEA) as co-solvent 469 2-(4-((27? or 2S,5R or 55)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-2methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1 -ol 123 / o Т ^z v ^z J TJ I z^ >$ o I Peak 2; IC-3 4.6 x 100 mm column with 40% (IPA with modifier 0.05% DEA) as co-solvent 469 2-(4-((25 or 2R,55 or 57?)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-2methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1 -ol

- 140 043752

124 / o *Y ^z v ^z ZJ ^ζ /Υ I z^ x> o I Peak 3; IC-3 4.6 x 100 mm column with 40% (ΙΡΑ with 0.05% DEA modifier) as cosolvent 469 2-(4-((2Λ or 25.55 or 57?)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-2methylpiperidin-1 -yl)- 1 /7-pyrazol-1 -yl)-2methylpropan-1 -ol 125 / o *Υ ^z v ^{z ζ} /Υ γ ζ^ Χ) ο τ Peak 4; IC-3 4.6 x 100 mm column with 40% (ΙΡΑ with 0.05% DEA modifier) as cosolvent 469 2-(4-((25 or 2R,5R or 55)-5-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2methylpiperidin-1-yl)-1/7-pyrazol-1-yl)-2methylpropan-1-ol 126 ^X o ^Y o t Peaks 1 and 2, overlap; Chiralcel OJ-3 4.6 x 100 mm column with 540% (MeOH with modifier 0.05% DEA) in as a co-solvent 469 rac-2-(4-((2K or 2S,5R or 55)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2 -yl) 2-methylpiperidin-1 -yl)-1 /7-pyrazol-1 -yl)-2methylpropan-1 -ol 127 ^X o ^Y o t Peak 3; Chiralcel OJ3 4.6 x 100 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent 469 2-(4-((2R or 25.55 or 57?)-5-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-2methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1 -ol 128 I o _m λΥ Υ ^ζ τι—σ / ^- Ζ μ ο \ Peak 4; Chiralcel OJ3 4.6 x 100 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent 469 1-(4-((25 or 2R.5R or 55)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-4methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-2-ol

Example 129 and Example 130: (R)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylsulfonyl)methyl)-1H- 141 043752 pyrazol-4-yl)piperidin-3 -yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-9-fluoro-8-methoxy-2-(1-(5methyl-1-((methylsulfonyl )methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5amine.

Step 1: mixture of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3-methyl-1-((methylthio)methyl)1H-pyrazole-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy- 2-( 1 -(5-methyl-1 -((methylthio)methyl)-1 H-pyrazol-4-yl)piperidin-3 yl)-[1,2,4]triazolo[1,5-c]quinazoline -5-amine

A 1 dram vessel was filled with a mixture of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3methyl-1H-pyrazol-4-yl)piperidin-3-yl) -[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-2-( 1 -(5- methyl-1H-pyrazol-4-yl)piperidin-3-yl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 117) (391 mg, 0.715 mmol) and (chloromethyl)(methyl)sulfane (359 µl, 4.29 mmol) in dioxane (7.0 ml). Cesium carbonate (466 mg, 1.43 mmol) was added to the mixture, and then the mixture was stirred and heated at 75° C. for 60 hours. The mixture was cooled to room temperature. The mixture was diluted with water and DCM. The mixture was poured into a phase separator. The DCM layer was collected and concentrated. The resulting residue was purified by silica gel column chromatography with 0-10% MeOH in DCM as eluent to give a mixture of (R)-N-(2,4dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(3- methyl-1 -((methylthio)methyl)-1 H-pyrazol-4-yl)piperidin-3 yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R) -N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(1-(5methyl-1-((methylthio)methyl)-1H-pyrazol-4-yl)piperidin-3-yl) -[1,2,4]triazolo[1,5-c]quinazolin-5-amine. LCMS (C30H35FN8O3S) (ES, m/z): 607 [M+H]+.

Step 2: (R)-9-fluoro-8-methoxy-2-( 1 -(3-methyl-1 -((methylsulfonyl)methyl)-1 H-pyrazol-4yl)piperidin-3-yl)-[1 ,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1((methylsulfonyl)methyl)-1H -pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine

Mixture of (R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-( 1 -(3-methyl-1 -((methylthio)methyl)-1H- 142 043752 pyrazole-4- yl)piperidin-3-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine and (R)-N-(2,4-dimethoxybenzyl)9-fluoro-8-methoxy -2-( 1 -(5-methyl-1 -((methylthio)methyl)-1 H-pyrazol-4-yl)piperidin-3 -yl)[1,2,4]triazolo[1,5-c] quinazoline-5-amine (328 mg, 0.541 mmol) was dissolved in acetone (4 ml) and water (1.35 ml). Oxone® (potassium peroxymonosulfate, 665 mg, 1.08 mmol) was added to the mixture. The mixture was stirred for 10 minutes at room temperature. The mixture was concentrated to remove acetone, diluted with water and DCM, and the organic layer was collected with a phase separator. The organic layer was concentrated. TFA (2.08 mL, 27.0 mmol) was added to the resulting residue, and the mixture was stirred and heated at 50° C. for 16 hours. The mixture was then diluted with water and DCM, and the DCM layer was collected with a phase separator and concentrated. The resulting residue was purified by reverse phase preparative HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm, MeCN/water (with 0.1% TFA modifier) as eluent) to obtain (R)-9-fluoro-8-methoxy -2-(1-(3-methyl-1((methylsulfonyl)methyl)-1H-pyrazol-4-yl)piperidin-3-yl)-[1,2,4]triαzolo[1,5-c]quinazoline -5-amine, TFA (compound of Example 129, first eluted peak) and (R)-9-fluoro-8-methoxy-2-(1-(5-methyl-1((methylsulfonyl)methyl)-1H-pyrazol- 4-yl)piperidin-3-yl)-[1,2,4]triαzolo[1,5-c]quinazolin-5-amine, TFA, (compound of Example 130, second eluted peak).

For compound example 129: LCMS (C ₂₁ H ₂₅ FN ₈ O ₃ S) (ES, m/z): 489 [M+H]+. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.87 (d, J=10.9 Hz, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 5.67 (s, 2H), 3.97 (s, 3H), 3.44 (m, 1H), 3.17 (s, 1H), 2 .99 (s, 3H), 2.31 (s, 3H), 2.20 (m, 1H), 1.87 (m, 3H).

For compound example 130: LCMS (C ₂₁ H ₂₅ FN ₈ O ₃ S) (ES, m/z): 489 [M+H] ⁺ . 1H NMR (500 MHz, DMSO-d6) δ 7.87 (dd, J=10.9, 3.6 Hz, 1H), 7.78 (s, 2H), 7.58 (s, 1H), 7 .19 (d, J=7.8 Hz, 1H), 5.52 (s, 2H), 3.97 (s, 3H), 3.48 (d, J=9.4 Hz, 1H), 3 .32 (d, J=10.1 Hz, 1H), 3.21 (d, J=11.2 Hz, 1H), 2.98 (s, 3H), 2.65 (m, 1H), 2 .18 (s, 3H), 1.97-1.71 (m, 3H).

Compounds of examples of the present invention in the following table. 27 was prepared in a manner similar to that described for the preparation of the compound of Example 129 and the compound of Example 130, from the appropriate intermediates and commercially available starting materials.

Table 27

Example Structure Observ. m/z [M + N] ⁺ Name 131 o II o=s— Cha \=/ nh ₂ / ^N— Ga ^N 'nT _n γν F 475 (77)-9-fluoro-8-methoxy-2-( 1-(1 -((methylsulfonyl)methyl)-177pyrazol-4-yl) piperidin-3-yl)-[1,2,4]triazolo [ 1,5 -с]quinazo lin-5 - amine 132 o II o=s— 1 ,Ν N ^CF ₂ H \=/ nh ₂ , ^N— H α ^Ν 'νΤ Ά F 525 (77)-2-( 1 -(3 -(difluoromethyl)-1 -((methylsulfonyl)methyl)- 177pyr azol-4-yl)piperidin-3-yl)-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazo lin-5-amine

Example 133: (S or R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-3fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol.

Step 1: (S or R)-1-(4-(3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1, 5c]quinazolin-2-yl)-3-fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

- 143 043752

(S or R)-N-(2,4-dimethoxybenzyl)-9-fluoro-2-(3-fluoropiperidin3-yl)-7-methoxy-[1,2,4]triazolo[1,5] was added to the reaction vessel -c]quinazolin-5-amine (intermediate 90) (78 mg, 0.161 mmol), 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 4) ( 52.9 mg, 0.241 mmol), tBuXPhos-Pd G3 (38.4 mg, 0.048 mmol) and sodium tert-butoxide (93 mg, 0.97 mmol) in THF (3 ml). The mixture was purged with nitrogen for 10 min. The mixture was stirred and heated at 90°C for 16 hours. The mixture was cooled to room temperature, filtered, and the solvents of the filtrate were evaporated. The residue was purified by silica gel chromatography with 0-8% MeOH in DCM (with 0.2% NH4OH) as eluent to give (S or R)-1-(4-(3-(5-((2,4- dimethoxybenzyl)amino)-9-fluoro-7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1-yl)-1H-pyrazol-1-yl )-2-methylpropan-2-ol. LCMS (C ₃₁ H ₃₆ F ₂ N ₈ O ₄ ) (ES, m/z): 623 [M+H]+.

Step 2: (S or R)-1-(4-(3-(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-3fluoropiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

An 8 ml scintillation vial was filled with (S or R)-1-(4-(3-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-7-methoxy-[1,2,4]triazolo[1 ,5-c]quinazolin-2-yl)-3-fluoropiperidin-1yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (70.0 mg, 0.112 mmol) and TFA (750 μl, 9.73 mmol). The mixture was stirred and heated at 40°C for 2 hours. The mixture was then cooled and the solvents were evaporated. The resulting residue was purified by reverse phase preparative HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm MeCN/H ₂ O with 0.05% TFA as eluent) to obtain (S or R)-1-(4-(3 -(5-amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-3-fluoropiperidin-1yl)-1H-pyrazol-1-yl )-2 methylpropan-2-ol 2,2,2-trifluoroacetate. LCMS (C ₂₂ H ₂₆ F ₂ N ₈ O ₂ ) (ES, m/z): 473 [M+H]+. 1H NMR (500 MHz, DMSO-d ₆ ) δ 7.89 (s, 2H), 7.48 (dd, J=8.3, 2.7 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=0.7 Hz, 1H), 7.21 (dd, J=11.1, 2.8 Hz, 1H), 3.93 (s, 3H), 3.88 (s , 2H), 3.68-3.47 (m, -1H), 3.45 - 3.42 (m, 1H), 3.223.08 (m, 1H), 2.84 -2.65 (m, 1H), 2.45-2.18 (m, 2H), 1.99 (d, J=9.7 Hz, 1H), 1.80 (dd, J=9.0, 4.0 Hz, 1H ), 1.03 (d, J=2.7 Hz, 6H).

Compound Example 134 in the following table. 28 was prepared from intermediate 91 and the corresponding starting materials in a manner similar to that described for the preparation of Example 133.

Table 28

Example 135: 1-(4-((2R or 2S,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-144 043752

c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol he

1-(4-((2R or 2S,5S or 5R)-5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy Mixture

[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1 H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate compound 113) (28.0 mg, 0.0440 mmol) in TFA (50.5 mg, 0.443 mmol) was heated at 60°C for 1 hour. The solvents were evaporated and the resulting residue was purified by preparative

Reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm McCN/H ₂ O with 0.1% TFA as eluent) to obtain 1-(4-((2R or 2S,5S or 5R)-5- (5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl )-2-methylpropan-2-ol.

LCMS (C24H31FN8O2) (ES, m/z): 483 [M+H]+. ¹ H NMR (500 MHz, methanol^) δ 7.97-7.89 (m, 2H), 7.70 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 4 .12 (s, 2H), 4.08-3.92 (m, 5H), 3.72-3.57 (m, 2H), 2.52-2.38 (m, 1H), 2.31 -2.14 (m, 2H), 2.09-1.98 (m, 1H), 1.75-1.56 (m, 2H), 1.18 (s, 6H), 0.94 (t , J=7.4 Hz, 3H).

Example 136: 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazoline-2 -yl)-2-ethylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol he

Example 136 was prepared from intermediate 114 in a manner similar to that described for Example 135. LCMS (C ₂₄ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, methanol-d4) δ 7.93 (d, J=11.9 Hz, 2H), 7.70 (s, 1H), 7.24 (d, J=7.5 Hz, 1H ), 4.12 (s, 2H), 4.07 - 3.93 (m, 5H), 3.69 - 3.58 (m, 2H), 2.51-2.37 (m, 1H), 2.32-2.15 (m, 2H), 2.10-1.99 (m, 1H), 1.74-1.58 (m, 2H), 1.17 (s, 6H), 0. 94 (t, J=7.3 Hz, 3H).

Example 137: 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazoline-2 -yl)-2-ethylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol he

Example 137 was prepared from intermediate 115 in a manner similar to that described for Example 135. LCMS (C ₂₄ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 483 [M+H]+. ^1H NMR (500 MHz, methanol-d4) δ 8.11 (s, 1H), 7.90-7.81 (m, 2H), 7.21 (d, J=7.5 Hz, 1H), 4.14 (d, J=20.7 Hz, 3H), 3.98 (d, J=12.7 Hz, 4H), 3.72-3.54 (m, 2H), 2.56 (d ,J=16.8 Hz, 1H), 2.45 (d, J=20.5 Hz, 1H), 2.21-2.07 (m, 1H), 1,981.82 (m, 1H), 1 .81-1.69 (m, 1H), 1.56-1.43 (m, 1H), 1.19 (s, 6H), 0.97 (t, J=7.3 Hz, 3H).

Example 138: 1-(4-((2S or 2R,5S or 5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazoline-2 -yl)-2-ethylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol

- 145 043752

Example 138 was prepared from intermediate 116 in a manner similar to that described for Example 135. LCMS (C ₂₄ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 483 [M+H]+. 1H NMR (500 MHz, methanol-d ₄ ) δ 8.13 (s, 1H), 7.86 (d, J=13.4 Hz, 2H), 7.21 (d, J=7.6 Hz, 1H), 4.15 (d, J=13.4 Hz, 3H), 3.99 (d, J=8.8 Hz, 4H), 3.74-3.54 (m, 2H), 2, 57 (d, J=11.0 Hz, 1H), 2.50-2.39 (m, 1H), 2.24-2.05 (m, 1H), 1.96 1.83 (m, 1H ), 1.82-1.67 (m, 1H), 1.59-1.42 (m, 1H), 1.18 (s, 6H), 0.97 (t, J=7.5 Hz, 3H).

Example 139: rac-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one.

Step 1: rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-1 -(1 -(2-hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)piperidin-2-one

Intermediate 89

rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2- yl)piperidin-2-one (intermediate 89) (0.102 g, 0.212 mmol), 1-(4-iodo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (0.172 g, 0.646 mmol) , copper(I) iodide (42.7 mg, 0.224 mmol), potassium phosphate (267 mg, 1.26 mmol) and anhydrous DMF (2.1 ml). The mixture was sprayed with nitrogen for 5 minutes. N ¹ ,N ² -dimethylethane-1,2-diamine (0.046 ml, 0.43 mmol) was added to the mixture. The mixture was stirred and heated at 100°C for 2 hours. The mixture was prepared by reverse phase HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/H ₂ O (with 0.l% TFA) as eluent) to give rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-1- (1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2-one. LCMS (C31H35FN8O5) (ES, m/z): 619 [M+H] ⁺ .

Step 2: rac-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2- Hydroxy2-methylpropyl)-1 H-pyrazol-4-yl)piperidin-2-one

rac-3-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)piperidin-2one (11.9 mg, 0.0192 mmol) and TFA (0.26 ml). The mixture was stirred and heated at 50°C for 1 hour. The mixture was concentrated. The residue was purified by reverse phase preparative HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/H ₂ O (with 0.l% TFA) as eluent) to obtain rac-3-(5-amino-9- fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-(2-hydroxy-2methylpropyl)-1H-pyrazol-4-yl)piperidine -2-she. LCMS (C ₂₂ H ₂₅ FN ₈ O ₃ ) (ES, m/z): 469 [M+H] ⁺ . ^1H NMR (499 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H), 7.88 (d, J=11.0 Hz, 1H), 7.79 (br s, 2H), 7, 66 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 4.18 (t, J=7.8 Hz, 1H), 3.99 - 3.93 (m, 5H ), 3.86 - 3.76 (m, 2H), 2.28 - 2.16 (m, 3H), 2.10 - 2.00 (m, 1H), 1.03 (s, 3H), 1.03(s, 3H).

Example 140 and Example 141: (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1, 5-c]quinazolin-2-yl)morpholino)-3-methyl-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol and (R)1-(4-(2-(5-( (2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- 146 043752 yl)morpholino)-5-methyl-1H- pyrαzol-1-yl)-2-methylpropan-2-ol.

Step 1: mixture of (R)-1 -(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c ]quinαzolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-((2, 4dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl1 H-pyrazol-1-yl)-2 -methylpropan-2-ol

Ome

(R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(morpholin-2yl)-[1,2,4]triazolo[1,5-c] was added to a 20 ml vessel ]quinazolin-5-amine (intermediate 87) (49.4 mg, 0.105 mmol), mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2methylpropan-2-ol (intermediate 7) (31.0 mg, 0.133 mmol), tBuXPhos-Pd G3 (33.5 mg, 0.0422 mmol), sodium tert-butoxide (60.8 mg, 0.633 mmol) and anhydrous THF (1.5 ml). The mixture was sprayed with nitrogen. The mixture was then stirred and heated at 100°C for several minutes and then cooled to 23°C and additional THF (1 ml) was added. The mixture was stirred and heated at 80°C for 14 hours. Additional amounts of a mixture of 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2methylpropan-2-ol and 1-(4-bromo- 5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 7) (42.5 mg, 0.182 mmol) and tBuXPhos-Pd G3 (33.5 mg, 0.0422 mmol) . The mixture was stirred and heated at 80°C for 8 hours. The mixture was diluted with DCM and MeOH and filtered through Celite® (diatomaceous earth). The filtrate was concentrated. The resulting residue was purified by chromatography on silica gel with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to obtain a mixture of (R)-1-(4-(2-(5-((2,4dimethoxybenzyl)amino )-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl1H-pyrazol-1-yl)-2-methylnron-2 -ola and (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c ]quinazolin-2-yl)morpholino)-5-methyl-1H-πpyrazol-1-yl)-2-methylπpropan-2-ol. LCMS (C ₃₁ H ₃₇ FN ₈ O ₅ ) (ES, m/z): 621 [M+H]+.

Step 2: (R)-1-(4-(2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino )3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and (R)-1-(4-(2-(5-amino-9-fluoro-8-methoxy[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol

A mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-147 043752 methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2ol and (R)-1-(4-(2-(5 -((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)morpholino)-5-methyl-1H-pyrazol- 1-yl)-2-methylpropan-2-ol (4.6 mg, 0.0074 mmol) and TFA (0.10 ml). The mixture was stirred at 23°C for 2 hours. The mixture was then stirred and heated at 50°C for 50 minutes. A mixture of (R)-1-(4-(2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2ol and (R)-1-(4-(2-(5-((2,4 -dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)morpholino)-5-methyl-1H-pyrazol-1-yl)-2 -methylpropan-2-ol (35.6 mg, 0.0574 mmol) and TFA (0.78 ml), and the mixture was stirred and heated at 50° C. for 50 minutes. The contents of the two reaction vessels were combined and concentrated to a residue. The residue was suspended in MeOH and filtered. The filtrate was concentrated to a residue. The resulting residue was subjected to chiral SFC separation (Chiral Technologies OJ-H 21x250 mm column with 15% (MeOH modifier 0.1% NH4OH) as co-solvent) to give (R)-1-(4-(2-(5- ((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-3-methyl-1H-pyrazol- 1-yl)-2-methylpropan-2-ol (compound of example 140) as peak 1, and the second peak. The second peak contained the impurity and was thus purified by SFC (Chiral Technologies AS-H 21x250 mm column with 20% (MeOH modifier 0.1% NH4OH) as co-solvent) to give (R)-1-(4- (2-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)morpholino)-5-methyl-1H-pyrazol-1-yl )-2-methylpropan-2-ol (compound of example 141).

For compound example 140: LCMS (C ₂₂ H ₂₇ FN ₈ O ₃ ) (ES, m/z): 471 [M+H]+. ¹ H NMR (499 MHz, DMSO-d ₆ ) δ 7.90 (d, J=10.9 Hz, 1H), 7.80 (br s, 2H), 7.37 (s, 1H), 7, 18 (d, J=7.9 Hz, 1H), 4.95 (dd, J=10.0, 2.5 Hz, 1H), 4.62 (s, 1H), 4.07 - 4.00 (m, 1H), 3.97 (s, 3H), 3.88 (td, J=11.1, 2.3 Hz, 1H), 3.83 (s, 2H), 3.07 - 2, 97 (m, 2H), 2.72 (td, J=11.5, 3.1 Hz, 1H), 2.12 (s, 3H), 1.03 (s, 3H), 1.02 (s , 3H).

For compound example 141: LCMS (C ₂₂ H ₂₇ FN ₈ O ₃ ) (ES, m/z): 471 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d6) δ 7.89 (d, J=10.9 Hz, 1H), 7.79 (br s, 2H), 7.34 (s, 1H), 7.18 ( d, J=7.9 Hz, 1H), 4.95 (dd, J=9.7, 2.6 Hz, 1H), 4.63 (s, 1H), 4.08-4.00 (m , 1H), 3.96 (s, 3H), 3.92-3.82 (m, 3H), 3.25-3.20 (m, 1H), 3.11 (dd, J=11.5 , 10.0 Hz, 1H), 2.96-2.90 (m, 1H), 2.87 (td, J=11.3, 3.1 Hz, 1H), 2.22 (s, 3H) , 1.07 (s, 3H), 1.06 (s, 3H).

Examples 142-145: (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4( 1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (S or R)-2-(5amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3methyl-1H-pyrazol-4-yl)thiomorpholine 1, 1-dioxide and (R or S)-2-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-( 1 -(2-hydroxy-2-methylpropyl)-5-methyl-1 H-pyrazol-4yl)thiomorpholine 1.1-dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1 ,2,4]triazolo[1,5-c]quinazolin2-yl)-4-( 1 -(2-hydroxy-2-methylpropyl)-5-methyl-1 H-pyrazol-4-yl)thiomorpholine 1,1 -dioxide

Step 1: mixture of 2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-4- ( 1 -(2-hydroxy-2-methylpropyl)-3 -methyl-1 H-pyrazol-4-yl)thiomorpholine 1,1 dioxide and 2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro -8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)4-( 1 -(2-hydroxy-2-methylpropyl)-5-methyl-1 H-pyrazol- 4-yl)thiomorpholine 1,1-dioxide

rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2- yl)thiomorpholine 1,1-dioxide (intermediate 88) (100 mg, 0.194 mmol), tBuXPhos-Pd G3 (154 mg, 0.194 mmol), 1-(4-bromo-3-methyl-1H-pyrazole-1) mixture -yl)-2methylpropan-2-ol and 1-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 7) (140 mg, 0.598 mmol) and dry THF (3 ml). The mixture was sprayed with nitrogen for 4 minutes. Sodium tert-butoxide (112 mg, 1.16 mmol) was added to the mixture.

The mixture was stirred and heated at 80°C for 18 hours. The mixture was concentrated. Received

- 148 043752 the residue was suspended in DCM, mixed with Celite® (diatomaceous earth) and filtered. The filtrate was concentrated. The resulting residue was purified by chromatography on silica gel with 0-70% EtOAc:EtOH (3:1) in hexanes as eluent to obtain a mixture of rac-2-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and rac-2-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-4-(1-(2-hydroxy-2methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide. LCMS (C ₃₁ H ₃₇ FN ₈ O6S) (ES, m/z): 669 [M+H]+.

Step 2: (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1 -(2hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (S or R)-2-(5-amino9-fluoro-8-methoxy-[1, 2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1Hpyrazol-4-yl)thiomorpholine 1,1-dioxide and (R or S)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-4-(1-(2- hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1 dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2, 4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide

Ome

F

A mixture of rac-2-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2 was added to a 20 ml vessel -yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4yl)thiomorpholine 1,1-dioxide and rac-2-(5-((2,4-dimethoxybenzyl )amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-5- methyl 1H-pyrazol-4yl)thiomorpholine 1,1-dioxide (48.1 mg, 0.0719 mmol) and TFA (0.96 ml). The mixture was stirred and heated at 50°C for 1 hour. The mixture was concentrated to a residue. The resulting residue was suspended in MeOH and filtered. The filtrate was concentrated to a residue, which was purified by SFC (Chiral Technologies AS-H 21x250 mm column with 20% (MeOH modifier 0.1% NH4OH) as co-solvent) to obtain four peaks, which were concentrated. Each peak was then purified separately by reverse phase preparative HPLC (Waters SunFire C18 OBD preparative column, 19 mm x 100 mm with MeCN/H ₂ O (with 0.1% TFA) as eluent) to obtain the final products, (R or S) 2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl )-3methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1, 5-c]quinazolin-2-yl)-4-(1-(2-hydroxy-2-methylpropyl)-3-methyl-III-pyrazol-4yl)thiomorpholine 1,1-dioxide and (R or S)-2 -(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)-4-( 1 -(2-hydroxy-2-methylpropyl)-5 -methyl-1 H-pyrazol-4-yl)thiomorpholine 1,1 dioxide and (S or R)-2-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5 -c]quinazolin-2-yl)-4-(1-(2hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)thiomorpholine 1,1-dioxide, which corresponds to the compound of example 142 (SFC peak 1), Example 143 (SFC Peak 2), Example 144 (SFC Peak 3), and Example 145 (SFC Peak 4), respectively.

For compound example 142: LCMS (C ₂₂ H ₂₇ FN ₈ O ₄ S) (ES, m/z): 519 [M+H] ⁺ . ¹ H NMR (499 MHz,

DMSO-d ₆ ) δ 7.91 (d, J=10.9 Hz, 1H), 7.88 (br s, 2H), 7.55 (s, 1H), 7.21 (d, J=7 .8 Hz, 1H), 4.96 (dd, J=10.3, 3.5 Hz, 1H), 3.99 (s, 3H), 3.87-3.76 (m, 3H), 3 .72-3.65 (m, 1H), 3.65-3.53 (m, 2H), 3.53 -3.45 (m, 1H), 3.44-3.34 (m, 1H) , 2.06 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).

For compound example 143: LCMS (C ₂₂ H ₂₇ FN ₈ O ₄ S) (ES, m/z): 519 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d ₆ ) δ 7.91 (d, J=10.9 Hz, 1H), 7.88 (br s, 2H), 7.55 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.3, 3.5 Hz, 1H), 3.99 (s, 3H), 3.87-3.76 ( m, 3H), 3.72-3.65 (m, 1H), 3.65-3.53 (m, 2H), 3.53 -3.45 (m, 1H), 3.44-3, 34 (m, 1H), 2.06 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H).

For compound example 144: LCMS (C ₂₂ H ₂₇ FN ₈ O ₄ S) (ES, m/z): 519 [M+H] ⁺ . ¹ H NMR (499 MHz, DMSO-d ₆ ) δ 7.89 (d, J=10.9 Hz, 1H), 7.86 (br s, 2H), 7.48 (s, 1H), 7, 20 (d, J=7.8 Hz, 1H), 4.96 (dd, J=10.1, 3.4 Hz, 1H), 3.98 (s, 3H), 3.87-3.78 (m, 3H), 3.64-3.54 (m, 3H), 3.51-3.35 (m, 2H), 2.15 (s, 3H), 1.05 (s, 3H), 1.04

- 149 043752 (s, 3H).

For compound example 145: LCMS (C ₂₂ H ₂₇ FN ₈ O ₄ S) (ES, m/z): 519 [M+H]+. 1H NMR (499 MHz,

DMSO-d ₆ ) δ 7.89 (d, J=10.9 Hz, 1H), 7.86 (br s, 2H), 7.48 (s, 1H), 7.20 (d, J=7 .8 Hz, 1H), 4.96 (dd, J=10.1, 3.4 Hz, 1H), 3.98 (s, 3H), 3.87-3.78 (m, 3H), 3 .64-3.54 (m, 3H), 3.51-3.35 (m, 2H), 2.15 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H ).

Example 146 and Example 147: (1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl) -1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol and (1S or 1R,3S or 3R)-3-(5-amino-9fluoro-8-methoxy-[1,2, 4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol

Intermediate 124

Intermediate 124 (70.0 mg, 0.170 mmol) was resolved by chiral SFC (AD

250x30mm column with MeOH (modifier 0.1% NH4OH) as co-solvent) to give (1R or 1S,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1Hpyrazol-4-yl)cyclohexan-1-ol (compound of Example 146, first peak eluted) and (1S or 1R,3S or 3R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H- pyrazol-4yl)cyclohexan-1-ol (compound of Example 147, second eluting peak).

For compound example 146: LCMS (C ₂₁ H ₂₄ FN ₇ O ₂ ) (ES, m/z) [M+H]+: 426. ¹ H NMR (400 MHz,

MeOD-d4) δ (ppm) 7.81 (s, 1H), 7.59-7.70 (m, 2H), 6.91 (br d, J=7.9 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.88-3.99 (m, 3H), 2.89-3.01 (m, 1H), 2.75 (br d, J=13, 2 Hz, 1H), 2.39 (br d, J=12.3 Hz, 1H), 1.97-2.13 (m, 2H), 1.88 (brdd, J=9.9, 3.3 Hz , 1H), 1.58-1.77 (m, 2H), 1.50-1.55 (m, 1H), 1.42-1.49 (m, 3H).

For compound example 147: LCMS (C ₂₁ H ₂₄ FN ₇ O ₂ ) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz,

MeOD-d ₄ ) δ (ppm) 7.71-7.87 (m, 2H), 7.64 (d, J=2.6 Hz, 1H), 6.96-7.18 (m, 1H) , 4.20 (q, J=7.3 Hz, 2H), 3.97 (br d, J=13.2 Hz, 3H), 2.89-3.05 (m, 1H), 2.73 (br d, J=12.7 Hz, 1H), 2.40 (br d, J=12.7 Hz, 1H), 1.99-2.13 (m, 2H), 1.91 (br d , J=13.2 Hz, 1H), 1.62-1.79 (m, 2H), 1.52-1.59 (m, 1H), 1.47 (t, J=7.5 Hz, 3H).

Example 148 and Example 149: (1S or 1R,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl) -1-(1-ethyl-III-pyrazol-4-yl)cyclohexan-1-ol and (1S or 1R,3R or 3S)-3-(5-amino-9fluoro-8-methoxy-[1,2, 4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol-4-yl)cyclohexan-1-ol

Intermediate 125

Intermediate 125 (50.0 mg, 0.120 mmol) was resolved by chiral SFC (AD

250x30mm column with IPA (modifier 0.1% NH4OH) as co-solvent) to give (1S or 1R,3R or 3S)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4 ]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-pyrazol4-yl)cyclohexan-1-ol (compound of Example 148, first peak eluted) and (1S or 1R,3R or 3S)-3(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1-ethyl-1H-πyrazole -4yl)cyclohexan-1-ol (compound of Example 149, second eluting peak).

For compound example 148: LCMS (C ₂₁ H ₂₄ FN ₇ O ₂ ) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 7.78- 7.94 (m, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.01-7.23 (m, 1H), 4.14 (q, J=7, 2 Hz, 2H), 3.99 (br s, 3H), 3.46-3.56 (m, 1H), 2.38 (br d, J=14.0 Hz, 1H), 1.92- 2.25 (m, 4H), 1.63-1.85 (m, 3H), 1.42 (t, J=7.2 Hz, 3H).

For compound example 149: LCMS (C ₂₁ H ₂₄ FN ₇ O ₂ ) (ES, m/z) [M+H]+: 426. 1H NMR (400 MHz,

MeOD-d ₄ ) δ (ppm) 7.81 (br s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.11 (br s, 1H), 4.09 -4.20 (m, 2H), 3.96 (br s, 3H), 3.51 (br s, 1H), 2.38 (br d, J=13.6 Hz, 1H), 1.96 -2.24 (m, 4H), 1.59-1.85 (m, 3H), 1.42 (t, J=7.2 Hz, 3H).

Example 150: (1R,3R or 1S,3S)-3-(5-amino-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1 -(2hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)cyclohexan-1-ol.

Step 1: Ethyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

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Add 2,6-di-tert-butylpyridine (11.1 mL, 49.4 mmol), ethyl 3-oxocyclohexane-1-carboxylate (6.32 mL, 35.3 mmol) and DCE to a 100 mL round bottom flask. (70.5 ml). The mixture was stirred and cooled at 0°C. A 1 M solution in THF Tf ₂ O (45.8 ml, 45.8 mmol) was added dropwise to the mixture over 5 minutes. The mixture was stirred for 30 minutes. The mixture was warmed to room temperature. After 2 hours the mixture was concentrated. 1:1 DCM:hexanes (20 ml) were added to the resulting residue and the solids were precipitated. Solids were removed by filtration. The filter cake was washed with 1:1 DCM:hexanes. The solvents in the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-100% EtOAc in hexanes as eluent to give ethyl 3(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

Step 2: Ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

Potassium acetate (3.96 g, 40.4 mmol), Pd(dppf)Cl ₂ (0.660 g, 0.808 mmol), bis(pinacolate)diborone (8.21 g, 32.3 mmol) was added to a 100 ml round bottom flask ) and ethyl 3(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (7.08 ml, 26.9 mmol). The flask was emptied and refilled with nitrogen three times. DMA (40 ml) was added to the flask. The mixture was stirred and heated at 90°C for 16 hours. The mixture was cooled to room temperature. The mixture was poured into a flask containing diethyl ether (150 ml). The mixture was stirred for 15 minutes. Solids were removed by filtration. The filtrate was washed with water (3x100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-30% EtOAc in hexanes as eluent to give ethyl 3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3- ene-1-carboxylate. LCMS (C ₁₅ H ₂₅ BO ₄ ) (ES, m/z) [M+H]+: 281.

Step 3: Ethyl (R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclohex-3-ene-1carboxylate

Pd(dppf)Cl ₂ (0.708 g, 0.968 mmol), K ₃ PO ₄ (15.4 g, 72.6 mmol), ethyl 3-(4,4,5,5-tetramethyl) were added to a 100 ml flask. -1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (7.12 g, 25.4 mmol) and 1-(4-bromo-1H-pyrazol-1-yl)- 2-Methylpropan-2-ol (intermediate 4) (5.30 g, 24.2 mmol). Dioxane (60 ml) and water (12 ml) were added to the flask. The mixture was sprayed with nitrogen for 5 minutes. The mixture was stirred and heated at 90°C for 2 hours. The mixture was diluted in EtOAc (10 ml) and filtered through

Celite® (diatomaceous earth) coated with anhydrous sodium sulfate. The solvents in the filtrate were evaporated. The resulting residue was purified by silica gel chromatography with 0-70% EtOAc in hexanes as eluent to give the racemate. The racemate was resolved by chiral SFC (ES Industries CCA 21x250 mm column, 15% (MeOH with NH4OH modifier) as cosolvent) to give ethyl(R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1H -pyrazol-4-yl)cyclohex-3-ene-1-carboxylate (first eluted peak). LCMS (C ₁₆ H ₂₄ N ₂ O ₃ ) (ES, m/z) [M+H]+: 293.

Step 4: ethyl(1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4yl)cyclohexane-1-carboxylate

- 151 043752

(R or S)-3-(1-(2-hydroxy-2-methylpropyl)-1Hpyrazol-4-yl)cyclohex-3-ene-1-carboxylate (933 mg, 3.19) was added to a 250 mL round bottom flask. mmol), cobalt (II) acetylacetonate hydrate (220 mg, 0.798 mmol) and THF (50 ml). Phenylsilane (1.18 mL, 9.57 mmol) was added to the mixture and the mixture was stirred and exposed to air at room temperature for 5 days. A 1 M solution of TBAF (6.38 mL, 6.38 mmol) in THF was added to the mixture. The mixture was stirred for 15 minutes. The solvents were evaporated. The resulting residue was purified by silica gel chromatography with 0-10% MeOH in DCM as eluent to give the trans-diastereomer ethyl(1R,3R or 1S,3S)-3-hydroxy-3-(1-(2hydroxy-2-methylpropyl) -1H-pyrazol-4-yl)cyclohexαn-1-carboxylate. LCMS (C ₁₆ H ₂₆ N ₂ O ₄ ) (ES, m/z) [M+H]+: 311.

Step 5: (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4yl)cyclohexane-1-carbazide

N-N N-N

Ethyl(1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2methylpropyl)-1H-pyrazol-4-yl)cyclohexane-1-carboxylate (190 mg) was added to a 20 ml vessel , 0.612 mmol), EtOH (1.5 ml) and hydrazine hydrate (0.210 ml, 3.67 mmol). The mixture was heated at 90°C for 24 hours. The solvents were evaporated to give (1R,3R or 1S,3S)-3-hydroxy-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4yl) cyclohexane-1-carbazide. LCMS (C ₁₄ H ₂₄ N ₂ O ₄ ) (ES, m/z) [M+H] ⁺ : 297.

Step 6: (1R,3R or 1S,3S)-3-(5-((2,4-dimethoxybenzyl)amino)-7-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2- yl)-1-(1 -(2-hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)cyclohexan-1 -ol

The asterisks (*) in the above diagram indicate chiral centers. (1R,3R or 1S,3S)-3-hydroxy-3-(1 -(2-hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)cyclohexane-1 carbazide (70 .0 mg, 0.236 mmol), 2-((((2,4-dimethoxybenzyl)imino)methylene)amino)-5-fluoro-3methoxybenzonitrile (105 mg, 0.307 mmol), dioxane (0.5 ml) and AcOH ( 7 µl, 0.12 mmol). The mixture was stirred and heated at 65°C for 2 hours. The solvents were evaporated. The residue was purified by silica gel chromatography with 0-100% EtOAc:EtOH (3:1) in hexanes as eluent to give (1R,3R or 1S,3S)-3-(5-((2,4-dimethoxybenzyl)amino )-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin2-yl)-1-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4 -yl)cyclohexan-1-ol. LCMS (C ₃₂ H ₃₉ N ₇ O ₅ ) (ES, m/z) [M+H] ⁺ : 602.

Step 7: (1R,3R or 1S,3S)-3-(5-αmino-7-methoxy-[1,2,4]triαzolo[1,5-c]quinazolin-2-yl)-1-(1 -(2hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)cyclohexan-1-ol

- 152 043752

DDQ (30.3 mg, 0.133 mmol) and DCM (1.0 mL) were added to a 20 mL vessel. The mixture was cooled at 0°C. Water (0.05 ml) was added to the mixture. (1R,3R or 1S,3S)-3-(5-((2,4dimethoxybenzyl)amino)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-1-(1-(2-hydroxy-2methylpropyl)-1H-pyrazol-4-yl)cyclohexan-1-ol (53.5 mg, 0.089 mmol) as a solution in DCM (1 ml). The mixture was stirred for 4 hours. 1M aqueous KOH (20 ml) was added to the mixture and then the mixture was extracted with DCM (2x20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by chromatography on silica gel with 0-100% EtOAc:EtOH (3:1) in hexane as eluent. The product was further purified by chiral SFC (Chiral Technologies OJ-H 21 x 250 mm column with 20% (NH4OH-modified MeOH) as co-solvent) to give (1R,3R or 1S,3S)-3-(5-amino- 7-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-1-(1 -(2-hydroxy-2-methylpropyl)-1 P-pyrazol-4-yl)cyclohexane -1 ol (compound example 150). LCMS (C ₂₃ P ₂₉ ^O ₃ ) (ES, m/z) [M+H]+: 452. 1H NMR (499 MHz, DMSO-d6) δ 7.73 (dd, J=8.0, 1 ,2 Hz, 3H), 7.56 (s, 1P), 7.39 (s, 1P), 7.29 (t, J=7.9 Hz, 1P), 7.24-7.10 (m , 1P), 4.81 (s, 1P), 4.65 (s, 1P), 3.95 (s, 2P), 3.90 (s, 3P), 3.48-3.40 (m, 1P), 2.22 (d, J=13.4 Hz, 1P), 2.09 (d, J=11.9 Hz, 1P), 1.98-1.84 (m, 3P), 1, 73-1.58 (m, 3P), 1.16-0.89 (m, 9P).

Example 151: (R)-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)piperidine-1 -yl)-1 P-pyrazol-1 -yl)-2-methylpropan-1 -ol

(R)-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3yl)-[1,2,4]triazolo[1,5-c] was added to a 20 ml vessel ]quinazoline-5-amine (intermediate 82) (400 mg, 0.857 mmol), sodium tert-butylate (330 mg, 3.43 mmol), 4-bromo-1-(2-methyl-1-((tetrahydro-2P- pyran-2-yl)oxy)propan-2yl)-1P-pyrazole (intermediate 151) (520 mg, 1.72 mmol), tBuXPhos-Pd G3 (272 mg, 0.343 mmol) and TPF (5.7 ml) . The mixture was purged with nitrogen for 5 minutes, capped and heated at 105°C for 16 hours. The racemic mixture was cooled to room temperature. Water (10 ml) and DCM (10 ml) were added to the mixture. The mixture was stirred for 10 minutes and filtered. The organic layer was collected with a phase separator. The solvents were evaporated. TFA (3.8 mL, 49 mmol) was added to the resulting residue and the mixture was heated at 50°C for 3 hours. The solvents were evaporated and DCM (10 mL) and 7 M ammonia in MeOH (1.07 mL) were added to the resulting residue. , 7.52 mmol). The mixture was stirred for 1 hour. The mixture was washed with water, then with saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated. The resulting residue was purified by silica gel column chromatography with 0-40% MeOH in DCM as eluent to give (R)-2-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1yl)-1P-pyrazol-1-yl)-2-methylpropan-1-ol (compound of Example 151). LCMS (C ₂₂ P ₂₇ FN ₈ O ₂ ) (ES, m/z): 455 [M+H] ⁺ . 1H NMR (600 MHz, methanol^) δ 8.18 (s, 1H), 7.92 (d, J=10.7 Hz, 1H), 7.82 (s, 1H), 7.25 (d, J=7.6 Hz, 1H), 4.14 (dd, J=12.0, 3.5 Hz, 1H), 3.84 (dd, J=26.2, 11.7 Hz, 2H), 3.76 (s, 2H), 3.66 (dt, J=9.9, 5.9 Hz, 1H), 3.57-3.46 (m, 1H), 2.51-2.39 (m, 1H), 2.30-2.02 (m, 3H), 1.59 (s, 6P).

Compounds of examples of the present invention in the following table. 29 was prepared from the corresponding starting aryl halide and amine intermediates in a manner similar to that described for the preparation of Example 151.

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Table 29

Example Structure Observ. m/z [M + N] ⁺ Name _NH; οΆι '—ι 152 [eleven F 469 (7?)-4-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin-2-yl)piperidin-1 -yl )-177-pyrazol-1-yl)-2methylbutan-2-ol but 1 \=/ nh ₂ οΆγ ^Ν ΛΑ f 153 L II 1 y'TT'F F 491 (7?)-1 -(4-(3 -(5 -amino-8-(difluoromethoxy)-9-fluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-177pyrazol-1-yl)-2-methylpropan-2-ol but j \=/ nh ₂ < ^N k..„e A _f 154 L II I f F 505 (7?)-1 -(4-(3 -(5 -amino-8-(difluoromethoxy)-9-fluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-3-methyl177-pyrazol-1-yl)-2-methylpropan-2-ol \==/ nh ₂ 155 , ^ν ΛΆ ΑΜλ ' (+/-) trans L II F 483 racemic, /ira//c-2-(4-(3-(5-amino-9-fluoro-8-methoxy- [ 1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)-2-methylpropan-1-ol \=/ nh ₂ 156 ' (+/-) trans k II F 469 racemic, /ira//c-2-(4-(3-(5-amino-9-fluoro-8-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-methylpiperidin-1-yl)177-pyrazol-1-yl)-2-methylpropan-1-ol

Example 157 and Example 158: 1-(4-((3R,5S or 3S,5R)-3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-s ]quinazolin-2-yl)-5-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-2-ol and 1-(4-((3S,5R or 3R,5S) -3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5-154 043752 methylpiperidin-1-yl)-1H -pyrazol-1-yl)-2-methylpropan-2-ol

A 20 ml microwave irradiation vessel equipped with a stirrer was filled with rac,cis-N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(5-methylpiperidin-3-yl)-[1,2 ,4]triazolo[1,5c]quinazolin-5-amine (intermediate 83) (400 mg, 0.832 mmol) and THF (5.20 ml). 1-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate 24) (388 mg, 1.67 mmol) was added to the mixture followed by tBuXPhos-Pd G3 (264 mg, 0.333 mmol) and sodium tert-butoxide (320 mg, 3.33 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The vessel was then sealed with a new stopper and heated at 90°C for 16 hours. The reaction was cooled, quenched with saturated ammonium chloride (1 ml) and celite was added. The two-phase mixture was filtered through celite coated with anhydrous MgSO ₄ and the solvents of the filtrate were concentrated. The resulting residue was dissolved in TFA (3.2 ml, 42 mmol) and heated at 50°C for 3 hours. The racemic mixture was cooled, diluted with DCM and quenched with saturated aqueous NaHCO ₃ . The biphasic mixture was separated and the aqueous phase was further extracted with DCM. The organic layers were combined, dried over anhydrous MgSO ₄ , filtered, and the solvents of the filtrate were concentrated. The resulting residue was purified by silica gel chromatography with 0-20% MeOH in DCM as eluent. The purified product was then subjected to chiral SFC separation (Chiral Technologies AD-H 21x250mm column with 30% (IPA modifier 0.1% NH4OH) co-solvent) to give 1-(4-((3R,5S or 3S,5R) -3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)5-methylnineridin-1-yl)-1H-nirazol- 1-yl)-2-methylnpronan-2-ol (compound of Example 157, first eluted peak) and 1-(4-((3S,5R or 3R,5S)-3-(5-amino-9-fluoro-8 -methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-5-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (compound example 158, second eluted peak).

For compound example 157: LCMS (C24H ₃₁ FN ₈ O ₂ ) (ES, m/z): 483 [M+H]+. Ή NMR (499 MHz,

DMSO-d ₆ ) δ 7.87 (d, J=11.0 Hz, 1H), 7.69 (s, 2H), 7.34 (s, 1H), 7.18 (d, J=7, 9 Hz, 1H), 4.61 (s, 1H), 3.97 (s, 3H), 3.83 (s, 2H), 3.46 (d, J=10.9 Hz, 1H), 3 .28 (d, J=11.8 Hz, 1H), 3.13 (d, J=8.6 Hz, 1H), 2.64 (t, J=11.3 Hz, 1H), 2.22 (d, J=13.4 Hz, 1H), 2.16 (t, J=11.1 Hz, 1H), 2.11 (s, 3H), 1.94 (s, 1H), 1.38 (q, J=12.3 Hz, 1H), 1.03 (d, J=3.1 Hz, 6H), 0.97 (d, J=6.6 Hz, 3H). For compound example 158: LCMS (C ₂₄ H ₃₁ FN ₈ O ₂ ) (ES, m/z): 483 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d ₆ ) δ 7.87 (d, J=11.0 Hz, 1H), 7.69 (s, 2H), 7.34 (s, 1H), 7.18 ( d, J=7.8 Hz, 1H), 4.61 (s, 1H), 3.97 (s, 3H), 3.83 (s, 2H), 3.47 (d, J=8.4 Hz, 1H), 3.29 (s, 1H), 3.13 (d, J=8.0 Hz, 1H), 2.64 (t, J=11.3 Hz, 1H), 2.22 ( d, J=12.5 Hz, 1H), 2.16 (t, J=11.0 Hz, 1H), 2.11 (s, 3H), 1.96 (s, 1H), 1.38 ( q, J=12.4 Hz, 1H), 1.03 (d, J=3.1 Hz, 6H), 0.97 (d, J=6.6 Hz, 3H).

Compounds of examples of the present invention in the following table. 30 was prepared from the corresponding starting amine and aryl halide in a manner similar to that described for the preparation of the compound of Example 157 and the compound of Example 158, where the resulting isomeric mixture of the respective final compounds was separated by SFC.

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Table 30

Example Structure SFC terms Observation m/z, [M + N] ⁺ Name 159 he ,Ν Ν > ΆΑ νη ₂ CIS F Peak 1; Cellulose-2 30 x 250 mm column with 5-15% (MeOH with modifier 0.05% DEA) as a co-solvent 469 1-(4-((ZL,55 or 35.5L)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-5 methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-2-ol 160 OH ,Ν Ν > nh ₂ CIS F Peak 2; Cellulose-2 30 x 250 mm column with 5-15% (MeOH with modifier 0.05% DEA) as a co-solvent 469 1-(4-((35.5R or 37?.55)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-2-ol

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161 OH ,NN nh ₂ cis G / ⁰ F Peak 1; Cellulose-3 4.6 χ 150 mm column with 5-15% (MeOH with modifier 0.05% DEA) as a co-solvent 483 1-(4-((ZL,55 or 35.5L)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-5 methylpiperidin-1 -yl)-3 -methyl-177-pyrazol-1 -yl)2-methylpropan-2-ol 162 OH ,NN nh ₂ CIS G / ⁰ F Peak 2; Cellulose-3 4.6 χ 150 mm column with 5-15% (MeOH with modifier 0.05% DEA) as a co-solvent 483 1-(4-((35.5R or 37?.55)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)2-methylpropan-2 -ol 163 OH Λ LL νη ₂ / ^Ν Λ_λ ^ν 'ν^ν \ / ' JL fm ^N CIS F Peak 1; Chiral Technologies ASH 21 × 250 mm column with 25% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 457 l-(4-((37?,5S or 35.57?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-с]quinazo lin-2- yl)-5 methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-2-ol 164 he Λ 'LL nh ₂ \ /* ' oL JL f cis F Peak 2; Chiral Technologies ASH 21 x 250 mm column with 25% (MeOH with modifier 457

- 157 043752

1-(4-((35.577 or 377.55)-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1-yl)-177-pyrazol-1-yl)-2- methylpropan-2-ol 0.1% NH ₄ OH) as co-solvent 165 __z . / z—4— j= LJQ § Y ^T z^z Y ΊΊ—y—Z k>o— Peak 1; Lux-4 21 × 250 mm column with 40% (MeOH with 0.1% ΝΗ4ΟΗ modifier) as co-solvent 469 2-(4-((377.55 or 35.577)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 5 methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1-ol 166 Ν >'L·# nh ₂ / ^N ~\ n~ _n A _n ! CIS F Peak 2; Lux-4 21 × 250 mm column with 40% (MeOH with 0.1% ΝΗ4ΟΗ modifier) as co-solvent 469 2-(4-((35.577 or 377.55)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)- 5 methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1 -ol 167 Ν'\ νη ₂ / ^N ^ z^N^N ργν cis γ JJ F Peak 1; Lux-4 21 × 250 mm column with 30% (MeOH with 0.1% ΝΗ4ΟΗ modifier) as co-solvent 471 1-(4-((377.55 or 35.577)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1 -yl)-3-methyl-1 /7-pyrazo l-1 -yl)2-methylpropan-2-ol

- 158 043752

168 U^on ,Ν Ν /> UU nh ₂ rch+Du CIS F Peak 2; Lux-4 21 × 250 mm column with 30% (MeOH with 0.1% ΝΗ ₄ ΟΗ modifier) as co-solvent 471 1-(4-((35.5R or 37?.55)-3-(5-amino-7,9-difluoro- [ 1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)2-methylpropan-2-ol 169 Ur^on N'\ УУ NH ₂ +^ ^νΛ Δ cis У. Jk о F ¹ Peak 1; Chiralpak AD-3 4.6 x 150 mm column with 0-40% (IPA with modifier 0.05% DEA) as a co-solvent 483 2-(4-((37?.55 or 35.57?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-5 methylpiperidin-1 -yl)-3 -methyl-177-pyrazol-1 -yl)2-methylpropan-1 -ol 170 UD^ON N'\ УУ nh ₂ / ^Ν ^λ ^Ν 'Ν^Ν Cis U. Jk o F ¹ Peak 2; Chiralpak AD-3 4.6 x 150 mm column with 0-40% (IPA with modifier 0.05% DEA) as a co-solvent 483 2-(4-((35.57? or 37?.55)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)2-methylpropan-1 - ol 171 ,Ν N > %У nh ₂ z ^N y. /NN^N cis U. 3k 0 F ¹ Peak 1; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (EtOH with modifier 0.05% DEA) in the form 469 2-(4-((37?.55 or 35.57?)-3-(5-amino-9-fluoro-8-

- 159 043752

methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1 -ol co-solvent 172 l nh ₂ / ^Ν γ_Λ ^Ν 'Ν^Ν cis Υ o F ¹ Peak 2; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent 469 2-(4-((35.5R or 37?.55)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1-ol 173 DM n NH ₂ CIS F Peak 1; ES Industries CCA 21 x 250 mm column with 25% (MeOH modifier 0.1% NH ₄ OH) as co-solvent 483 l-(4-((37?.55 or 35.57?)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-с]quinazolin-2 -yl)-5 methylpiperidin-1 -yl)-5 -methyl-1 /7-pyrazo l-1 -yl)2-methylpropan-2-ol 174 ^z 1 z~. V_ с'О О' § Y ¹ z^z У ΤΊ^-C у—Z 63 о— Peak 2; ES Industries CCA 21 x 250 mm column with 25% (MeOH modifier 0.1% NH4OH) as co-solvent 483 1-(4-((35.5R or 37?.55)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1 -yl)-5-methyl-1/7-pyrazo l-1 -yl)2- methylpropan-2-ol

- 160 043752

175 jz—zL· jz LJO ο γ ¹ Z^Z ΤΊ^-ν y—Z n> o— Peak 1; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent 483 2-(4-((ZL,55 or 35.5L)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl) -5 methylpiperidin-1 -yl) -3 -methyl-172-pyrazol-1 -yl)2-methylpropan-1 -ol 176 1 z—γ Χ ^χΧ4 'ζ· ^χ ^ ^/ / jz IJ O ο γ ¹ z^z ΤΊ—σ y— Ζ yu ο— Peak 2; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent 483 2-(4-((35.5R or 37?.55)-3-(5-amino-9-fluoro-7- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1 -yl)-3-methyl-172-pyrazol-1 -yl)2-methylpropan-1 -ol 177 N'\ nh ₂ CIS F Peak 1; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent 471 2-(4-((37?.55 or 35.57?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-5 methylpiperidin-1 -yl)-3 -methyl-172-pyrazol-1 -yl)2-methylpropan-1 -ol 178 ,ν N > nh ₂ , ^ν Χ_λ ^ν Ά _Ν CIS F Peak 2; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent 471 2-(4-((35.5R or 37?.55)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-5 -

- 161 043752

methylpiperidin-1 -yl)-3-methyl-1 /7-pyrazol-1 -yl)2-methylpropan-1 -ol 179 N'\nh ₂ trans F Peak 1; Chiral Technologies OJH 21 x 250 mm column with 20% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 457 2-(4-((35.55 or 37?.57?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-с]quinazolin-2- yl)-5 methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1 -ol 180 4ά>η Ν'\ ΝΗ ₂ trans F Peak 2; Chiral Technologies OJH 21 x 250 mm column with 20% (MeOH with modifier 0.1% NH4OH) as a co-solvent 457 2-(4-((3Λ,5Λ or 35.55)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl) -5 methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1 -ol 181 ^-Ζ Z—. \_ * 1 /\ ω - ¹ - o JL ζ^ζ _m lCH ΤΊ^-y y—Ζ ιό Peak 1; Chiral Technologies OJH 21 x 250 mm column with 20% (MeOH with modifier 0.1% NH4OH) as a co-solvent 457 1-(4-((35.55 or 37?.57?)-3-(5-amino-7,9-difluoro- [ 1,2,4]triazolo [1,5 -с]quinazolin-2-yl)-5 methylpiperidin-1 -yl)-1 /7-pyrazol-1 -yl)-2- methylpropan-2-ol

- 162 043752

182 |Άη ,Ν N to \L_7 NH ₂ / ^Ν Λζ, ^Ν 'Ν^Ν taken into account trans F Peak 2; Chiral Technologies OJH 21 x 250 mm column with 20% (MeOH modifier 0.1% NH ₄ OH) as co-solvent 457 1-(4-((ZL,5L or 35.55)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl) -5 methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-2-ol 183 _-Z L. J o\\ z^z Kz ΤΊ—C y—Z yu ABOUT \ Peak 1; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent 469 (R or 5)-1-(4-((7?)-3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazoline-2 -yl)piperidin-1 yl)-1 /7-pyrazol-1 -yl)-2-methylbutan-2-ol 184 ^z ~Λ / C J o ζ^ζ τι—g y—z yu ABOUT \ Peak 2; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent 469 (S or 7?)-1-(4-((7?)-3-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin- 2-yl)piperidin-1 yl)-177-pyrazol-1 -yl)-2-methylbutan-2-ol 185 ^z f A.__/ o , ^z —(* s 2 τι—Г у—Z Ki o— Peak 1; ES Industries CCA 21 × 250 mm column with 30% (MeOH modifier 0.1% NH4OH) as cosolvent 455 (25.35 or 27?,37?)-3-(4-((L)-3-(5-amino-9-fluoro-7-

- 163 043752

methoxy-[1,2,4]triazolo[1,5-c]quinazo lin-2 yl)piperidin-1 -yl)-177-pyrazol-1 -yl)butan-2-ol 186 / 1 __/ o y-—(* ^s 2 ΤΊ—and y—Z ^m O— Peak 2; ES Industries CCA 21 x 250 mm column with 30% (MeOH with modifier 0.1% NH ₄ OH) as co-solvent 455 (27?,37? or 25.35)-3-(4-((7?)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5 -с ]quinazo lin-2 - yl)piperidin-1 -yl)- 177-pyrazol-1 -yl)butan-2-ol 187 ^syn^H nh ₂ 2—/ ⁴ vXXx τ 1 F 1 Peak 1; Chiral Technologies ASH 21 x 250 mm column with 30% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 455 (2S,3S or 27?,37?)-3-(4-((7?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5 -с ]quinazo lin-2 yl)piperidin-1 -yl)- 177-pyrazol-1 -yl)butan-2-ol 188 ^sin^N Su nh ₂ Tjl F 1 Peak 2; Chiral Technologies ASH 21 x 250 mm column with 30% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 455 (27?,37? or 25.35)-3-(4-((7?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5 -с ]quinazo lin-2 - yl)piperidin-1 -yl)- 177-pyrazol-1 -yl)butan-2-ol 189 —o nX Peak 1; ES Industries CCA 21 x 250 mm column with 15% (MeOH with modifier 0.1% NH ₄ OH) as 469 (2S,3S or 27?,37?)-3-(4-((7?)-3-(5-amino-9-fluoro-7-

- 164 043752

methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2yl) piperidin-1-yl)-3-methyl-177-pyrazol-1 yl)butan-2-ol co-solvent 190 -O Peak 2; ES Industries CCA 21 x 250 mm column with 15% (MeOH modifier 0.1% NH ₄ OH) as co-solvent 469 (2R,3R or 25.35)-3-(4-((/?)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2yl)piperidin-1-yl)-3-methyl-177-pyrazol-1 yl)butan-2-ol 191 ^sin £H A /Μ Ν ^Η 2 '—/ 'nAAzF tu F Peak 1; Chiral Technologies ADH 21 x 250 mm column with 30% (MeOH with modifier 0.1% NH4OH) as a co-solvent 457 (25.35 or 2L.37?)-3-(4-((7?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo [1,5-c]quinazo lin-2-yl)piperidin-1 yl)-3 -methyl-177-pyrazol-1 -yl)butan-2-ol 192 nA nh ₂ y ^4- g \'nAA/F tu F Peak 2; Chiral Technologies ADH 21 x 250 mm column with 30% (MeOH with modifier 0.1% NH4OH) as a co-solvent 457 (2R,3R or 25,35)-3-(4-((7?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazoline -2-yl)piperidin-1-yl)-3-methyl-177-pyrazol-1-yl)butan-2-ol

- 165 043752

193 —o V-L Peak 1; Chiral Technologies ADH 21 x 250 mm column with 25% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 469 (2S,3S or 2L,ZL)-3-(4-((L)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo [1,5-c]quinazo lin-2 yl) piperidin-1 -yl) -5 -methyl- 177-pyrazol-1 yl) butan-2-ol 194 N'V nh ₂ / ^N ~3 2^|Αν । that F Peak 2; Chiral Technologies ADH 21 x 250 mm column with 25% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 469 (1R,3R or 25,35)-3-(4-((L)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo[1,5-c]quinazo lin-2 yl) piperidin-1 -yl) -5 -methyl- 177-pyrazol-1 yl) butan-2-ol 195 ς,ΑΑ O ΠΊ—σ y—Ζ yu -O Peak 1; Chiral Technologies IG 21 x 250 mm column with 35% (MeOH with modifier 0.1% NH ₄ OH) as co-solvent 469 (2S,3S or 27?,37?)-3-(4-((7?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo [1,5 - c]quinazolin-2yl)piperidin-1-yl)-5-methyl-177-pyrazol-1yl)butan-2-ol 196 N'V nh ₂ , ^Ν— Υ У TO F 1 Peak 2; Chiral Technologies IG 21 x 250 mm column with 35% (MeOH with modifier 469

- 166 043752

(2R,3R or 25,35)-3-(4-((7?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo [1,5-c]quinazo lin-2 yl) piperidin-1 -yl) -5 -methyl- 177-pyrazol-1 yl) butan-2-ol 0.1% NH ₄ 0H) as co-solvent 197 ^sin^ νΛ Hell νη ₂ / ^Ν ~-- /ΥνΤ _ν '—/ 'nTT/F tu F Peak 1; Chiralpak AS-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent 443 (2S,3S or 27?,37?)-3-(4-((7?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo [1,5 -с] quinazol-lin-2-yl)piperidin-1-yl)-177-pyrazol-1-yl)butan-2-ol 198 Λ Hell nh ₂ / ^N ~-- /Yn^n '—/ 'nTT/F tu F Peak 2; Chiralpak AS-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent 443 (2R,3R or 25,35)-3-(4-((7?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazoline -2-yl)piperidin-1 yl)- 177-pyrazol-1 -yl)butan-2-ol 199 anti he Ά Hell nh ₂ / ^Ν— ^,Ν'-ν'Τν \/ ⁴ tu F । Peak 1; Chiral Technologies OJH 21 x 250 mm column with 15% (MeOH with modifier 0.1% NH4OH) as a co-solvent 455 (2R,3S or 25.37?)-3-(4-((7?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo [1,5 -с] quinazo lin-2 yl)piperidin-1 -yl)- 177-pyrazol-1 -yl)butan-2-ol

- 167 043752

200 anti OH n'\ νη ₂ Τ ^Ν ^ ^Ν \/ No. TU\ t 1 7g θ F । Peak 2; Chiral Technologies OJH 21 x 250 mm column with 15% (MeOH modifier 0.1% NH ₄ OH) as co-solvent 455 (2S,3R or 2L,ZE-3-(4-((L)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo [1,5-c]quinazo lin- 2 yl)piperidin-1 -yl)- 177-pyrazol-1 -yl)butan-2-ol 201 anti OH <7 nh ₂ / ^N— g tu F Peak 1; Chiral Technologies ADH 21 x 250 mm column with 35% (MeOH with modifier 0.1% NH4OH) as a co-solvent 455 (2R,3S or 25.37?)-3-(4-((7?)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo [1,5 -с] quinazo lin-2 yl)piperidin-1 -yl)- 177-pyrazol-1 -yl)butan-2-ol 202 Antion A nh ₂ / ^N— g tu F Peak 2; Chiral Technologies ADH 21 x 250 mm column with 35% (MeOH with modifier 0.1% NH4OH) as a co-solvent 455 (2S,3R or 27?,35)-3-(4-((7?)-3-(5-amino-9-fluoro-7methoxy-[1,2,4]triazolo [1,5 -с] quinazo lin-2 yl)piperidin-1 -yl)- 177-pyrazol-1 -yl)butan-2-ol 203 anti he nh ₂ T ⁿ ^ ⁿ '—/ 'TA/ tu F Peak 1; Chiralpak AS-3 4.6 x 100 mm column with 0-40% (IPA with modifier 0.05% DEA) as a co-solvent 443 (2R,3S or 25.37?)-3-(4-((7?)-3-(5-amino-7,9-difluoro[1,2,4]triazolo [1,5-c]quinazo lin-2-yl)piperidin-1-yl)-177-pyrazol-1-yl)butan-2-ol

- 168 043752

204 anti^ON L Ad nh ₂ / ^N— 7^'N-^N \—/ 'nA/T tu F Peak 2; Chiralpak AS-3 4.6 x 100 mm column with 0-40% (IPA with modifier 0.05% DEA) as a co-solvent 443 (2S,3R or 2L,35)-3-(4-((L)-3-(5-amino-7,9-difluoro[1,2,4]triazolo [1,5-c]quinazo lin- 2-yl)piperidin-1-yl)-177-pyrazol-1-yl)butan-2-ol 205 .1 z—/X *[ T /—θ T* S o 1 ζ^ζ AW* ΤΙ—г у—Ζ ιό Ο— Peak 1; Chiralpak AD-3 4.6 x 100 mm column with 5-40% (IPA with 0.05% DEA modifier) as co-solvent. Then peak 1; Chiral Technologies ADH 21 x 250 mm column with 20% (IPA with 0.1% NH ₄ OH modifier) as co-solvent 497 (R or 5)-3-(4-((37/.55 or 35.57/)-3-(5-amino-9-fluoro7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5methylpiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)3-methylbutan-2-ol 206 .1 z—/X *1 T /—θ JZ t» S o 1 ζ^ζ τι—г у—Ζ ιό Ο— Peak 1; Chiralpak AD-3 4.6 x 100 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. Then peak 2; Chiral 497 (5 or 7/)-3-(4-((37/.55 or 35.57/)-3-(5-amino-9-fluoro7-methoxy-[1,2,4]triazolo[1,5 -c]quinazolin-2-yl)-5methylpiperidin-1-yl)-3-methyl-177-pyrazol-1-yl)- 3-methylbutan-2-ol

- 169 043752

Technologies ADH 21 x 250 mm column with 20% (IPA with 0.1% NH ₄ OH modifier) as co-solvent 207 OH nA p-y NH ₂ / ^N ^y /^N^N | /* CIS T |T F Peak 2; Chiralpak AD-3 4.6 x 100 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 497 (R or 5)-3-(4-((35.5R or 37?.55)-3-(5-amino-9-fluoro7-methoxy-[1,2,4]triazolo[1,5 -с ]quinazolin-2-yl)-5 methylpiperidin-1 -yl)-3 -methyl-177-pyrazol-1 -yl)3-methylbutan-2-ol 208 'γΑ nA 'Ср νη ₂ /А* ,^Ν^Ν )—/ ⁴ / * cis 1 Η F Peak 1; ES Industries CC4 21 x 250 mm column with 35% (MeOH modifier 0.1% NH4OH) as co-solvent. Then peak 1; ES Industries CCA 21 x 250 mm column with 15% (MeOH modifier 0.1% NH4OH) as co-solvent 483 (25,35 or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1, 5c]quinazolin-2-yl)-5 -methylpiperidin-1 -yl)-3 methyl-177-pyrazol-1 -yl)butan-2-ol

- 170 043752

209 A nh ₂ A. A ^N ^ ^N )—' n*\Yx / * cis | | yV F Peak 1; ES Industries CC4 21 x 250 mm column with 35% (MeOH modifier 0.1% NH ₄ OH) as co-solvent. Then peak 2; ES Industries CCA 21 x 250 mm column with 15% (MeOH modifier 0.1% NH4OH) as co-solvent 483 (2R,3R or 2S,35)-3-(4-((37^.55 or 35.5^)-3-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[ 1,5c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)butan-2-ol 210 ^sin^ nA A/ nh ₂ /A* /An^n )—/ nA/\ / * cis 1 Π F Peak 2; ES Industries CC4 21 x 250 mm column with 35% (MeOH modifier 0.1% NH4OH) as co-solvent. 483 (2R,3R or 25.35)-3-(4-((35.5R or 3R,58)-3-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1, 5c]quinazolin-2-yl)-5 -methylpiperidin-1 -yl)-3 methyl-177-pyrazol-1 -yl)butan-2-ol 211 A A/ nh ₂ / ^Ν Α» zAn^n )—' nAY\ / * cis T | γΑ F Peak 3; ES Industries CC4 21 x 250 mm column with 35% (MeOH modifier 0.1% NH4OH) as co-solvent. 483 (25,35 or 2R,3R)-3-(4-((3S,5R or 3R,55)-3-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1, 5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)butan-2-ol

- 171 043752

212 A Λλ Τ ² )—/ ' / * CIS Γ || F Peak 1; Chiral Technologies ADH 30 x 250 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 471 (25.35 or 2Λ,3Λ)-3-(4-((3Λ.55 or 35.5Λ)-3-(5amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin2-yl)-5-methylpiperidin-1-yl)-3-methyl-1Hpyrazol-1-yl)butan-2-ol 213 Ζ , O Г ' / I _x Υ^ζ—4 and [ 1 / I β X/ I T» ζ^ζ my—z yu Peak 2; Chiral Technologies ADH 30 x 250 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 471 (2R,3R or 25,35)-3-(4-((3Λ,55 or 3S,5R)-3-(5amino-7,9-difluoro-[1,2,4]triazolo [1,5 - c]quinazolin2-yl)-5-methylpiperidin-1-yl)-3-methyl-1Hpyrazol-1-yl)butan-2-ol 214 syn^ON A Λλ T ² \'nYX/F / * cis Г J F Peak 3; Chiral Technologies ADH 30 x 250 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 471 (2R,3R or 25.35)-3-(4-((35.5R or 3R.55)-3-(5amino-7,9-difluoro-[1,2,4]triazolo [1,5 - c]quinazolin2-yl)-5-methylpiperidin-1-yl)-3-methyl-1Hpyrazol-1-yl) butan-2-ol 215 xi^on A Λλ 7 ^H2 \'N^YaY-F / * cis G J F Peak 4; Chiral Technologies ADH 30 x 250 mm column with 5-40% (IPA with modifier 471

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(25.35 or 27?,370-3-(4-((35.57? or 37?.55)-3-(5amino-7,9-difluoro-[1,2,4]triazolo[1, 5-c]quinazolin2-yl)-5-methylpiperidin-1-yl)-3-methyl-177pyrazol-1-yl)butan-2-ol 0.05% DEA) in form co-solvent. 216 ^syn^ ⁿ ' ^N /A V/ νη ₂ )—/ ' / * ^cis 1 |1 F Peak l;IG50 χ 250 mm column with 540% (EtOH with 0.05% DEA modifier) as co-solvent. 471 (25,35 or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5amino-7,9-difluoro[1,2,4]triazolo[1,5- c]quinazolin2-yl)-5-methylpiperidin-1-yl)-5-methyl- 177pyrazol-1-yl)butan-2-ol 217 ^sin^ N'V \L/Z NH ₂ / ^N A* )—/ 'n^XXy-f / * cis 1 |[ F Peak 2; IG 50 χ 250 mm column with 540% (EtOH with 0.05% DEA modifier) as co-solvent. 471 (27?,37? or 25.35)-3-(4-((37?,55 or 3S,5R)-3-(5amino-7,9-difluoro-[1,2,4]triazolo[1 ,5-c]quinazolin2-yl)-5-methylpiperidin-1-yl)-5-methyl-177pyrazol-1-yl)butan-2-ol 218 X^-A A/ nh ₂ / * cis | |[F PikZ;I50 χ 250 mm column with 540% (EtOH with 0.05% DEA modifier) as a co-solvent. 471 (27?,37? or 25.35)-3-(4-((35.5R or 3R,5S)-3-(5amino-7,9-difluoro-[1,2,4]triazolo[1, 5-c]quinazolin2-yl)-5-methylpiperidin-1-yl)-5-methyl-177pyrazol-1-yl)butan-2-ol

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219 N'V nh ₂ )—''гУДу / * cis T |Т F Peak 4; IG 50 χ 250 mm column with 540% (EtOH with 0.05% DEA modifier) as co-solvent. 471 (25.35 or 2Λ,3Λ)-3-(4-((35.5Λ or 3Λ,55)-3-(5amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin2-yl)-5-methylpiperidin-1-yl)-5-methyl-177pyrazol-1-yl)butan-2-ol 220 -O Peak 1; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 483 (25.35 or 27?,37?)-3-(4-((37?.55 or 35.57?)-3-(5amino-9-fluoro-7-methoxy-[1,2,4] triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5 methyl-177-pyrazol-1-yl)butan-2-ol 221 -O 1° Peak 2; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 483 (2R,3R or 25.35)-3-(4-((37?.55 or 35.57?)-3-(5amino-9-fluoro-7-methoxy-[1,2,4]triazolo[ 1.5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5 methyl-177-pyrazol-1-yl)butan-2-ol 222 -O 1° Peak 3; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) in 483

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(2R,3R or 25.35)-3-(4-((35.5R or 3^.55)-3-(5amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1 ,5c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-5 methyl-177-pyrazol-1-yl)butan-2-ol form co-solvent. 223 -O 1° Peak 4; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 483 (25,35 or 2R,3R)-3-(4-((3S,5R or 3R,58)-3-(5amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1, 5c]quinazolin-2-yl)-5 -methylpiperidin-1 -yl)-5 methyl- 1 //-pyrazol-1 -yl)butan-2-ol 224 —o ^z ^ ^z o * ^s o—4 1* Peak 1; Chiral Technologies ADH 30 x 250 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. Then peak 1; Chiral Technologies ADH 30 x 250 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 483 (25,35 or 2R,3R)-3-(4-((3R,5S or 3S,5R)-3-(5amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1, 5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)butan-2-ol

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225 -о « ^s о-4 1* ίκχ ^z ^\ Peak 1; Chiral Technologies ADH 30 x 250 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. Then peak 2; Chiral Technologies ADH 30 x 250 mm column with 5-40% (IPA with modifier 0.05% DEA) as a co-solvent. 483 (2R,3R or 2S,3S)-3-G-((3R,5S or 35.5Λ)-3-(5amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5с ]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)butan-2-ol 226 —о ζ^,ζ О « ^s о—4 1* ίΗΎ ^ζ ^\ Peak 2; Chiral Technologies ADH 30 x 250 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. 483 (2R,3R or 25.35)-3-(4-((35.5R or 37?.55)-3-(5amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1 ,5c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)butan-2-ol 227 —o ζ^,ζ « ^s 0—4 1* 1Г<Х ^z ^\ Peak 3; Chiral Technologies ADH 30 x 250 mm column with 5-40% (EtOH with modifier 0.05% DEA) in the form 483 (25.35 or 27?,37?)-3-(4-((35.57? or 3R,5S)-3-(5- amino-9-fluoro-7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-5-methylpiperidin-1-yl)-3 methyl-177-pyrazol-1-yl)butan-2-ol co-solvent.

Example 228-231: (2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2, 4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-III-pyrazol-1-yl)butan-2-ol and (2S,3S or 2R,3R)- 3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2- yl)-2methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2R,3R or 2S,3S)-3-(4-((2R,5S or 2S,5R)- 5-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1H-pyrazol-1yl) butan-2-ol and (2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2 ,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperudin-1-yl)-1H-pyrazol-1-yl)butan-2-ol

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Step 1: mixture of diastereomers (2S,3S and 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-((2,4dimethoxybenzyl)amino)-9-fluoro-8 -methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1yl)-1 H-pyrazol-1 -yl)butan-2-ol.

To a solution of N-(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-((3R,6S and 3S,6R)-6-methyl-1-(1H-pyrazol4-yl)piperidin-3- yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (intermediate 177) (530 mg, 0.970 mmol) in DMF (10 ml) was added cis-2,3-dimethyloxirane ( 846 µl, 9.70 mmol) and cesium carbonate (1.26 g, 3.88 mmol). The mixture was stirred and heated at 125°C for 5 hours. The mixture was cooled to room temperature and the mixture was diluted with water (20 ml) and ethyl acetate (20 ml). The biphasic mixture was separated and the aqueous phase was further extracted with ethyl acetate (20 ml). The combined organic layers were then washed with water (2x20 ml) and brine (1x20 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvents were evaporated. The residue was purified by silica gel chromatography with 0-20% MeOH in DCM as eluent to give a mixture of diastereomer intermediates (2S,3S and 2R,3R)-3-(4-((2S,5R or 2R,5S)-5 -(5-((2,4-dimethoxybenzyl)amino)9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1- yl)-1H-pyrazol-1yl)butan-2-ol.

Step 2: (2S,3S or 2R,3R)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2,4] triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)butan-2-ol and (2S,3S or 2R,3R)-3 -(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol and (2R,3R or 2S,3S)-3-(4-((2R,5S or 2S,5R)-5 -(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1yl)butane -2-ol and (2R,3R or 2S,3S)-3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2, 4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol.

3-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]) was added to a 20 ml vessel. quinazolin-2-yl)-2-methylpiperidin-1-yl)-1 H-pyrazol-1-yl)butan-2-ol (475 mg, 0.768 mmol) and TFA (1.77 ml, 23.0 mmol) . The mixture was stirred and heated at 50°C for 3 hours. The mixture was cooled at room temperature and the solvents were evaporated. The residue was dissolved in MeOH (10 ml) and quenched with 7 M ammonia in MeOH (1.10 ml, 7.68 mmol). The mixture was stirred for 20 minutes. The mixture was filtered, the solids were washed with MeOH and the filtrate was concentrated. The residue was suspended in DCM and filtered to remove any remaining ammonium salts. The filtrate was loaded directly onto a silica gel column and eluted with 0-15% MeOH in DCM to obtain a mixture of isomers. The mixture was subjected to chiral SFC separation (Phenomenex Lux-2 21x250 mm column with 45% (MeOH modifier 0.1% NH ₄ OH) as co-solvent) to obtain a mixture of compound Example 228 and compound Example 229 (peak 1), (2R, 3R or 2S,3S)-3-(4-((2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2-methylpineridin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (compound of example 230, peak 2) and (2R,3R or 2S,3S)- 3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2-methylpiperidin-1 -yl)-1H-pyrazol-1 -yl)butan-2-ol (compound of example 231, peak 3). The mixture obtained in peak 1 was further purified by SFC separation (Chiral Technologies AS-H 21x250 mm column with 20% (MeOH modifier 0.1% NH4OH) as co-solvent) to give (2S,3S or 2R,3R)- 3-(4-((2S,5R or 2R,5S)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl )-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)butan-2-ol (compound of example 228, peak 1) and (2S,3S or 2R,3R)-3-{4-{{ 2R,5S or 2S,5R)-5-(5-amino-9-fluoro-8-methoxy[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1H-pyrazol-1-yl)butan-2-ol (compound of example 229, peak 2).

For compound example 228: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H]+. ¹ H NMR (499 MHz, DMSO-d ₆ ) δ 7.90 (d, J=10.6 Hz, 1H), 7.73 (s, 2H), 7.22 (s, 1H), 7.19 (d, J=7.4 Hz, 1H), 7.12 (s, 1H), 4.73 (d, J=5.0 Hz, 1H), 4.13 - 4.05 (m, 1H), 3 .98 (s, 3H), 3.88 - 3.78 (m, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=11.5 Hz, W), 2.01 (d, J=21.4 Hz, 3H), 1.70 (d, J=9.1 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 0.92 (d,

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J=6.1 Hz, 3H).

For compound example 229: LCMS (C ₂₃ H ₂₉ FN8O ₂ ) (ES, m/z): 469 [M+H]+. 1H NMR (499 MHz,

DMSO-d6) δ 7.90 (d, J=8.2 Hz, 1H), 7.73 (s, 2H), 7.25 - 7.21 (m, 1H), 7.19 (d, J =4.8 Hz, 1H), 7.12 (d, J=2.9 Hz,

1H), 4.72 (s, 1H), 4.09 (s, 1H), 3.98 (d, J=2.7 Hz, 3H), 3.83 (s, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=10.5 Hz,

1H), 1.99 (s, 3H), 1.72 (s, 1H), 1.43-1.30 (m, 3H), 1.03 (d, J=3.4 Hz, 3H), 0.92 (d,J=3.0 Hz, 3H).

For compound example 230: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d6) δ 7.90 (d, J=11.0 Hz, 1H), 7.72 (s, 2H), 7.22 (s, 1H), 7.18 (d ,J=7.8 Hz, 1H), 7.11 (s, 1H), 4.77-4.64 (m, 1H), 4.14-4.04 (m, 1H), 4.02-3, 94 (m, 3H), 3.88-3.78 (m, 1H), 3.71 (d, J=9.9 Hz, 1H), 3.18 (dd, J=6.4, 4.4 Hz , 1H), 3.09 (t, J=11.4 Hz, 1H), 2.01 (d, J=22.2 Hz, 3H), 1.70 (d, J=10.4 Hz, 1H ), 1.38-1.31 (m, 3H), 1.03 (d, J=6.4 Hz, 3H), 0.95-0.89 (m, 3H).

For compound example 231: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H] ⁺ . 1H NMR (499 MHz, DMSO-d ₆ ) δ 7.90 (d,J=9.6 Hz, 1H), 7.73 (s, 2H), 7.22 (s, 1H), 7.19 ( d, J=6.7 Hz, 1H), 7.12 (s, 1H), 4.73 (d, J=3.3 Hz, 1H), 4.15-4.03 (m, 1H), 3, 98 (s, 3H), 3.83 (d, J=5.2 Hz, 1H), 3.70 (s, 1H), 3.19 (s, 1H), 3.10 (t, J=11 .0 Hz, 1H), 2.01 (d, J=21.8 Hz, 3H), 1.70 (d, J=9.6 Hz, 1H), 1.33 (d, J=5.7 Hz, 3H), 1.03 (d,J=5.4 Hz, 3H), 0.92 (d, J=5.0 Hz, 3H).

Compounds of examples of the present invention in the following table. 31 was prepared in a manner similar to that described for the preparation of the compounds of Examples 228-231, from the corresponding starting materials and intermediates, where the resulting isomeric mixture of the corresponding final compounds was separated by the SFC method.

Table 31

Example Structure SFC terms Observ. m/z [M + H] ⁺ Name 232 nA еу nh ₂ _?А a _n A _n А—'N^^^X^^yF cis Г J F Peak 1 (mixture of compound of example 232 and compound of example 233); Phenomenex Lux-2 457

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(25.35 or 2A,ZA)-3-(4-((25.5A or 2L.55)-5-(5amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin2-yl)-2-methylpiperidin-1-yl)-1 (7-pyrazol-1 yl)butan-2-ol 21 x 250 mm column with 45% (MeOH modifier 0.1% NH ₄ OH) as co-solvent. Then peak 1; Chiral Technologies AS-H 21 x 250 mm column with 20% (MeOH modifier 0.1% NH4OH) as co-solvent. 233 n'\ νη ₂ __/ ^Ν ^\ cis Γ J F Peak 1 (mixture of compound of example 232 and compound of example 233); Phenomenex Lux-2 21 x 250 mm column with 45% (MeOH with modifier 0.1% NH4OH) as a co-solvent. Then peak 2; Chiral Technologies AS-H 21 x 250 mm column with 20% (MeOH with modifier 0.1% NH4OH) as a co-solvent. 457 (2R,3R or 25,35)-3-(4-((25,5Λ or 2R,5S)-5-(5amino-7,9-difluoro-[1,2,4]triazolo[1,5- c]quinazolin2-yl)-2-methylpiperidin-1-yl)-1 (7-pyrazol-1 yl)butan-2-ol

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234 'ChhJ^H nA νη ₂ ~—Ζ* ⁴ N^A^yF cis Γ || F Peak 2; Phenomenex Lux-2 21 × 250 mm column with 45% (MeOH modifier 0.1% NH ₄ OH) as co-solvent. 457 (2R,3R or 25,35)-3-(4-((27?,55 or 2S,5R)-5-(5amino-7,9-difluoro-[1,2,4]triazolo[1,5 -c]quinazolin2-yl)-2-methylpiperidin-1-yl)- 172-pyrazol-1 yl)butan-2-ol 235 νη ₂ _/ ^Ν γ —Ζ* ⁴ cis Γ J F Peak 3; Phenomenex Lux-2 21 x 250 mm column with 45% (MeOH with modifier 0.1% NH4OH) as a co-solvent. 457 (25,35 or 27?,37?)-3-(4-((27?,55 or 2S,5R)-5-(5amino-7,9-difluoro-[1,2,4]triazolo[1 ,5-c]quinazolin2-yl)-2-methylpiperidin-1 -yl)- 172-pyrazol-1 yl)butan-2-ol 236 antt^ON νη ₂ ^^^'Ν^Ν —/* 'N^^yA Cis Γ II F Peak 1; Chiral Technologies AD-H 21 x 250 mm column with 40% (MeOH with modifier 0.1% NH4OH) as a co-solvent. 469 (25.37? or 27?.35)-3-(4-((25.57? or 27?.55)-5-(5amino-9-fluoro-8-methoxy-[1,2,4] triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1-yl)- 177pyrazol-1-yl)butan-2-ol 237 ann^on nA νη ₂ _/Νγ *\—/* ⁴ cis Γ II F Peak 2; Chiral Technologies AD-H 21 x 250 mm column with 40% (MeOH with modifier 469

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(277.35 or 25.377)-3-(4-((25.577 or 277.55)-5-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)- 177pyrazol-1-yl)butan-2-ol 0.1% NH ₄ OH) as a co-solvent. 238 anpNEN Αγ ^ΝΗ 2 _/ ^Ν ^\ ,ν-νΑ _ν cis G II F Peak 1; Phenomenex Lux-3 21 x 250 mm column with 15% (MeOH with modifier 0.1% NH4OH) as a co-solvent. 469 (25.377 or 277.35)-3-(4-((277.55 or 25.577)-5-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)- 177pyrazol-1-yl)butan-2-ol 239 anti^OH A Αγ νη ₂ —/* ⁴ cis Γ II γΌ' F Peak 2; Phenomenex Lux-3 21 x 250 mm column with 15% (MeOH with modifier 0.1% NH4OH) as a co-solvent. 469 (277.35 or 25.377)-3-(4-((277.55 or 25.577)-5-(5amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c]quinazolin- 2-yl)-2-methylpiperidin-1-yl)- 177pyrazol-1-yl)butan-2-ol 240 OH nA A_^ νη ₂ _/ ^Ν ^ ,Ν- _Ν Ά _Ν cis Γ JI F Peak 1; Chiral Technologies AS-H 21 x 250 mm column with 25% (MeOH with modifier 0.1% NH4OH) as a co-solvent. 469 (77 or 5)-1-(4-((25.577 or 277.55)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)-2methylpiperidin-1 -yl)- 177-pyrazol-1 -yl)propan-2- ol 241 OH nA Αγ νη ₂ _/ ^Ν ~\ ν^ _ν Α _ν —'* 'nAJ\ cis Г I) γ^ο^ F Peak 2; Chiral Technologies AS-H 21 x 250 mm column with 25% (MeOH with modifier 0.1% NH4OH) as a co-solvent. 469 (5 or 77)-1-(4-((25.577 or 277.55)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)-2methylpiperidin-1 -yl)- 177-pyrazol-1 -yl)propan-2- ol

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Example 242 and Example 243: (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5c] quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol and (S or R)-3-(4-((R)-3-(5amino -9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3methylbutan-2- ol

Step 1: (R)-3-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidine1 -yl)-1 H-pyrazol-1 -yl)-3 -methylbutan-2-one.

A 5 ml microwave irradiation vessel equipped with a stirrer was filled with (R)-N(2,4-dimethoxybenzyl)-9-fluoro-8-methoxy-2-(piperidin-3-yl)-[1,2,4] triazolo[1,5-c]quinazolin-5-amine (intermediate 82) (100 mg, 0.214 mmol) and THF (1.3 ml). 3-(4-bromo-1Hpyrazol-1-yl)-3-methylbutan-2-one (intermediate 137) (99.0 mg, 0.429 mmol) was added to the mixture, followed by tBuXPhos-Pd G3 (85.0 mg , 0.107 mmol) and sodium tert-butoxide (82.0 mg, 0.857 mmol). Nitrogen was bubbled through the mixture for 10 minutes. The vessel was then sealed with a new cap and heated at 105°C for 16 hours. The racemic mixture was cooled to room temperature and water (10 ml) and DCM (10 ml) were added to the mixture. The mixture was stirred for 10 minutes and filtered. The organic layer was collected and concentrated. TFA (826 μL, 10.7 mmol) was added to the resulting residue and the mixture was heated at 50°C for 3 hours. The solvents were evaporated. The resulting residue was dissolved in MeOH (5 ml) and a 7 M ammonia solution in MeOH (1.53 ml, 10.7 mmol) was added to the mixture. The mixture was stirred for 30 minutes and filtered. The solids were washed with methanol. The filtrate was concentrated. The residue was dissolved in DCM and the resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents were evaporated. The resulting residue was purified by silica gel chromatography with 5-30% MeOH in DCM as eluent to give (R)-3-(4-(3-(5-amino-9-fluoro8-methoxy-[1,2,4] triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1 H-pyrazol-1-yl)-3-methylbutan-2-one, LCMS (C ₂₃ H ₂₇ FN ₈ O ₂ ) (ES, m/z): 467 [M+H]+.

Step 2: (R or S)-3-(4-((R)-3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol and (S or R)-3-(4-((R)-3-(5-amino- 9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol .

To a solution of (R)-3-(4-(3-(5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)pineridin1- yl)-1H-pyrazol-1-yl)-3-methylbutan-2-one (49.0 mg, 0.105 mmol) in EtOH (1 ml) was added NaBH ₄ (11.9 mg, 0.315 mmol) and the mixture was stirred at room temperature for 1 hour. The solvents were evaporated. DCM was added to the resulting residue, and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents of the filtrate were evaporated to obtain a mixture of isomers. The mixture was subjected to chiral separation by SFC (Chiral Technologies IA 21x250 mm column with 45% (MeOH modifier 0.1% NH4OH) as co-solvent) to give (R or S)-3(4-((R)-3-( 5-amino-9-fluoro-8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol1-yl)-3-methylbutane -2-ol (compound of example 242, peak 1) and (S or R)-3-(4-((R)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo [1,5-c]quinazolin-2-yl)piperidin-1-yl)-1H-pyrazol-1-yl)-3-methylbutan-2-ol (compound of example 243, peak 2).

For compound example 242: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H] ⁺ . ¹ H NMR (499 MHz,

DMSO-d ₆ ) δ 7.88 (dd, J=10.9, 2.3 Hz, 1H), 7.71 (s, 2H), 7.42 - 7.34 (m, 1H), 7, 24 - 7.07 (m, 2H), 4.80 (s, 1H), 3.97 (d, J=2.2 Hz, 3H), 3.82 (s, 1H), 3.62 (d , J=11.3 Hz, 1H), 3.36 (s, 1H), 3.24 (s, 1H), 2.82 (t, J=10.2 Hz, 1H), 2.15 (s , 1H), 1.80 (d, J=40.9 Hz, 3H), 1.48 - 1.42 (m, 3H), 1.42 - 1.34 (m, 3H), 0.73 ( dd,J=6,1,2,3 Hz, 3H).

For compound example 243: LCMS (C ₂₃ H ₂₉ FN ₈ O ₂ ) (ES, m/z): 469 [M+H] ⁺ . 1H NMR (499 MHz, DMSO- _d6 ) δ 7.93-7.83 (m, 1H), 7.71 (s, 2H), 7.38 (s, 1H), 7.22 - 7.10 (m, 2H), 4.81 (s, 1H), 4.01 -3.95 (m, 3H), 3.82 (s, 1H), 3.62 (d, J=10.8 Hz, 1H), 3.37 (s, 1H), 3.24 (s, 1H), 2.82 (t, J=11.3 Hz, 1H), 2.55 (d, J=9.7 Hz, 1H), 2.15 (s, 1H), 1.90-1.67 (m, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 0.76-0.67 (m, 3H).

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Compounds of examples of the present invention in the following table. 32 was prepared in a manner similar to that described for the preparation of Example 242 and Example 243 from the corresponding starting amine and aryl halide, wherein the resulting isomeric mixture of the respective final compounds was separated by SFC.

Table 32

Example Structure SFC terms Observ. m/z, [M + N] ⁺ Name 244 he N'\ nh ₂ / ^N ~3 N^n 1 F Peak 1; Chiral Technologies ΙΑ 21 * 250 mm column with 40% (MeOH with modifier 0.1% ΝΗ4ΟΗ) in the form of a co-solvent 469 (R or 5)-3-(4-((70-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1 -yl)-177-pyrazol-1-yl)-3-methylbutan-2-ol 245 -o.A x 1 Peak 2; Chiral Technologies ΙΑ 21 * 250 mm column with 40% (MeOH with modifier 0.1% ΝΗ4ΟΗ) in the form of a co-solvent 469 (S or 70-3-(4-((70-3-(5-amino-9-fluoro-7-methoxy- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1 -yl)-177-pyrazol-1-yl)-3-methylbutan-2-ol 246 OH N'\ nh ₂ , ^n— F Peak 1; ES Industries CCA 21 x 250 mm column with 35% (MeOH modifier 0.1% NH4OH) as co-solvent 457 (R or 5)-3-(4-((70-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1 -yl)-177-pyrazol-1-yl)-3-methylbutan-2-ol 247 Z. Ζ t /~ ^ζ 1 Peak 2; ES Industries CCA 21 x 250 mm column with 35% (MeOH with 0.1% ΝΗ4ΟΗ modifier) as cosolvent 457 (S or 70-3-(4-((70-3-(5-amino-7,9-difluoro- [1,2,4]triazolo[1,5-c]quinazolin-2-yl)piperidin- 1 -yl)-177-pyrazol-1-yl)-3-methylbutan-2-ol

Example 248 and Example 249: 2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5c]quinazoline- 2-yl)-2-methylpiperidin-1-yl)-1H-nirazol-1-yl)-2-methylpropan-1,3-diol and 2-(4-((2R,5S or

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2S,5R)-5-(5-amino-7.9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1Hpyrazol-1 -yl)-2-methylpropane-1,3-diol

Step 1: 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7.9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2yl)-2 -methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-1,3-diol.

To a solution of 1-(1-(1,3-dihydroxy-2-methylpropan-2-yl)-1 H-pyrazol-4-yl)-6-methylpiperidin-3carbazide (105 mg, 0.336 mmol) (intermediate 166) in DMF (1 ml) add AcOH (9.63 µl, 0.168 mmol), 2-((((3,4-dimethylbenzyl)imino)methylene)amino)-3,5-difluorobenzonitrile (intermediate 37) (100 mg , 0.336 mmol) at 50°C in a nitrogen atmosphere. The mixture was stirred and heated at 50°C for 16 hours. The mixture was cooled, diluted with water (20 ml) and extracted with EtOAc (2x20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and the solvents were evaporated. The resulting residue was purified by preparative TLC on silica gel with 10% MeOH in DCM as eluent to give 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1, 2,4]triazolo[1,5c]quinazolin-2-yl)-2-methylpiperidin-1 -yl)-1 H-pyrazol-1 -yl)-2-methylpropan-1,3-diol. LCMS (C31H36F2N8O4) (ES, m/z): 623 [M+H]+.

Step 2: 2-(4-(5-(5-amino-7.9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1yl)-1 H-pyrazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate.

To a solution of 2-(4-(5-(5-((2,4-dimethoxybenzyl)amino)-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2yl)- 2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1,3-diol (60 mg, 0.096 mmol) in DCM (2 ml) was added TFA (2.0 ml, 26 mmol ) at 10°C in a nitrogen atmosphere. The mixture was stirred at 10°C for 16 hours. The solvents were evaporated to give the crude product 2-(4-(5-(5-amino-7,9difluoro-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)-2-methylpiperidin-1-yl)-1H-pyrazol-1-yl)-3-hydroxy-2methylpropyl 2,2,2-trifluoroacetate, which was used in the next step without any further purification. LCMS (C ₂₄ H2 ₅ F ₅ N ₈ O ₃ ) (ES, m/z): 569 [M+H] ⁺ .

Step 3: 2-(4-((2S,5R or 2R,5S)-5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ul )-2methylpiperidin-1-yl)-1H-pyrazol-1-yl)-2-methylpropan-1.3-diol and 2-(4-((2R,5S or 2S,5R)-5-(5-amino7.9 -difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylπuperidin-1-yl)-1H-πurazol-1-yl)-2methylpropan-1,3-diol .

To a solution of 2-(4-(5-(5-amino-7,9-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1yl)- 1H-nirazol-1-yl)-3-hydroxy-2-methylpropyl 2,2,2-trifluoroacetate (40 mg, 0.070 mmol) in MeOH (2 ml) was added Na ₂ CO ₃ (7.5 mg, 0.070 mmol) at 10°C in a nitrogen atmosphere. The mixture was stirred at 10°C for 1 hour. The solvents were evaporated to obtain a mixture of isomers. The mixture was subjected to chiral separation by SFC (Chiralpak AD-3 4.6x150 mm column with 5-40% (MeOH modifier 0.05% DEA) as co-solvent) to give 2-(4-((2S,5R or 2R, 5S)-5-(5-amino-7,9-difluoro[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1 H-pyrazole -1-yl)-2-methylpropan-1,3diol (compound of example 248, peak 1) and 2-(4-((2R,5S or 2S,5R)-5-(5-amino-7,9-difluoro [1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2-methylpiperidin-1-yl)-1 H-pyrazol-1-yl)-2-methylpropan-1,3diol (compound example 249, peak 2).

For compound example 248: LCMS (C ₂ 2H2 ₆ F2N ₈ O2) (ES, m/z): 473 [M+H] ⁺ . ^1H NMR (500 MHz, methanol^) δ = 7.71 (br dd, J=1.3, 6.8 Hz, 1H), 7.38-7.26 (m, 2H), 7.22 ( s, 1H), 3.78-3.68 (m, 4H), 3.64 (br dd, J=3.8, 6.1 Hz, 1H), 3.41 (br d, J=8, 2 Hz, 1H), 2.96 (s, 1H), 2.82 (s, 1H), 2.06-1.99 (m, 2H), 1.98 (s, 1H), 1.73 ( br dd, J=3.1, 12.7 Hz, 1H), 1.42 (s, 3H), 1.03 (d, J=6.7 Hz, 3H).

For compound example 249: LCMS (C ₂ 2H2 ₆ F2N ₈ O2) (ES, m/z): 473 [M+H] ⁺ . 1H NMR (500 MHz, methanol- _d4 ) δ = 7.84 (br s, 1H), 7.53 - 7.41 (m, 2H), 7.36 (br s, 1H), 3.93 - 3.79 (m, 4H), 3.78 (br s, 1H), 3.55 (br s, 1H), 2.22 (br s, 1H), 2.18 - 2.09 (m, 2H ), 1.87 (br d, J=10.1 Hz, 1H), 1.54 (s, 3H), 1.31 (s, 2H), 1.16 (d, J=6.6 Hz, 3H).

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Compounds of examples of the present invention in the following table. 33 was prepared in a manner similar to that described for the preparation of Example 248 and Example 249 from the corresponding starting hydrazide, wherein the resulting isomeric mixture of the respective final compounds was separated by SFC.

Table 33

Example Structure SFC terms Observ. m/z, [M + N] ⁺ Name 250 OH noAchl \=/ nh ₂ cis ^Ν у^о F ¹ Peak 1; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent 485 2-(4-((25.5R or 27?.55)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,3-diol 251 OH \=/ nh ₂ N^A _n cis F ¹ Peak 2; Chiralpak AD-3 4.6 x 150 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent 485 2-(4-((27?.55 or 25.57?)-5-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2 -yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,3-diol 252 BUT H(A Ν Υ νη ₂ * cis F ¹ Peak 2; Chiralcel OJ-3 4.6 x 100 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. Then peak 1; Chiralpak AD-3 4.6 x 150 mm column with 40% (MeOH modifier 0.05% DEA) as co-solvent. 485 (R or 5)-2-(4-((25.5R or 27?.55)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo [1,5 -с ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol

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253 NO NOA k ,Ν N / \=/ nh ₂ _/T* umTm cis ^N УХ ΥΌ F ¹ Peak 2; Chiralcel OJ-3 4.6 x 100 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. Then peak 2; Chiralpak AD-3 4.6 x 150 mm column with 40% (MeOH modifier 0.05% DEA) as co-solvent. 485 (S or R)-2-(4-((2S,5R or 27?.55)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo [1,5 -с ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol 254 BUT not \=/ nh ₂ cis ^N XjI F ¹ Peak 3; Chiralcel OJ-3 4.6 x 100 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. 485 (R or 5)-2-(4-((27?,5S or 25.57?)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo [1,5 - c]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol 255 BUT noA k ,Ν N / \=/ nh ₂ _/T* cis ^N УХ F ¹ Peak 4; Chiralcel OJ-3 4.6 x 100 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. 485 (5 or R)-2-(4-((2R.5S or 25.57?)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo [1,5 -s ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol

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256 but notT to ,Ν N H A=/ nh ₂ _/ ^N ~y An^n '—/ ' _N AAyF CIS F Peak 3; Cellulose 2 4.6 x 100 mm column with 40% (MeOH with modifier 0.05% DEA) as a co-solvent. Then peak 1; Chiralpak AS-3 4.6 χ 150 mm column with 540% (ΙΡΑ with modifier 0.05% DEA) as a co-solvent. 473 (R or 5)-2-(4-((25.57/ or III.55)-5-(5-amino-7,9difluoro-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)-2methylpiperidin-1 -yl)-177-pyrazol-1 -yl)-2methylpropan-1,2-diol 257 BUT NOT CHCH \=/ nh ₂ ΛΑνΑΛ/Ρ cis | F Peak 3; Cellulose 2 4.6 x 100 mm column with 40% (MeOH with modifier 0.05% DEA) as a co-solvent. Then peak 2; Chiralpak AS-3 4.6 χ 150 mm column with 540% (ΙΡΑ with modifier 0.05% DEA) as a co-solvent. 473 (5 or 7/)-2-(4-((25.57/ or 27/.55)-5-(5-amino-7,9difluoro-[1,2,4]triazolo[1,5-c ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol 258 BUT noA CHH \=/ nh ₂ cis | F Peak 4; Cellulose 2 4.6 x 100 mm column with 40% (MeOH with modifier 0.05% DEA) as a co-solvent. 473 (7/ or 5)-2-(4-((27/.55 or 25.57/)-5-(5-amino-7,9difluoro-[1,2,4]triazolo[1,5-c ]quinazolin-2-yl)-2methylpiperidin-1 -yl)- 177-pyrazol-1 -yl)-2-

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methylpropane-1,2-diol 259 BUT ^Н0 >< к ,Ν N к к=/ nh ₂ _/%* χ^-νΆν cis F Peak 5; Cellulose 2 4.6 x 100 mm column with 40% (MeOH with modifier 0.05% DEA) as a co-solvent. 473 (.S' or 7?)-2-(4-((27?,5S or 25.5L)-5-(5-amino-7,9difluoro-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol 260 BUT A.” N to \=/ nh ₂ _/Ά/ z+nA cis F Peak 1; Chiralpak AS3 4.6 x 100 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent. 487 (7? or 5)-2-(4-((27?,5S or 25.57?)-5-(5-amino-7,9difluoro-[1,2,4]triazolo[1,5-s ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol 261 GL*1s /. Z J g o t Peak 2; Chiralpak AS3 4.6 x 100 mm column with 5-40% (MeOH with modifier 0.05% DEA) as a co-solvent. 487 (.S' or R)-2-(4-((2R,5S or 25.57?)-5-(5-amino-7,9difluoro-[1,2,4]triazolo[1,5-s ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-2methylpropan-1,2-diol

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262 h ₂ nJ/ k ,Ν Ν \=/ νη ₂ _/ ^Ν γ_// ^Ν 'Ν^Ν cis y'O'' F Peak 1; ES Industries CC4 21 x 250 mm column with 40% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent. 468 2-((3R,6S or 35,677)-1-(1-(2-amino-2-methylpropyl)1R-pyrazol-4-yl)-6-methylpiperidin-3-yl)-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 263 h ₂ nJ/ CHH \=/ nh ₂ '---' ⁴ cis F Peak 2; ES Industries CC4 21 x 250 mm column with 40% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent. 468 2-((35.677 or 377.65)-1-(1-(2-amino-2-methylpropyl)1R-pyrazol-4-yl)-6-methylpiperidin-3-yl)-9-fluoro- 8-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine 264 nh ₂ _/ ^Ν γ_ΑΝ-^Ν * F ¹ Peak 1; ES Industries CCA 21 x 250 mm column with 25% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 483 (77 or 5)-3-(4-((25.577 or 277.55)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-3 methylbutan-2-ol 265 S^OH Λ nh ₂ * ^N Cl 0 F ¹ Peak 2 (mixture of example 265 and compounds of example 266); ES Industries CCA 21 χ 250 mm column with 25% (MeOH with modifier 483 (5 or 77)-3-(4-((25.577 or 277.55)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo[1,5-c]quinazoline -2-yl) -2methylpiperidin-1 -yl)-177-pyrazo l-1 -yl) -3 -

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methylbutan-2-ol 0.Ι%ΝΗ4θΗ) as a co-solvent. Then peak 1; Lux-4 21 χ 250 mm column with 35% (MeOH with modifier 0.1% NH ₄ OH) 266 N'\ A^ nh ₂ * CIS Ax A 0 F ¹ Peak 2 (mixture of compound of example 265 and compound of example 266); ES Industries CCA 21 x 250 mm column with 25% (MeOH modifier 0.1% ΝΗ ₄ ΟΗ) as co-solvent. Then peak 2; Lux-4 21 χ 250 mm column with 35% (MeOH with modifier 0.1% NH ₄ OH) 483 (R or 5)-3-(4-((27?.55 or 25.57?)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo [1,5 - c]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-3 methylbutan-2-ol 267 S^OH A7 nh ₂ _/ΑχΑν^ν * CIS Ah ZA o F ¹ Peak 3; ES Industries CCA 21 x 250 mm column with 25% (MeOH with 0.1% NH ₄ OH modifier) as co-solvent 483 (S or 77)-3-(4-((2Λ.55 or 25.57?)-5-(5-amino-9-fluoro8-methoxy-[1,2,4]triazolo [1,5 -s ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-3 methylbutan-2-ol

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268 / o -1- I* Q X I ο ί 1 ^σ —\ / 1 * / Peak 1 (mixture of compound of example 268 and compound of example 269); Chiral Technologies OJ-H 21 x 250 mm column with 10% (MeOH modifier 0.1% NH ₄ OH) as co-solvent. Then peak 1; ID 21 x 250 mm column with 35% (MeOH with 0.1% ΝΗ ₄ ΟΗ modifier) as co-solvent. 483 (R or 5)-3-(4-((25.5R or 2L.55)-5-(5-amino-9-fluoro7-methoxy-[1,2,4]triazolo[1,5-c] quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-3 methylbutan-2-ol 269 Ch^on ,Ν Ν > See νη ₂ _, ^ν ^Ν'ν^ν CIS F Peak 1 (mixture of compound of example 268 and compound of example 269); Chiral Technologies OJ-H 21 x 250 mm column with 10% (MeOH modifier 0.1% NH ₄ OH) as co-solvent. Then peak 2; ID 21 x 250 mm column with 35% (MeOH with 0.1% ΝΗ ₄ ΟΗ modifier) as co-solvent. 483 (5 or 77)-3-(4-((25.57? or 27?.55)-5-(5-amino-9-fluoro7-methoxy-[1,2,4]triazolo[1,5- c]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-3 methylbutan-2-ol

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270 Ά ^ΟΗ ,Ν ν > νη ₂ _/ ¹ %% ⁷ ¼ Α74*γγ°χ cis Α-Α F Peak 2; Chiral Technologies OJ-H 21 x 250 mm column with 10% (MeOH with 0.1% NH ₄ OH modifier) as a co-solvent. 483 (R or 5)-3-(4-((2Λ.55 or 25.57?)-5-(5-amino-9-fluoro7-methoxy-[1,2,4] triazolo [1,5 -с ]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-3 methylbutan-2-ol 271 Άοη Ν > NH ₂ _/ ^N Y_/ _z ⁿ 'nYn cis F Peak 3; Chiral Technologies OJ-H 21 x 250 mm column with 10% (MeOH with 0.1% NH ₄ OH modifier) as a co-solvent. 483 (S or 7?)-3-(4-((27?.55 or 25.57?)-5-(5-amino-9-fluoro7-methoxy-[1,2,4] triazolo [1,5 -c]quinazolin-2-yl)-2methylpiperidin-1-yl)-177-pyrazol-1-yl)-3 methylbutan-2-ol 272 ΑθΗ W7 nh ₂ _/Yz'N'n'Yn * CIS kx Yx- ο F ¹ Peak 1; Chiralpak AS3 4.6 x 150 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. 467 1-((4-((25.57? or 27?.55)-5-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2- methylpiperidin-1 -yl)- 177-pyrazol-1 - yl)methyl)cyclopropan-1-ol 273 o— ΐΎΥ ^Υ z Υ ₈ <A Peak 2; Chiralpak AS3 4.6 x 150 mm column with 5-40% (EtOH with modifier 0.05% DEA) as a co-solvent. 467 1-((4-((27?.55 or 25.57?)-5-(5-amino-9-fluoro-8-

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methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-2methylpiperidin-1 -yl)-127-pyrazol-1 - yl)methyl)cyclopropan-1-ol 274 Hon N'V Su nh ₂ cis o F ¹ Peak 2; Chiral Technologies AD-H 21 x 250 mm column with 30% (MeOH modifier 0.1% NH ₄ OH) as co-solvent. 483 1-(4-((37?.55 or 35.57?)-3-(5-amino-9-fluoro-8methoxy-[1,2,4]triazolo[1,5-c]quinazoline-2- yl)-5 methylpiperidin-1 -yl)-5 -methyl-177-pyrazol-1 -yl)-2methylpropan-2-ol 275 Hon ,Ν NX Su nh ₂ /Τ'ν AT CIS γ ο F ¹ Peak 3; Chiral Technologies AD-H 21 x 250 mm column with 30% (MeOH modifier 0.1% NH ₄ OH) as co-solvent. 483 1-(4-((35.5R or 37?.55)-3-(5-amino-9-fluoro-8- methoxy-[1,2,4]triazolo[1,5-c]quinazolin-2-yl)-5 methylpiperidin-1-yl)-5-methyl-177-pyrazol-1-yl)-2methylpropan-2-ol

Biological analyses.

The IC ₅₀ values reported for each of the compounds of the present invention presented in the table below were measured in accordance with the methods described below.

The A2a receptor binding affinity assay quantifies the binding of a tritium-labeled high affinity adenosine A2a receptor ligand to membranes prepared from HEK293 or CHO cells recombinantly expressing the human adenosine A2a receptor in the presence of various concentrations of a compound of the present invention. In each assay, test compounds of the present invention are solubilized in 100% DMSO and then diluted in 100% DMSO to typically produce 10-point titrations at half-log intervals such that final assay concentrations do not exceed 10 μM compound or 1% DMSO.

Measurement of A2a Binding Affinity Using Radioligand Binding 148 μl (5 μg/ml) membranes (Perkin Elmer, catalog number RBHA2aM400UA) and 2 μl of compounds of the present invention to be tested (test compound) were added to individual wells of a 96-well polypropylene assay plate and incubated for 15 to 30 min at room temperature. [ ^3H ]SCH58261 ((7-(2-phenylethyl)-5-amino-2-(2-furyl)pyrazolo-[4,3-e]1,2,4-triazolo-[1,5-c] pyrimidine)) was diluted with assay buffer (50 mM Tris, pH 7.4, 10 mM MgCl ₂ , 0.005% Tween20) to a concentration of 4 nM and 50 μl was transferred to each well of the assay plate. To determine total and nonspecific binding, wells containing 1% DMSO and 1 μM ZM241385 (Tocris Bioscience, catalog number 1036), respectively, were also provided. The assay plate was incubated at room temperature for 60 min with stirring. Using a FilterMate Harvester® (Perkin Elmer), the contents of the assay plate were filtered through a PEI-coated UniFilter-96® plate (Perkin Elmer, part number 6005274 or 6005277). Filtration was accomplished by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cold wash buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl) and allowing the plate to dry using a vacuum manifold for 30 seconds. The filter plate was incubated for at least 1 hour at 55°C and allowed to dry. The lower part of the filter plate was sealed with protective tape. 40 µl of Ultima Gold™ (Perkin Elmer, part number 6013329) was added to each well of the filter plate and the top of the plate was covered with TopSeal-A PLUS® clear plate film (Perkin

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Elmer, part number 6050185). The plate was incubated for at least 20 minutes and then the radioactivity remaining in each well was quantified using a TopCount® scintillation counter (Perkin Elmer). After normalization for total and nonspecific binding, the percentage effect at each compound concentration was calculated. A plot of the effect as a percentage of the logarithm of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to obtain IC ₅₀ values.

A2b binding affinity measurement.

The reported affinity of the compounds of the present invention for the human adenosine A2b receptor was determined experimentally using a filtered radioligand binding assay. This assay quantifies the binding of a tritium-labeled proprietary A2b receptor antagonist in the presence and absence of a compound of the present invention to membranes prepared from HEK293 cells recombinantly expressing the human adenosine A2b receptor (Perkin Elmer, cat. no. ES-013-C ).

To perform an assay, the compounds to be tested according to the present invention are first solubilized in 100% DMSO and then diluted in 100% DMSO to produce typically 10-point titrations at semi-log intervals such that final assay concentrations do not exceed 10 μM of compound or 1% DMSO. 148 μl (135 μg/ml) of membranes and 2 μl of test compounds were added to individual wells of a 96-well polypropylene assay plate and incubated for 15 to 30 min at room temperature with stirring. The tritium-labeled radioligand was diluted to a concentration of 14 nM with assay buffer (phosphate buffered saline without magnesium and calcium, pH 7.4; GE Healthcare Life Sciences, part number SH30256.01), and then 50 μl of the solution was transferred to each well of the assay plate . To determine total and nonspecific binding, wells containing 1% DMSO and 20 μM N-ethylcarboxamidoadenosine (Tocris Bioscience, cat. no. 1691), respectively, were also included. Assay plate wells were incubated at room temperature for 60 min with agitation, then filtered using a FilterMate Harvester® (Perkin Elmer) or similar equipment through a PEI-coated UniFilter-96® plate (Perkin Elmer, part number 6005274 or 6005277). Filtration was accomplished by aspirating the contents of the assay plate for 5 seconds, then washing and aspirating the contents three times with ice-cold wash buffer (assay buffer plus 0.0025% Brij58) and allowing the plate to dry using a vacuum manifold for 30 seconds. The filter plate was incubated for at least 1 hour at 55°C and allowed to dry. The bottom of the filter plate was then sealed with protective tape. 40 µl of Ultima Gold™ (Perkin Elmer, part number 6013329) was added to each well of the filter plate and the top of the plate was covered with TopSeal-A PLUS® clear plate film (Perkin Elmer, part number 6050185). The plate was incubated for at least 20 minutes and then the radioactivity remaining in each well was quantified using a TopCount® scintillation counter (Perkin Elmer). After normalization for total and nonspecific binding, the percentage effect at each compound concentration was calculated. A plot of the effect as a percentage of the logarithm of compound concentration was analyzed electronically using a 4-parameter logistic fit based on the Levenberg-Marquardt algorithm to obtain IC ₅₀ values.

Example IC50 binding A _2a (nM) IC50 binding A ₂ in (nM) 1 7.5 554.2 2 3.7 9.4 3 1.5 180.4 4 4.6 2.6 5 z, z 1.6 6 2.0 85.9 7 3.7 104.1 8 4.5 149.3 9 0.5 136.0

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10 3.5 63.4 eleven 0.5 56.0 12 1.7 75.0 13 0.7 72.6 14 h,o 224.9 15 38.4 905.2 16 0.8 426.0 17 1.7 433.9 18 0.7 13.5 19 0.7 87.3 20 5.8 163 21 o, s 514.6 22 8.6 27.6 23 2.0 15.9 24 13.8 480.5 25 0.6 61.7 26 3.9 48.7 27 1.8 860.8 28 2.8 76.3 29 1.5 301.1 thirty 0.4 97.9 31 1.7 94.8 32 0.5 6.9 33 3.6 17.5 34 1.4 29.7 35 0.6 12.2 36 1.6 93.0 37 1.1 468.1 38 16.9 182.4 39 1.1 43.3 40 1.2 9.2 41 1.2 42.8 42 4.3 475.7 43 0.7 3.4 44 1.3 20.4 45 1.8 150.4 46 0.6 86.4

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47 8.2 284.2 48 0.6 17.6 49 0.3 2.7 50 18.3 1889 51 21.0 2079 52 18.3 3006 53 44.1 4239 54 3.3 194.6 55 10.6 500.2 56 1.8 846.5 57 48.3 85.6 58 13.6 136.2 59 67.0 4744 60 31.4 5862 61 5.0 99.0 62 146.1 382.8 63 242.2 2431 64 ι,ο 555.3 65 1.2 227.9 66 0.6 957.1 67 44% inhibition at 1000 nM 31% inhibition at 10000 nM 68 181.4 31% inhibition at 10000 nM 69 2.6 561.4 70 0.6 786.5 71 35.6 43% inhibition at 10000 nM 72 2.0 484 73 436.0 5124 74 0.9 153.3 75 56.9 54% inhibition at 10000 nM 76 256.4 34% inhibition at 10000 nM 77 0.4 107.9 78 0.9 233.7

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79 16.0 3141 80 11.6 404.5 81 121.1 6582 82 4.9 63.0 83 2.7 113.0 84 2.3 116.6 85 5.2 192.1 86 o, s 164.7 87 0.4 133.8 88 ο,ι 1.8 89 0.2 3.4 90 1.2 29.0 91 44.7 4624 92 10.9 602.3 93 5.8 314.6 94 7.8 752.0 95 205 5041 96 0.7 24.6 97 0.6 33.3 98 0.9 116.4 99 4.4 230.9 100 1.4 4.8 101 32.7 390.0 102 103.5 538.7 103 0.5 136.7 104 17.7 766.1 105 328.6 743.0 106 316.4 429.6 107 126.9 1522 108 36% inhibition at 1000 nM 8474 109 0.7 7.8 BY 0.2 1.8 111 0.7 16.5 112 0.4 7.9 113 58.1 470.5 114 50.6 2905

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115 2.9 895.1 116 207.4 35% inhibition at 10000 nM 117 0.2 13.0 118 1.9 386.7 119 51.6 1302 120 0.6 7.8 121 55.4 5344 122 368.7 2058 123 o, s 422.2 124 o, s 1.7 125 86.4 2501 126 2.6 2158 127 120.5 1158 128 o, s 2.4 129 4.1 469.9 130 1.2 78.7 131 11.8 66.0 132 6.7 242.6 133 4.3 558.5 134 123.6 4288 135 14.1 583.3 136 ι,ο 7.9 137 79.3 924.5 138 13.2 2257 139 16.8 2824 140 0.8 2723 141 24.1 1756 142 32% inhibition at 1000 nM 7937 143 984.1 7557 144 30% inhibition at 1000 nM 7143 145 32% inhibition at 1000 nM 8046 146 2.1 137.1 147 870.2 6333 148 385.1 4429 149 1.8 96.6 150 1.4 180.6

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Measuring A2A and A2B antagonism in a cell-based cAMP assay.

The ability of the compounds to antagonize human adenosine A2A and _A2B receptors was determined using a kit to measure changes in intracellular cyclic AMP levels (LANCE cAMP 384 kit, Perkin Elmer, catalog number AD0264). HEK293 cells recombinantly expressing human A _2A or A _2B receptors, previously frozen in recovery medium (Life Technologies, catalog number 12648-010), were thawed and diluted with stimulation buffer (HBSS (Hyclone SH 30268.01), 5 mM HEPES (Gibco 15630-106), 200 nM rolipram (Tocris, catalog number 0905) and 1.5% (v/v) BSA stabilizer (kit component). The cell suspension was centrifuged at 200xg for 10 min and then resuspended in stimulation buffer supplemented with anti-cAMP antibody Alexa Fluor 647 at a dilution of 1:10000 to a density of 6.0 x 105 cells/ml. A Labcyte Echo 550 acoustic dispenser was used to transfer up to 25 nl of test compound dissolved in DMSO into the wells of a dry Optiplate-plate. 384 (Perkin Elmer, catalog number 6008289). All subsequent liquid additions were made using a multichannel pipette device. Then 5 μl of the cell suspension was added to the Optiplate-384 wells and incubated for 30 minutes at 37°C and 5% CO ₂ in humidified environment. After this time, 5 μl of either 300 nM or 600 nM adenosine (Sigma, catalog number A9251) for A _2A and A _2B , respectively, was added and incubated for 30 min at 37°C and 5% CO ₂ in humidified environment. At this time, a detection mixture was prepared by combining LANCE Eu-W8044-labeled streptavidin and biotin-cAMP in detection buffer according to the manufacturer's protocol. 10 μl of detection mixture was added to each well of Optiplate-384, which was covered with plate film, and incubated at ambient conditions for 2 h before plate reading using an Envision multimode plate reader (Perkin Elmer, Waltham, MA). Data were normalized by defining the minimum effect as stimulation in the presence of 0.25% (v/v) DMSO and the maximum effect as stimulation in the presence of 1 μM ZM241385 (Cayman, catalog number 1036). A 4-parameter concentration-response curve fitting algorithm was used to fit the percent effect data relative to the logarithm of compound concentration to calculate IC ₅₀ values. The concentrations of compounds tested were 10000, 3333, 1111, 370.4, 123.4, 41.2, 13.7, 4.6, 1.5 and 0.5 nM with 0.25% residual DMSO.

Example IC50 cAMP in relation to A _2A (nM) IC50 cAMP in relation to A ₂ in (nM) 151 3.8 56.9 152 5.9 371 153 7.4 719.8

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154 1.2 974.1 155 23.9 1436 156 9.5 358.1 157 33.4 4481 158 1.1 32.9 159 ι,ο 29.3 160 8.7 647.8 161 38.9 3268 162 0.7 20.7 163 36.0 5306 164 1.9 47.7 165 0.8 6.4 166 20.0 2769 167 0.6 46.0 168 23.9 4723 169 96.5 3382 170 0.8 14.1 171 1.2 11.3 172 60.5 14% inhibition at 10000 nM 173 20.7 2022 174 0.6 30.7 175 30.2 2004 176 0.9 10.2 177 154 3957 178 0.6 I.5 179 4.0 335.5 180 54.0 5342 181 16.0 5099 182 361.9 >10000 183 2.0 90.6 184 4.9 345.5 185 1.1 49.8 186 ι,ο 25.8 187 2.6 95.8 188 1.5 53.1 189 0.5 53.4

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190 0.8 55.9 191 0.9 92.4 192 0.8 72.4 193 1.3 250.7 194 1.7 318.4 195 3.4 389.5 196 3.7 474.9 197 6.4 93.0 198 4.3 52.4 199 2.5 97.5 200 2.5 102.5 201 1.9 38.4 202 1.4 62.4 203 7.7 53.2 204 7.8 87.7 205 7.0 1146 206 13.0 4314 207 0.9 10.37 208 0.7 2799 209 0.7 634.9 210 16.2 35% inhibition at 10000 nM 211 89.3 >10000 212 121.7 27% inhibition at 10000 nM 213 330.8 >10000 214 0.5 34.09 215 0.4 27.5 216 ι,ο 159.7 217 1.1 161.3 218 235.8 5775 219 246.7 27% inhibition at 10000 nM 220 20.4 30% inhibition at 10000 nM 221 0.5 63 222 34.6 3277

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223 0.7 46 224 0.4 13.1 225 0.4 12.1 226 17.6 1611 227 40.2 5071 228 0.8 16.1 229 ι,ο 6.6 230 32.9 723.7 231 121.5 3845 232 1.3 12.7 233 0.7 5.6 234 46.8 1195 235 438.8 4450 236 ι,ο 5.1 237 0.8 8.7 238 21.8 2438 239 75.1 10% inhibition at 10000 nM 240 1.2 22.6 241 1.3 21.7 242 2.0 34.9 243 2.6 50.7 244 0.9 18.8 245 2.0 25.8 246 3.2 21.3 247 4.5 21.8 248 1.4 8.4 249 26.9 197.1 250 0.7 4.9 251 39.5 387.1 252 95.0 8157 253 123.1 >10000 254 1.5 Yu, 255 2.6 28.8 256 240.7 3892 257 540.6 25% inhibition at 10000 nM

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Claims (24)

CLAIM 1. Compound of structural formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from F and Cl; R ² represents O(C ₁ -C ₆ )alkyl; ring A is a fragment selected from: R ³ is selected from pyrazolyl, triazolyl and pyridinyl, wherein said pyrazolyl and said triazolyl are substituted with 1 or 2 R ^3A groups and wherein said pyridinyl is substituted with 1, 2 or 3 R ^3A groups, wherein each R ^3A is independently selected from (C ₁ -C ₆ )alkyl, O(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl-OH, (C1C ₆ )haloalkyl, O(C ₁ -C ₆ )haloalkyl, oxo, (C ₁ -C ₄ )alkylC (O)(C ₁ -C ₃ )alkyl, (C ₁ -C ₄ )alkylCH(OH)(C ₁ C ₃ )alkyl, (C ₁ -C ₄ )alkyl-S(O) ₂ (C ₁ -C ₃ ) alkyl, -(CH ₂ ) _n (C ₃ -C ₇ )cycloalkyl and -(CH ₂ )n4-7-membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected from oxygen and nitrogen, and the specified (C ₃ -C ₇ )cycloalkyl and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2 or 3 groups independently selected from F, Cl, OH, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )haloalkyl; n is 0, 1 or 2; R ^a1 is selected from H and (C1-C ₄ )alkyl; R ^A2 is selected from H, F and (C1-C ₄ )alkyl; R ^A3 is selected from H, F and (C1-C ₄ )alkyl; - 203 043752 R ^A4 is selected from H and OH; And R ^A5 is selected from H, F and (C1-C ₄ )alkyl. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ¹ represents F; and R ² represents OCH ₃ . 3. A compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a fragment selected from: where R ³ is selected from where each R ^3A is a fragment selected from: each R ^3Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ )haloalkyl. 4. A compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a fragment: where R ³ is selected from where each R ^3A is a fragment selected from: - 204 043752 each R ^3Aa is independently selected from (C1- _C4 )alkyl, O( _C1 - _C4 )alkyl, ( _C1 - _C4 )haloalkyl and O( _C1C4 )haloalkyl. 5. A compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, where ring A is a fragment: where R ³ is selected from where each R ^3A is a fragment selected from: each R ^3Aa is independently selected from (C1-C ₄ )alkyl, O(C1-C ₄ )alkyl, (C1-C ₄ )haloalkyl and O(C1C ₄ )haloalkyl. 6. A compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a fragment: where R ³ is selected from where each R ^3A is a fragment selected from: - 205 043752 wherein R ³ is selected from each R ^3Aa independently selected from (C1-C ₄ )alkyl, O(C1-C ₄ )alkyl, (C1-C ₄ )haloalkyl and O(C1C ₄ )haloalkyl. 7. A compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a fragment: each R ^3Aa is independently selected from (C1-C ₄ )alkyl, O(C1-C ₄ )alkyl, (C1-C ₄ )haloalkyl and O(C1C ₄ )haloalkyl. 8. A compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a fragment: where each R ^3A is a fragment selected from: where R ³ is selected from where each R ^3A is a fragment selected from: - 206 043752 and each R ^3Aa is independently selected from (C1-C ₄ )alkyl, O(C1-C ₄ )alkyl, (C1-C ₄ )haloalkyl and O(C1C ₄ )haloalkyl. 9. A compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a fragment: where R ³ is selected from where each R ^3A is a fragment selected from: each R ^Aa is independently selected from (C ₁ -C ₄ )alkyl, O(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl and O(C1C ₄ ) haloalkyl. 10. A compound or a pharmaceutically acceptable salt thereof, where said compound is selected from: - 207 043752 - 208 043752 - 209 043752 - 210 043752 - 211 043752 - 212 043752 - 213 043752 - 214 043752 - 215 043752 - 216 043752 - 217 043752 - 218 043752 - 219 043752 - 220 043752 - 221 043752 - 222 043752 11. A pharmaceutical composition containing a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for - 223 043752 treatment of cancer mediated by adenosine A2a and/or A2b receptors. 13. Use according to claim 12, wherein said cancer is selected from melanoma, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, cancer with high microsatellite instability, non-small cell cancer lung, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal cell carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, kidney cancer, mesothelioma , ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary gland cancer, prostate cancer and metastatic castration-resistant prostate cancer. 14. Application according to i. 13, wherein said compound or a pharmaceutically acceptable salt thereof is used in combination with a PD-1 antagonist. 15. The use of claim 14, wherein the PD-1 antagonist is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab. 16. Application according to i. 14, in which the PD-1 antagonist is pembrolizumab. 17. A compound or a pharmaceutically acceptable salt thereof, where the compound is: O 18. Connection, wherein the connection is: 19. A pharmaceutical composition containing a compound according to claim 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 20. Use of a compound according to claim 17 or a pharmaceutically acceptable salt thereof for the treatment of cancer mediated by adenosine A2a and/or A2b receptors. 21. Use according to claim 20, wherein said cancer is selected from melanoma, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, cancer with high microsatellite instability, non-small cell cancer lung, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal cell carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, kidney cancer, mesothelioma , ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary gland cancer, prostate cancer and metastatic castration-resistant prostate cancer. 22. Use according to claim 20, wherein said compound or a pharmaceutically acceptable salt thereof is used in combination with a PD-1 antagonist. 23. The use of claim 22, wherein the PD-1 antagonist is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab. 24. The use of claim 22, wherein the PD-1 antagonist is pembrolizumab.