WO2022109580A1

WO2022109580A1 - Inhibition of tyk2 dependent signaling pathways

Info

Publication number: WO2022109580A1
Application number: PCT/US2021/072483
Authority: WO
Inventors: Tami MARRONE; Dale Rudolph; Brock Shireman; Jocelyn WANG
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2020-11-20
Filing date: 2021-11-18
Publication date: 2022-05-27

Abstract

The present application discloses compounds of Formula (I') or pharmaceutically acceptable salt thereof, wherein, Formula (A), R1, R5, Z and m are defined in the specification, as well as methods of making and using the compounds disclosed herein for treating or ameliorating an TYK2 mediated syndrome, disorder and/or disease.

Description

Inhibition of TYK2 Dependent Signaling Pathways

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/116,176, filed November 20, 2020, the disclosure of which is incorporated herein by reference in its entirety.

Sequence Listing

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 16, 2021, is named JBI6430WOPCT_SL.txt and is 3,327 bytes in size.

Field

Disclosed herein are compounds, and pharmaceutical compositions thereof, which modulate TYK2. Also disclosed herein is the therapeutic use of such compounds, for example, in treating and/or ameliorating a TYK2 mediated inflammatory syndrome, disorder, and/or disease.

Background

Tyrosine kinase 2 (TYK2) is a member of the Janus Kinase (JAK) family, which consists of non-receptor tyrosine kinases essential for type I and type II cell-surface cytokine receptors signaling. There are four JAK family members: JAK1, JAK2, JAK3, and TYK2. Different cytokine receptor families utilize specific JAK isoforms for their signal transduction. Phosphorylation of a JAK when a cytokine binds to its cognate receptor leads to phosphorylation of other intracellular molecules that eventually lead to gene transcription (O’Shea, J. J. et al. Annu. Rev. Med. 2015, 66, 311-328). Evidence exists that selective inhibitors of TYK2 dependent signaling pathways (e.g., interleukin-12 and/or interleukin-23) would be efficacious for the treatment of multiple autoimmune and inflammatory diseases such as psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), juvenile idiopathic arthritis (JIA), and primary biliary cirrhosis (PBC) (Shaw, M. H. et al., Proc. Natl. Acad. Sci. 2003, 100, 11594-9; Lazear, H. M. et al. Immunity 2015, 43, 15-28; Karaghiosoff, M. et al. Immunity 2000, 13, 549-560; Dendrou, C.A. et al. Sci. Transl. Med. 2016, 8, 363ral49; Schwartz, M. et al., Nat. Rev. Drug Discov. 2017, 16, 843-862; Teng, W. L. Nature Medicine 2015, 21,719-729; Papp, K. et al., N. Engl. J. Med. 2018, 379; 1313-1321 ; Psarras, A. et al. Rheumatology 2017, 56 (10), 1662-1675).

All the JAK family members share a high degree of homology between their active sites in the kinase catalytic domain (called Janus Homology Domain 1 or JH1); thus it would be challenging to obtain selectivity for TYK2 over the other JAK family members with ATP- competitive small molecule inhibitors. However, the JAK family also has a pseudokinase domain (called Janus Homology Domain 2 or JH2). The TYK2 pseudokinase domain, despite its lack of intrinsic kinase activity, has been shown to be important in regulating TYK2 kinase activity (Min, X. et al., J. Biol. Chem. 2015, 290, 27261-27270; Lupardus, P.J. et al., PNAS, 2014, 111 (22) 8025-8030. Also, there are several coding SNPs in this region that regulate TYK2 kinase activity and have been associated with multiple autoimmune and inflammatory diseases Dendrou, C.A. et al. Sci. Transl. Med. 2016, 8, 363ral49, Li, Z et al. PLoS ONE 2020, 15(1): e0225289; Boisson-Dupuis S. et al. Sci. Immunol. 2018. 3, eaau8714). Given the ongoing need to treat the numerous autoimmune and inflammatory diseases mentioned above, there is an ongoing need for selective allosteric TYK2 inhibitors that bind to the JH2 domain. These inhibitors would specifically block signaling downstream from IL-12, IL-23, and Type 1 Interferon receptors that use TYK2 for signal transduction while sparing signaling from cytokine receptors that use the other JAK family members. Accordingly, specifically targeting TYK2 with a small molecule inhibitor as described herein may provide an opportunity to avoid certain adverse effects observed with certain JAK inhibitors (Gadina, M. etal Rheumatology, 2019, 58, i4— i16), such as the pan- JAK inhibitor Tofacitinib (Xeljanz®), which may have dose-limiting and systemically-mediated adverse events. Brief Summary

The present application describes a compound of Formula I’:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O, S(O) or SO₂; m is 1 or 2;

R¹ is -C_(1-4)alkyl unsubstituted or substituted with one to six fluorine atoms; -OCH₃; -OH;

R^1a independently for each occurrence is H or -C_(1-2)alkyl;

R^1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3;

X is -O-, -NH-, -SO₂-, or -C_(1-4)alkyl- that is unsubstituted or substituted with -OH or -CN;

Y is -CH₂-, or -CH(OH)-;

U is 0 or 1;

R² is -NH₂, -NH(CH₃), -C₃-C₆ cycloalkyl or -C_(1-4)alkyl that is unsubstituted or substituted with -OH;

R³ is H;

-C_(1-4)alkyl that is unsubstituted or substituted with one to six fluorine atoms;

-C₃-C₆ cycloalkyl that is unsubstituted or substituted with one or two R^3a groups, wherein R^3a independently for each occurrence is -OH, -CN or -C(O)NH₂; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; wherein the 5-membered heteroaryl is unsubstituted or substituted with one R⁴ group;

R⁴ is H or -C_(1-2)alkyl; and R⁵ is -C_(1-4)alkyl.

The present application also discloses compounds of Formula I. All compounds of Formula I are compounds of Formula I’. Some compounds of Formula I’ are compounds of Formula I.

Accordingly disclosed herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-4)alkyl, -O(CH₂)₂OC_(1-4)alkyl,

wherein n is 0, 1, 2, or 3 and the -C_(1-4)alkyl is unsubstituted or substituted with one to six fluorine atoms;

X is O, NH, SO₂, or -C_(1-4)alkyl that is unsubstituted or substituted with -OH or CN;

R² is -NH₂ or -C_(1-4)alkyl; and

R³ is H, -C_(1-4)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-4)alkyl.

In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I’, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments, the compounds of Formula I’ disclosed herein selectively bind to the pseudokinase (JH2) domain of TYK2. In some embodiments, the compounds disclosed herein are modulators of a TYK2 dependent signaling pathway (e.g., interleukin- 12 and/or interleukin- 23).

In some embodiments, disclosed herein is a method for treating and/or ameliorating a TYK2 dependent signaling pathway (e.g., interleukin- 12 and/or interleukin-23). In some embodiments, disclosed herein is a method for treating and/or ameliorating TYK2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.) comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is the use of a therapeutically effective amount of compound of Formula I’ , or a pharmaceutically acceptable salt thereof, for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.).

In some embodiments, disclosed herein is the use of a compound of Formula I’ , or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.).

In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a. compound of Formula I’ or pharmaceutically acceptable salts thereof.

In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments, the compounds of Formula I disclosed herein selectively bind to the pseudokinase (JH2) domain of TYK2. In some embodiments, the compounds disclosed herein are modulators of a TYK2 dependent signaling pathway (e.g., interleukin- 12 and/or interleukin- 23).

In some embodiments, disclosed herein is a method for treating and/or ameliorating a TYK2 dependent signaling pathway (e.g., interleukin- 12 and/or interleukin-23). In some embodiments, disclosed herein is a method for treating and/or ameliorating TYK2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.) comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula. I, or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is the use of a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.). In some embodiments, disclosed herein is the use of a compound of Formula I, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.).

In some embodiments, provided herein are processes and intermediates disclosed herein that are usefill for preparing a compound of Formula I or pharmaceutically acceptable salts thereof.

The disclosure also provides a compound or method as described herein.

Detailed Description

I. Definitions

Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein.

It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

In an attempt to help the reader of the application, the description has been separated in various paragraphs or sections, or is directed to various embodiments of the application. These separations should not be considered as disconnecting the substance of a paragraph or section or embodiments from the substance of another paragraph or section or embodiments. To the contraiy, one skilled in the art will understand that the description has broad application and encompasses all the combinations of the various sections, paragraphs and sentences that can be contemplated. The discussion of any embodiment is meant only to be exemplary and is not intended to suggest that the scope of the disclosure, including the claims, is limited to these examples.

The term "administering" with respect to the methods of the invention, means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof. Such methods include administering a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy.

The term "subject" refers to a patient, which may be an animal, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human.

The term "therapeutically effective amount" or "effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

As used herein, the term “treat”, “treating”, or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physiological or biochemical parameter associated with or causative of the disease, condition, syndrome or disorder, including those which may not be discernible by the patient. In a further embodiment, “treat”, “treating”, or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In yet another embodiment, “treat'’, “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.

As used herein, the term “QD” means once daily.

As used herein, the term “BID” means twice daily.

The term “alkyl” is a straight or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 12 carbon atoms (i.e., (C₁-C₁₂)alkyl) or 1 to 6 carbon atoms (i.e., (C₁- C₆)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH₃), ethyl (Et, -CH₂CH₃), 1 -propyl (n-Pr, n-propyl, -CH₂CH₂CH₃), isopropyl (i-Pr, i-propyl, -CH(CH₃)₂), 1- butyl (n-Bu, n-butyl, -CH₂CH₂CH₂CH₃), 2-butyl (s-Bu, s-butyl, -CH(CH₃)CH₂CH₃), tert-butyl (t-Bu, t-butyl, -CH(CH₃)₃), 1 -pentyl (n-pentyl, -CH₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH(CH₃) CH₂CH₂CH₃), 1 -hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2 -hexyl (-CH(CH₃)CH₂CH₂CH₂CH₃), heptyl (-(CH₂)₆CH₃), octyl (-(CH₂)₇CH₃), 2,2,4-trimethylpentyl (-CH₂C(CH₃)₂CH₂CH(CH₃)₂), nonyl (-(CH₂)₈CH₃), decyl (-(CH₂)₉CH₃), undecyl (-(CH₂)₁₀CH₃ ), and dodecyl (-(CH₂)₁₁CH₃). Any alkyl group may be unsubstituted or substituted.

The term “C_(a-b)” (where a and b are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive. For example, C_(1-4) denotes a radical containing 1, 2, 3 or 4 carbon atoms.

The term “heterocycle” or “heterocyclyl” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. Exemplary heterocycles include, but are not limited to oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.

The term “cycloalkyl” refers to a saturated or partially unsaturated all carbon ring system having 3 to 8 carbon atoms (i.e., C_(3-8)cycloalkyl), and preferably 3 to 6 carbon atoms (i.e., C_(3- ₆₎cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in a spirocyclic or bicyclic form. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl . Unless otherwise stated specifically in the specification, a cycloalkyl group may be unsubstituted or substituted. Some cycloalkyl groups may exist as spirocycloalkyls, wherein two cycloalkyl rings are fused through a single carbon atom; for example and without limitation, an example of a spiropentyl group is

for example and without limitation, examples of spirohexyl groups include

for example and without limitation examples of cycloheptyl groups

. examples of cyclooctyl groups include

Unless otherwise stated specifically in the specification, a siprocycloalkyl group may be unsubstituted or substituted. Bicyclic cycloalkyl ring systems also include

The term “heteroaryl” refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. The term “heteroaryl” includes single aromatic rings of from 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Exemplary heteroaryl ring systems include but are not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.

The term “halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F) or iodo (-I).

Where the compounds of Formula I disclosed herein have at least one stereo center, they may accordingly exist as enantiomers or diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

“Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A “racemic” mixture is a 1 : 1 mixture of a pair of enantiomers. A “scalemic” mixture of enantiomers is mixture of enantiomers at a ratio other than 1 :1. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, a scalemic mixture, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p- toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral column vial HPLC or SFC. In some instances retainers of compounds may exist which are observable by ¹H NMR leading to complex multiplets and peak integration in the ¹H NMR spectrum.

The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. Chiral centers, of which the absolute configurations are known, are labelled by prefixes R and S, assigned by the standard sequence-rule procedure, and preceded when necessary by the appropriate locants (Pure & Appl. Chem. 45, 1976, 11-30). Certain examples contain chemical structures that are depicted or labelled as an (*R) or (*S). When (*R) or (*S) is used in the name of a compound or in the chemical representation of the compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, absolute configuration of that stereocenter has not been established. Thus, a compound designated as (*R) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S), and a compound designated as (*S) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S). For example, (*R)- N-( 1 -(4-(Difluoromethyl)-6-(3 -methoxy tetrahy drofuran-3 -yl)pyridine-2-yl)-3-methyl- 1H- pyrazol o[4,3 -c]pyridine-6-yl)acetamide:

refers to a compound that is:

Pseudoasymmetric stereogenic centers are treated in the same way as chiral centers, but are given lower-case symbols, r or 5 (Angew. Chem. Int. Ed Engl. 1982, 21, 567-583).

During any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Furthermore, it is intended that within the scope of the present invention, any element, in particular when mentioned in relation to a compound of Formula I, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope ¹H, ²H (i.e., deuterium or D), and ³H (i.e., tritium or T). In some embodiments, the compounds described herein include a ²H (i.e., deuterium) isotope. By way of example, the group denoted -C_(1-6)alkyl includes not only -CH₃, but also CD₃; not only CH₂CH₃, but also CD₂CD₃, etc. . Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁵O and ¹⁶O and ¹⁷O and ¹⁸O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of Formula I may include a radioactive isotope selected from the group comprising 3H, ¹¹C, ¹⁸F, ³⁵S, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

II. Compounds of Formula I’ and Formula I

The present application describes a compound of Formula I’ :

or a pharmaceutically acceptable salt thereof, wherein:

Z is O, S(O) or SO₂; m is 1 or 2; R¹ is -C_(1-4)alkyl unsubstituted or substituted with one to six fluorine atoms; -OCH₃; -OH;

R^1a independently for each occurrence is H or -C_(1-2)alkyl;

R^1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3;

Y is -CH₂-, or -CH(OH)-;

U is 0 or 1;

R³ is H;

R⁴ is H or -C_(1-2)alkyl; and R⁵ is -C_(1-4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein:

Z is O, S(O) or SO₂; m is 1 or 2;

R¹ is -C_(1-2)alkyl unsubstituted or substituted with one to three fluorine atoms; -OCH₃, -

R^1a independently for each occurrence is H or -C_(1-2)alkyl;

R^1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3;

X is -O- or -SO₂-;

Y is -CH₂-, or -CH(OH)-;

U is 0 or 1;

R² is -NH₂, -NH(CH₃), -C₃-C₅ cycloalkyl or -C_(1-4)alkyl that is unsubstituted or substituted with -OH;

R³ is H;

-C_(1-4)alkyl that is unsubstituted or substituted with one to three fluorine atoms;

R⁴ is H or -C_(1-2)alkyl; and R⁵ is -C_(1-4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein: R¹ is -C_(1-3)alkyl, -O(CH₂)₂OCH₃,

wherein the -C_(1-3)alkyl is unsubstituted or substituted with one to three fluorine atoms.

R¹ is -CH₃, -CHF₂, -CF₃, -CF₂CH₃, -O(CH₂)₂OCH₃,

R² is -NH₂, -NH(CH₃), -C₃-C₄ cycloalkyl or -C_(1-2)alkyl that is unsubstituted or substituted with -OH. In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein:

R² is -NH₂, -NH(CH₃), -CH₃, -CD₃, -CH₂OH, or

R³ is H;

-C_(1-3)alkyl that is unsubstituted or substituted with one to three fluorine atoms;

-C₃-C₄ cycloalkyl that is unsubstituted or substituted with one or two R^3a groups, wherein R^3a independently for each occurrence is -OH, -CN or -C(O)NH₂; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5-membered heteroaryl having 1 to 2 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with one R⁴ group; and

R⁴ is -C_(1-2)alkyl.

R³ is H, -CH₃, -CD₃, -CF₃, -C₃-C₄ cycloalkyl that is unsubstituted or substituted with one or two R^3a groups; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5- membered heteroaryl having 1 to 2 heteroatoms selected from N and O, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-2)alkyl.

In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein: wherein R³ is H, -CH₃, -CD₃, -CF₃,

R³ is H, -CH₃, -CD₃, -CF₃,

In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof which is a compound of Formula I’a:

In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof which is a compound of Formula I’b:

Also disclosed herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-4)alkyl, -O(CH₂)₂OC_(1-4)alkyl,

R² is -NH₂ or -C_(1-4)alkyl; and

R³ is H, -C_(1-4)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from

N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-4)alkyl, -O(CH₂)₂OCH₃,

wherein n is 0, 1, or 2 and the -C_(1-4)alkyl is unsubstituted or substituted with one to six fluorine atoms;

X is O, SO₂, or -C_(1-4)alkyl that is unsubstituted or substituted with -OH;

R² is -NH₂ or -C_(1-4)alkyl; and R³ is H, -C_(1-4)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-3)alkyl.

R¹ is -C_(1-4)alkyl, -O(CH₂)₂OCH₃,

wherein the -C_(1-4)alkyl is unsubstituted or substituted with one to three fluorine atoms;

R² is -NH₂ or -C_(1-4)alkyl; and

N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-3)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R¹ is -C_(1-3)alkyl, -O(CH₂)₂OCH₃,

wherein the -C_(1-3)alkyl is unsubstituted or substituted with one to three fluorine atoms. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein

R¹ is -CH₃, -CHF₂, -CF₃, -O(CH₂)₂OCH₃,

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein

R¹ is -O(CH₂)₂OCH₃,

R² is -NH₂, -CH₃, or -CH₂CH₃.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R² is -NH₂, or -CH₃.

R³ is H, -C_(1-3)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R³ is H, -C_(1-3)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-2)alkyl.

R³ is H, -C_(1-3)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N or O, wherein the 5-membered heteroaryl is unsubstituted or substituted with - C_(1-2)alkyl.

R³ is H, -C_(1-3)alkyl,

R⁴ is H or -C_(1-2)alkyl.

R³ is H, -CH₃,

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula la:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula lb:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds in Table 1 A.

Table 1A

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

Table 2

In some embodiments, disclosed herein is a pharmaceutical composition, comprising a compound of Formula I’, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).

In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of Formula I’, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments, disclosed herein is a process for making a pharmaceutical composition comprising mixing a compound of Formula I’, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments, disclosed herein is a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).

In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments, disclosed herein is a process for making a pharmaceutical composition comprising mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

III. Therapeutic Use

The present application also describes a method of selectively inhibiting the pseudokinase (JH2) domain of TYK2 for the treatment of multiple autoimmune and inflammatory diseases such as psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), juvenile idiopathic arthritis (JIA), and primary biliary cirrhosis (PBC). In some embodiments, disclosed herein is a method of inhibiting one or more TYK2 dependent signaling pathways (e.g., interleukin-12, interleukin-23, and/or Typel interferons) for the treatment of multiple autoimmune and inflammatory diseases such as psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), juvenile idiopathic arthritis (JIA), and primary biliary cirrhosis (PBC). In some embodiments, described herein is a method for treating and/or ameliorating a TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof

In some embodiments, disclosed herein is a method for treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriasis. In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is lupus nephritis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is inflammatory bowel disease, ulcerative colitis or Crohn’s disease.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis. In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

In some embodiments, disclosed herein is a method for treating or ameliorating and/an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is Sjogren’s syndrome.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the compound of Formula I’ or the pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 5 mg to 150 mg BID.

In some embodiments, disclosed herein is the use of a therapeutically effective amount of compound of Formula I’, or a pharmaceutically acceptable salt thereof, for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is the use of a compound of Formula I’, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

In some embodiments, disclosed herein is a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

In some embodiments, disclosed herein is a method of treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, and systemic lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof. In some embodiments, disclosed herein are methods of modulating TYK2 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I’, or pharmaceutically acceptable salt thereof.

The present application also describes a method of selectively inhibiting the pseudokinase (JH2) domain of TYK2 for the treatment of multiple autoimmune and inflammatory diseases such as psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), juvenile idiopathic arthritis (JIA), and primary biliary cirrhosis (PBC). In some embodiments, disclosed herein is a method of inhibiting one or more TYK2 dependent signaling pathways (e.g., interleukin- 12, interleukin-23, and/or Typel interferons) for the treatment of multiple autoimmune and inflammatory diseases such as psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), juvenile idiopathic arthritis (JIA), and primary biliary cirrhosis (PBC). In some embodiments, described herein is a method for treating and/or ameliorating a TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof.

In some embodiments, disclosed herein is a method for treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriasis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is lupus nephritis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is inflammatory bowel disease, ulcerative colitis or Crohn’s disease.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

In some embodiments, disclosed herein is a method for treating or ameliorating and/an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is Sjogren’s syndrome.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 5 mg to 150 mg BID.

In some embodiments, disclosed herein is the use of a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is the use of a compound of Formula I, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

In some embodiments, disclosed herein is a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

In some embodiments, disclosed herein is a method of treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, and systemic lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

In some embodiments, disclosed herein are methods of modulating TYK2 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, or pharmaceutically acceptable salt thereof.

IV. Combination Therapy

A compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof may also be used in combination with one or more additional therapeutic agents.

A compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof may also be used in combination with one or more additional therapeutic agents.

In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressive agents.

In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: (a) anti-TNFalpha agents such as infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®/hnnovid®); and

(b) anti-pl 9 antibody agents such as tildrakizumab (Ilumya™/Humetri), risankizumab (Skyrizi™), and mirikizumab.

In some embodiments, disclosed herein is a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I’, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I’, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is psoriasis, psoriatic arthritis, or systemic lupus erythematosus. In some embodiments, the TYK2 mediated inflammatory syndrome, disorder or disease is psoriasis. In some embodiments, the TYK2 mediated inflammatory syndrome, disorder or disease is psoriatic arthritis. In some embodiments, the TYK2 mediated inflammatory syndrome, disorder or disease is systemic lupus erythematosus. In some embodiments, disclosed herein is a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

In some embodiments, disclosed herein is a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is psoriasis, psoriatic arthritis, or systemic lupus erythematosus. In some embodiments, the TYK2 mediated inflammatory syndrome, disorder or disease is psoriasis. In some embodiments, the TYK2 mediated inflammatory syndrome, disorder or disease is psoriatic arthritis. In some embodiments, the TYK2 mediated inflammatory syndrome, disorder or disease is systemic lupus erythematosus.

V. Dosage Regimen

When employed as TYK2 modulators, the compounds disclosed herein may be administered in an effective amount within the dosage range of about 0.5 mg to about 1 g, preferably between about 0.5 mg to about 500 mg, in single or divided daily doses. In some embodiments, the dosage amount is about 5 mg to 400 mg. In some embodiments, the dosage amount is about 10 mg to 300 mg. In some embodiments, the dosage amount is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof In some embodiments, the dosage amount is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof.

In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

When employed as TYK2 modulators, the compounds disclosed herein may be administered in an effective amount within the dosage range of about 0.5 mg to about 1 g, preferably between about 0.5 mg to about 500 mg, in single or divided daily doses. In some embodiments, the dosage amount is about 5 mg to 400 mg. In some embodiments, the dosage amount is about 10 mg to 300 mg. In some embodiments, the dosage amount is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof.

In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

The dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments. It is also apparent to one skilled in the art that the therapeutically effective dose for compounds of the present invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

VI. Pharmaceutically Acceptable Salts

Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and triethiodide. Organic or inorganic acids also include, and are not limited to, hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic, hydroxyethanesulfonic, oxalic, 2- naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, saccharinic or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, 2- amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine, piperidine, potassium, potassium- t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

VII. Pharmaceutical Compositions

The compounds of Formula I’, or pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents. Exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula I’, or pharmaceutically acceptable salt thereof, include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts and salts with amino acids such as arginine. Also, the basic nitrogen-containing groups may be quatemized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route. Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes. Also disclosed herein is a method of making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I’, or pharmaceutically acceptable salt thereof. Additionally, the present application includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention.

The compounds of Formula I, or pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents. Exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula I, or pharmaceutically acceptable salt thereof, include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts and salts with amino acids such as arginine. Also, the basic nitrogen-containing groups may be quatemized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route. Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes. Also disclosed herein is a method of making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I, or pharmaceutically acceptable salt thereof. Additionally, the present application includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention.

EXAMPLES

Herein and throughout the application, the following abbreviations may be used.

In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of Formula I or pharmaceutically acceptable salts thereof.

GENERAL SCHEMES:

Compounds of Formula I are synthesized in accordance with synthetic methods described herein, which are only meant to represent synthetic examples and are in no way meant to be limitations. Unless otherwise specified, the substituent groups in Schemes 1-9 are as defined above in reference to Formula I. If no temperature or temperature range is stated, it is to be understood that the reaction is run at room temperature.

In the schemes below, a Suzuki reaction or a Suzuki coupling (Suzuki, A., Angew. Chem. Int. Ed 2011, 50: 6723-6737) may be performed using the following conditions: One coupling reactant has a boron component that is in the form of, for example, a potassium trifluoroborate, an organoborane, a boronate or a boronic acid. The second coupling reactant is in the form of, for example, an aryl, alkyl, alkenyl or alkynyl halide. These two coupling reactants react in the presence of (i) a palladium source, such as tetrakis-triphenylphosphine palladium or (2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-(2'-amino-1,1’- biphenyl))palladium(II) methanesulfonate (RuPhos Pd-G3), (ii) optionally, an additive such as 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), and (iii) a base, such as K₂CO₃, in a solvent such as benzene or dioxane and water, at a temperature range of about room temperature to about reflux temperature of the solvent. The aforementioned conditions are referred to as “Suzuki coupling conditions”.

In the schemes below a Boc protecting group may be removed using the following conditions: HC1 in dioxane or ethyl acetate or TFA in CH₂CI₂. The concentration of the HCl in dioxane or ethyl acetate may be from 1.0 M to 4.0 M, and the reaction may be run in a solvent such as isopropanol or CH₂CI₂. Alternatively, a Boc protecting group can be removed by subjecting the compound to microwave irradiation at 120 °C in a solvent such as 1, 1,1, 3,3,3- hexafluoro-2-propanol. The aforementioned conditions are referred to as “Boc deprotection conditions”.

Scheme 1

As shown in Scheme 1, a compound of formula VII is prepared in two steps from a compound of formula V. In a first step, a compound of formula V is reacted with a base such as n-BuLi, in a suitable solvent such as DCM, at a temperature of about -78 °C, followed by the addition of dihydrofuran-3(2H)-one to provide a compound of formula VI. In a second step, a compound of formula VI is treated with a base such as NaH, LiH, KOH, NaOMe, NaOH, or t- BuOK in a suitable solvent such as DMF, at a temperature of about 0 °C, followed by the addition of an alkyl halide such as CH₃I, to provide a compound of formula VII.

Scheme 1a

As shown in Scheme la, compounds of formula VII-a and Vll-aa, can be prepared in two or three steps from a compound of formula V. In a first step, a compound of formula V is initially treated with a base such as n-BuLi in a suitable solvent such as DCM, at a temperature of about -78 °C, followed by the addition of a cyclic ketone, such as dihydro-2H-pyran-3(4H)- one or dihydrothi ophen-3(2H)-one to provide a compound of formula Vl-a. In a second step, a compound of formula Vl-a is treated with a base such as NaH, LiH, KOH, NaOMe, NaOH, or t- BuOK in a suitable solvent such as THF or DMF, at a temperature of about 0 °C, followed by the addition of an alkyl halide such as CH₃CH₂I or CH₃I, to provide a compound of formula VII-a. In a third step, a compound of formula Vll-a, where Z=S, is treated with an oxidant such as oxone or 30% aqueous H₂O₂ in a suitable solvent such as MeOH, H₂O or 1,1, 1,3,3, 3-hexafluoro- 2-propanol at a temperature of about 0 °C to room temperature for approximately 1 h, to provide a compound of formula Vll-aa. A compound of formula V where R^a is NO₂ can be converted to a compound of formula Vll-a where R^a is

displacement with an amine nucleophile, such as piperidine or 4-(benzyloxy)piperidine, respectively

Scheme 1b

As shown in Scheme 1b, compounds of formula VII-c, can be prepared in four steps from a compound of formula VII. In a first step, a compound of formula VII is treated with an acid, such as concentrated HC1, in a suitable solvent, such as water, to provide an intermediate aldehyde which is then treated with a Grignard reagent, such as MeMgCl in a suitable solvent, such as THF at a temperature of about -78 °C to provide a compound of formula Vll-b. In a third step, a compound of formula VII-b is treated with an oxidant such as Dess-Martin periodinane, in a suitable solvent such as DCM at a temperature around room temperature to provide an intermediate ketone which is then treated with DAST, in a suitable solvent such as DCM at a temperature of about 0 °C to provide a compound of formula VII-c.

Scheme 2

As shown in Scheme 2, 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (a compound of formula VII where R¹ is OH) is alkylated with a compound of formula IX, where and LG¹ is a leaving group such as halo, -OMs, or -OTs, and R^bb is -(CH₂)₂OCH₃,

in the presence of a base such as NaH, in a suitable solvent such as DMF, at a temperature ranging from about 0 °C to about 85 °C, to afford a compound of formula VIII.

Scheme 3

As shown in Scheme 3, a compound of formula XIII is prepared from a compound of formula X, by reaction with a compound of formula XI, in the presence of a catalyst such as Pd(dppf)Cl₂, a base such as K₃PO₄, in a solvent such as 1,4-dioxane and water, or a combination thereof, at a temperature of about 80 °C for about 3 h. A compound of formula XV is prepared from a compound of formula XIII, by reaction with a compound of formula XIV, under Cu- mediated amination conditions using cuprous bromide, in the presence of a ligand, such as 1,2- dimethylethylenediamine, and a base such as K₂CO₃, at a temperature of about 105 °C for about 3 h. These conditions are referred to herein as “Cu-mediated amination conditions”.

Scheme 3a

As shown in Scheme 3a, a compound of formula XIII-c can be prepared from 5-bromo- 2,4-dichloropyridine. In a first step, 5-bromo-2,4-dichloropyridine is reacted with a Grignard reagent such as i-PrMgCl • LiCl, copper (I) bromide, and a compound of formula Xlll-a, in a suitable solvent such as THF, at temperatures ranging from about 0 °C to about 25 °C to provide compound of formula XIII-b. In a second step, a compound of formula Xlll-b is reacted with hydrazine, hydrazine hydrate, hydrazine monohydrochloride, or hydrazine dihydrochloride neat or in a suitable solvent such as EtOH, at temperatures ranging from about -78 °C to about 25 °C to provide a compound of formula XIII-c. Scheme 3b

As shown in Scheme 3b, a compound of formula XV-a can be prepared from a compound of formula Xlll-d. , Reaction of compound of formula X-IIId with a compound of formula Vll-a under Cu-mediated amination conditions provides compound of formula XV-a.

Scheme 4a

As shown in Scheme 4a, a compound of formula XXI, is prepared from a compound of formula XX and a compound of formula XX is prepared from either a compound of formula XIX or XXIV.

Scheme 4b

As shown in Scheme 4b, ethyl 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate and a compound of formula XII are reacted using Suzuki coupling conditions to afford a compound of formula XVI. A compound of formula XVI is reacted with XVII using Suzuki conditions to provide a compound of formula XVIII. Alternatively, a compound of formula XVI can be reacted with the appropriate boronate ester or boronic acid (structures not shown) to provide a compound of formula XVIII. A compound of formula XIX is prepared from a compound of formula XVIII through hydrolysis. This hydrolysis is accomplished by treatment of the substituent being hydrolyzed (an ester in the compound of formula XVIII) with a suitable base such as lithium hydroxide or sodium hydroxide, in a solvent system such as dioxane or water or combinations thereof, at a suitable temperature such as room temperature. These hydrolysis conditions are referred to as “basic hydrolysis conditions”. A compound of formula XIX undergoes a Curtius rearrangement to provide a compound of formula XX. Curtius rearrangement conditions include a carboxylic acid (as shown in a compound of formula XIX), that is reacted with diphenyl phosphoryl azide (DPPA), in the presence of base such as triethylamine, in a suitable solvent such as tert-butanol, at a temperature of about 85 °C. These conditions are referred to herein as “Curtius rearrangement conditions”.

To prepare a compound of formula XXII, ethyl 7-chloropyrrolo[1,2-c]pyrimidine-3- carboxylate is reacted in a Suzuki coupling reaction with a boronic ester XI or suitably substituted 1,3,5,2,4,6-trioxatriborinane XVII A compound of formula XXII is hydrolyzed using basic hydrolysis conditions to provide a compound of formula XXIII. A compound of formula XXIII is subjected to Curtius rearrangement conditions to provide a compound of formula XXIV. A compound of formula XXIV is reacted in a metal-mediated cross coupling reaction with a compound of formula VII under Heck reaction conditions. Heck reaction conditions include a reaction that is run in the presence of a palladium catalyst Pd(OAc)₂, with or without the addition of a ligand such as tricyclohexyl phosphine, a base such as cesium carbonate, in a suitable solvent such as 1,4-dioxane, at a temperature of about 130 °C to afford a compound of formula XX. A compound of formula XX is deprotected to provide a compound of formula XXI using Boc deprotection conditions. When R³ is an unsaturated heterocycle, it can be converted to a saturated heterocycle using hydrogenation conditions in the presence of a metal such as Pd/C under an atmosphere of hydrogen gas in a solvent such as EtOH, THF or mixtures thereof. These conditions will be known as “hydrogenation conditions”.

Scheme 5

As shown in Scheme 5, a compound of formula XXVI is prepared from a compound of formula XXV, by reaction with 1-(4-methoxybenzyl)urea in the presence of a catalyst such as BrettPhos Pd G3 and a base such as such as Cs₂CO₃, in a solvent such as THF, at a temperature of about 70 °C for about 2 h. A compound of formula XXVII is prepared from a compound of formula XXVI by heating in a solvent such as TFA at a temperature of about 60 °C for about 2 h.

Scheme 5a

As shown in Scheme 5a, a compound of formula XXVI-a can be prepared from a compound of formula XXV-a, by reaction of compound of formula XXV-a with 1-(4- methoxybenzyl)urea in the presence of a catalyst such as BrettPhos Pd G3 and a base such as such as Cs₂CO₃, in a solvent such as THF, at a temperature of about 70 °C for about 2 h. A compound of formula XXVII-a is prepared from a compound of formula XXVI-a by heating a compound of formula XXVI-a in a solvent such as TFA at a temperature of about 60 °C for about 2 h.

Scheme 6

As shown in Scheme 6, a compound of formula XXIX is prepared from a compound of formula XXVIII, by treatment with 2,2,2-trichloroacetyl isocyanate in a suitable solvent such as DCM, THF, MeCN, benzene, pyridine or DMF or mixtures thereof, at a temperature of about 0 °C for approximately 2 h. The product of this reaction was then stirred at a temperature of about 0 °C with a base such as saturated aqueous sodium bicarbonate solution in a solvent such as MeOH for a period of about 1 hour to about 4 hours with warming to about room temperature.

Scheme 7

As shown in Scheme 7, a compound of formula XXX is reacted with a substituted primary amide XXXI under Pd-catalyzed amination of heteroaryl halide conditions. The Pd- catalyzed amination of heteroaryl halide conditions include a palladium catalyst such as Pd₂(dba)₃, Pd(OAc)₂, or BrettPhos Pd G3, a ligand such as 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (XantPhos), or 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (XPhos), a base such as Cs₂CO₃, LHMDS, NaOtBu, or K₃PO₄, in a suitable solvent such as toluene, THF, DMA, dioxane, or mixtures thereof, at temperatures ranging from about 80 °C to about 150 °C. This reaction may employ microwave or conventional heating for a period of about 0.5 h to about 18 h to provide a compound of formula XXXII.

Scheme 8

As shown in Scheme 8, a compound of formula XXXIV is prepared from a compound of formula XXXIII, by acylation of the amine moiety. Conditions to acylate the amine include treating the amine with an acylating reagent such as acetic anhydride, acetyl chloride or acetyl-d₃ chloride; in a suitable solvent such as DCM or pyridine or mixtures thereof, at a temperature of about 0 °C to about room temperature, for about 0.5 h to about 24 h. These conditions will be referred to herein as “amine acylation conditions”.

Scheme 9

As shown in Scheme 9, a compound of formula XXXVI is prepared from a compound of formula XXXV, by subjecting a compound of formula XXXV to amine acylation conditions.

Scheme 10

As shown in Scheme 10, a compound of formula XXXVII is reacted with a substituted primary amide XXXVIII under Pd-catalyzed amination of heteroaryl halide conditions to provide a compound of formula XXXIX. The Pd-catalyzed amination of heteroaryl halide conditions include a palladium catalyst such as Pd₂(dba)₃, Pd(OAc)₂, or BrettPhos Pd G3, a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), or 2- (dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (XPhos), a base such as Cs₂CO₃, LHMDS, NaOtBu, or K₃PO₄, in a suitable solvent such as toluene, THF, DMA, 1,4-dioxane, or mixtures thereof, at temperatures ranging from about 80 °C to about 150 °C. This reaction may employ microwave or conventional heating for a period of about 0.5 h to about 18 h.

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

Unless otherwise specified, reaction solutions were stirred at room temperature under a N_2(g) or Ar_(g) atmosphere. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure, when solutions were dried, they are typically dried over a drying agent such as MgSO₄ or Na₂SO₄.

Normal phase flash column chromatography (FCC) was performed on silica gel with prepackaged silica gel columns, such as RediSep®, using ethyl acetate (EtOAc)/petroleum ether, CH₂Cl₂/MeOH, or CH₂Cl₂/10% 2NNH₃ in MeOH, as eluent, unless otherwise indicated.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm x 7.5 cm 250 μm or 5.0 cm x 10.0 cm 250 μm pre-coated silica gel plates. Preparative thin-layer chromatography was performed using EM Science silica gel 60 F₂₅₄20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm concentrating zone. Mass spectra were obtained on Shimadzu LCMS-2020 using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated mass corresponds to the exact mass. NMR spectra were obtained on either a Broker Avance (300 MHz) or Avance (400 MHz) spectrometer. The format of the ¹H NMR data below is as follows: Chemical shift in ppm down field of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Reagent concentrations that are given as percentages refer to mass ratios, unless indicated differently.

In general, chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem VI.4.0.4 (Open Eye). INTERMEDIATES

Intermediate 1 : 3-(6-Bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol.

To a solution of 2,6-dibromo-4-methylpyridine (5.0 g, 19.9 mmol) in DCM (100 mL) at - 78 °C under N₂ was added n-BuLi (2.5 M in hexane, 8.8 mL) slowly. After 15 minutes, di hydrofur an- 3 (2H)- one (2.059 g, 23.91 mmol) was added slowly. The resulting mixture was stirred at -78 °C under N₂ for 2 h. The reaction was quenched with saturated aq. NH₄CI (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (0-40% ethyl acetate in petroleum ether) afforded the title compound as a yellow solid (3.8 g, 74%). MS (ESI): mass calcd. for C₁₀H₁₂BrNO₂, 257.0; m/z found, 258.0 [M+H]⁺.

Intermediate 2: (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine.

Step A. (R,S)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine. To a solution of 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol ( Intermediate 1, 3.9 g, 15 mmol) in DMF (90 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 435.2 mg, 18.13 mmol) and then CH₃I (2.146 g, 15.11 mmol). The resulting mixture was stirred at 25 °C for 3 h under N₂. The reaction was quenched with saturated aq. NH₄CI (100 mL), and the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried ( Na₂SO₄), filtered, and concentrated. The reaction product was initially purified by silica gel chromatography (0-20% ethyl acetate in petroleum ether) to yield (R,S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine. Step B: (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine.The enantiomers of (R,S)-2-bromo-6-(3 -methoxytetrahy drofuran-3-yl)-4-methylpyridine were separated by SFC using an SFC column, such as a Chiralpak IC, 2 x 25cm, 5 μm column (isocratic elution: 15:85 IP A (containing 0.5% 2 M NH₃-MeOH): supercritical CO₂) yielding as a first eluting enantiomer, (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine and as a second eluting enantiomer, (S) -2 -brom 0-6 -(3 -methoxytetrahydrofuran-3-yl)-4- methylpyridine (Intermediate 3). The fractions containing (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine were collected and concentrated under reduced pressure afford (R)-2-bromo-6-(3-methoxytetrahy drofuran-3 -yl)-4-methylpyridine as a yellow oil (1.1 g, 27%). SFC R_t = 5.26 min.

Intermediate 3: (S)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine.

The chiral separation described for Intermediate 2 provided (S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (1.2 g, 29%) as a yellow oil. The absolute configuration was determined by X-ray crystallography. SFC R_t = 6.27 min.

0.2, MeOH), MS (ESI): mass calcd. for C₁₁H₁₄BrNO₂, 271.0; m/z found, 272.0 [M+H]⁺ .

Intermediate 4 : 3 -(6-Bromo-4-(1,3-dioxolan-2-yl)pyridin-2-yl)tetrahydrofuran-3-ol.

Step A. (2,6-Dibromopyridin-4-yl)methanol. To a solution of 2,6-dibromoisonicotinic acid (100 g, 0.36 mol) in tetrahydrofuran (1 L) at 0 °C was added borane THF-complex (1 M in THF, 537 mL, 0.537 mol) dropwise from an addition funnel, keeping the internal temperature around 30 °C. The reaction mixture was heated at 50 °C for 3 hours. The reaction was cooled to room temperature and methanol (50 mL) was added dropwise. The reaction mixture was then heated at 50 °C for 20 min. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated to afford the title compound as a colorless oil (70 g, 74%). MS (ESI): mass calcd. for C₆H₅Br₂NO, 264.9; m/z found, 265.8 [M+H]⁺.

Step B. 2,6-Dibromoisonicotinaldehyde. To a solution of oxalyl chloride (35 mL, 410 mmol) in dichloromethane (700 mL) under N₂ was added a solution of dimethyl sulfoxide (56 mL) in dichloromethane (200 mL) dropwise at -78 °C. The resulting solution was stirred at -78 °C for 60 min. To the reaction mixture was added a solution of (2,6-dibromopyridin-4- yl)methanol (140 g, 43 mmol) in dichloromethane (700 mL) dropwise at -78 °C and the resulting mixture was stirred for an additional hour at -78 °C. Triethylamine (330 mL, 2.4 mol) was added to the reaction mixture, and the resulting mixture was stirred for an additional 2 h at 25 °C. The resulting solution was diluted with di chloromethane (1500 mL) and washed with 400 mL of 5% aqueous hydrogen chloride, 400 mL of saturated aqueous sodium bicarbonate, and 400 mL of saturated aqueous sodium chloride, respectively. The organic layer was dried (Na₂SO₄), filtered, and concentrated to afford the title compound as a colorless oil (100 g).

Step C. 2,6-Dibromo-4-(1,3-dioxolan-2-yl)pyridine. To a solution of 2,6- dibromoisonicotinaldehyde (100 g, 0.38 mol) in toluene (1000 mL), was added ethane-1,2-diol (46.8 g, 0.76 mol) and 4-methylbenzenesulfonic acid (6.5 g, 0.04 mol) at room temperature. The reaction mixture was heated to reflux at 110 °C with a Dean Stark trap for 16 hours. The reaction was quenched with water (10 mL) and the resulting solution was extracted with dichloromethane (3 x 500 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (50: 1 to 3 : 1 petroleum etherethyl acetate) afforded the title compound as a white solid (70 g, 42% over 2 steps). MS (ESI): mass calcd. for C₈H₇Br₂NO₂, 306.9; m/z found: 307.9 [M+H]⁺.

Step D. 3-(6-Bromo-4-(1,3-dioxolan-2-yl)pyridin-2-yl)tetrahydrofuran-3-ol. The title compound was prepared in a manner analogous to Intermediate 1, using 2,6-dibromo-4-(1,3- dioxolan-2-yl)pyridine instead of 2,6-dibromo-4-methylpyridine. MS (ESI): mass calcd. for C₁₂H₁₄BrNO₄, 315.0; m/z found 316.1 [M+H]⁺.

Intermediate 5 : 2-Bromo-4-(1,3-dioxolan-2-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.

The title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromo-4-(1,3-dioxolan-2-yl)pyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 4) instead of 3- (6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 1). MS (ESI): mass calcd. for C₁₃H₁₆BrNO₄329.0; m/z found, 330.0 [M+H]⁺.

Intermediate 6: (R)-2-Bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.

Step A. 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)isonicotinaldehyde. To a solution of 2-bromo-4-(1,3-dioxolan-2-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 5, 30 g, 0.09 mol) in water (300 mL) was added concentrated hydrochloric acid (300 ml) at room temperature. The reaction mixture was heated at 50 °C for 2 h. The reaction was cooled to room temperature and the pH was adjusted to 7 with 2 N sodium hydroxide. The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (20:1 to 3:1 petroleum ether : ethyl acetate) afforded the title compound as a colorless oil (15 g, 60%). MS (ESI): mass calcd. for C₁₁H₁₂BrNO₃, 285.0; m/z found, 286.0 [M+H]⁺.

Step B. (R,S)-2-Bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine. To a solution of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)isonicotinaldehyde (15 g, 0.05 mol) in dichloromethane (150 mL) under N₂ was added diethylaminosulfur trifluoride (40 g, 0.25 mol) dropwise at -78 °C over 10 min. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was carefully poured into ice water and extracted with dichloromethane (3 x 200 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate (200 mL) and saturated aqueous sodium chloride (200 mL) respectively. The organic phase was dried (Na₂SO₄), filtered, and concentrated to afford the title compound. Step C. (R)-2-Bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine. The enantiomers of (R,S)-2-Bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine were separated by HPLC using an HPLC column, such as a YMC-SC 4.6 x 250 mm, 5μm column (isocratic elution: 4% 4:1 IPA/ACN in heptane) yielding as a first eluting enantiomer, (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine and as a second eluting enantiomer, (S)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 7). The fractions containing (R)-2-bromo-4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3-yl)pyridine were collected and concentrated under reduced pressure to provide the title compound as a colorless oil (5 g, 31%). SFC R_t = 8.384 min. MS (ESI): mass calcd. for C₁₁H₁₂BrF₂NO₂, 307.0; m/z found, 308.0 [M+H]⁺. [α]²²=+2.79 (c=0.0307, dichloromethane,).

Intermediate 7 : (S)-2-Bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.

The chiral separation described for Intermediate 6 provided (S)-2-bromo-4- (difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine as a colorless oil (5 g, 31%). SFC R_t = 9.268 min. MS (ESI): mass calcd. for C₁₁H₁₂BrF₂NO₂, 307.0; m/z found, 308.0 [M+H]⁺. [α]²²= -3.03 (c=0.0251, dichloromethane). The absolute configuration was determined by X-ray crystallography.

Intermediate 8: (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol.

Step A. 3-(6-Bromopyridin-2-yl)tetrahydrofuran-3-ol. The title compound was prepared in a manner analogous to Intermediate 1, using 2,6-dibromopyridine instead of 2,6-dibromo-4- methylpyridine. MS (ESI): mass calcd. for C₉H₁₀BrNO₂, 243.0; m/z found, 243.9 [M+H]⁺.

Step B. 2-Bromo-6-(3 -methoxy tetrahydrofuran-3-yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromopyridin-2- yl)tetrahydrofuran-3-ol instead of 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 1). MS (ESI): mass calcd. for C₁₀H₁₂BrNO₂, 257.0; m/z found, 258.0 [M+H]⁺.

Step C. 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine. A solution of 2-bromo-6-(3 -methoxy tetrahydrofuran-3-yl)pyridine (30 g, 120 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (44.3 g, 174 mmol) in cyclohexane (300 mL) was sparged with nitrogen for 30 min. Chloro(l,5- cyclooctadiene)iridium(I) dimer (781 mg, 1.16 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridine (624 mg, 2.33 mmol) were added to the solution at room temperature and the resulting mixture was heated at 75 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was triturated with heptane overnight, filtered, and the solid was washed with heptane and dried under reduced pressure at 50 °C to afford the title compound as a yellow solid (25 g, 56%). MS (ESI): mass calcd. for C₁₆H₂₃BBrNO₄, 383.1; m/z found, 384.1 [M+H]⁺.

Step D. (R,S)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol. To a solution of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (25 g, 65 mmol) in tetrahydrofuran (125 mL) at 0 °C was added a solution of potassium peroxymonosulfate (13.1 g, 78.1 mmol) in water (125 mL) dropwise via addition funnel, keeping the internal temperature below 30 °C. After the addition was completed, the resulting solution was stirred at room temperature for 20 min. The reaction was quenched with ammonium chloride and partitioned between ethyl acetate and saturated aqueous sodium thiosulfate (50 mL), extracted with ethyl acetate (3 x 100 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (50:1 to 5:1 petroleum ether: ethyl acetate) provided a residue containing (R,S)-2-bromo-6-(3- methoxytetrahy drofuran-3 -yl)pyridin-4-ol .

Step E. (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol. The enantiomers of (R,S)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol were separated by SFC using an SFC column, such as a Chiralpak IC, 20 x 250 mm, 5μm column (isocratic elution: 5:95 EtOH (containing 1% DEA) supercritical CO₂) yielding as a first eluting enantiomer, (R)-2-bromo-6- (3-methoxytetrahydrofuran-3-yl)pyridin-4-ol and as a second eluting enantiomer, (S)-2-bromo-6- (3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 9). The fractions containing (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol were concentrated to give the title compound as a colorless oil (5 g, 28%). SFC R_t = 2.188 min. MS (ESI): mass calcd. for C₁₀H₁₂BrNO₃, 273.0; m/z found, 274.1 [M+H]⁺.

Intermediate 9: (S)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol.

The chiral separation described for Intermediate 8 provided (S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-ol as a colorless oil (5 g, 28%). SFC R_t = 2.530 min. MS (ESI): mass calcd. for C₁₀H₁₂BrNO₃, 273.0; m/z found, 274.1 [M+H]⁺. The absolute configuration was determined by X-ray crystallography.

Intermediate 10: (R)-2-Bromo-4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.

To a solution of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 8, 1 g, 3.6 mmol) in N, N-dimethylformamide (15 mL) under N₂ was added sodium hydride (60 % dispersion in mineral oil, 175.1 mg, 4.378 mmol) at 0 °C. The mixture was stirred for 30 minutes at room temperature before 1-bromo-2-methoxy ethane (1.01 g, 7.30 mmol) was added at room temperature. The reaction mixture was heated at 80 °C for 2 hours, then cooled to room temperature and quenched with water (2 mL). The resulting solution was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% EtOAc in petroleum ether) provided the title compound as a colorless oil (1 g, 80%). MS (ESI): mass calcd. for C₁₃H₁₈BrNO₄ 331.0; m/z found, 331.9 [M+H]⁺.

Intermediate 11 : (S)-2-Bromo-4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.

The title compound was prepared in a manner analogous to Intermediate 10, using (S)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 9) instead of (R)-2-bromo- 6-(3-methoxytetrahy drofuran-3 -yl)pyridin-4-ol (Intermediate 8). MS (ESI): mass calcd. for C₁₃H₁₈BrNO₄, 331.0; m/z found, 332.1 [M+H]⁺.

Intermediate 12: 2-Bromo-4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahy drofuran-3 -yl)pyridine

Step A. (R)-2-Hydroxypropyl 4-methylbenzenesulfonate. To a solution of (R)-(+)-1, 2- propanediol (2.0 g, 26 mmol) and 4-methylbenzene-1-sulfonyl chloride (5.512 g, 28.91 mmol) in dichloromethane (50 mL) under N₂ was added triethylamine (4.0 mL, 39 mmol), followed by 4- dimethylaminopyridine (0.16 g, 1.3 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (20 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (50:1 to 3:1 petroleum ether: ethyl acetate) provided the title compound as a yellow oil (3 g, 47%). MS (ESI): mass calcd. for C₁₀H₁₄O₄S, 230.1; m/z found, 231.1 [M+H]⁺. Step B. (R)-2-((tert-Butyldimethylsilyl)oxy)propyl 4-methylbenzenesulfonate. To a cooled solution of (R)-2-hydroxypropyl 4-methylbenzenesulfonate (3 g, 13 mmol) and imidazole (1.329 g, 19.54 mmol) in dichloromethane (90 mL) under N₂ at 0 °C was added 4- dimethylaminopyridine (159 mg, 1.30 mmol) and tert-butyldimethylsilylchloride (2.16 g, 14.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. Purification of the crude residue by silica gel chromatography (50: 1 to 10: 1 petroleum ether: ethyl acetate) afforded the title compound as a yellow oil (4 g, 84%). MS (ESI): mass calcd. for C₁₆H₂₈O₄SSi, 344.2; m/z found, 345.3 [M+H]⁺.

Step C. 2-Bromo-4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridine . The title compound was prepared in a manner analogous to Intermediate 10, using (R)-2-((tert-butyldimethylsilyl)oxy)propyl 4-methylbenzenesulfonate instead of 1-bromo-2-methoxyethane. MS (ESI): mass calcd. for C₁₉H₃₂BrNO₄Si, 445.1; m/z found, 446.2 [M+H]⁺.

Intermediate 13 : 2-Bromo-4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahy drofuran-3 -yl)pyridine.

The title compound was prepared in a manner analogous to Intermediate 10, using (S)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 9) instead of (R)-2-bromo- 6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 8) and butyldimethylsilyl)oxy)propyl 4-methylbenzenesulfonate (Intermediate 12B) instead of 1-bromo- 2-methoxyethane. MS (ESI): mass calcd. for C₁₉H₃₂BrNO₄Si, 445.1; m/z found, 446.2 [M+H]⁺.

Intermediate 14: (R)-2 -Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridine.

Step A. Oxetan-3-ylmethyl 4-methylbenzenesulfonate. The title compound was prepared in a manner analogous to Intermediate 12 A, using oxetan-3-ylmethanol instead of (R)-(+)-1, 2- propanediol. MS (ESI): mass calcd. for C₁₁H₁₄O₄S, 242.1; m/z found, 243.0 [M+H]⁺.

Step B. (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridine. The title compound was prepared in a manner analogous to Intermediate 10, except the reaction mixture was heated at 85 °C instead of 80 °C, using oxetan-3-ylmethyl 4- methylbenzenesulfonate instead of 1-bromo-2-methoxy ethane. MS (ESI): mass calcd. for C₁₄H₁₈BrNO₄, 343.0; m/z found, 344.1 [M+H]⁺.

Intermediate 15: (S)-2 -Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridine.

The title compound was prepared in a manner analogous to Intermediate 10, using (S)-2- bromo-6-(3 -methoxy tetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 9) instead of (R)-2-bromo- 6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 8) and oxetan-3-ylmethyl 4- methylbenzenesulfonate (Intermediate 14A) instead of 1-bromo-2-methoxy ethane. MS (ESI): mass calcd. for C₁₄H₁₈BrNO₄, 343.0; m/z found, 344.0 [M+H]⁺

Intermediate 16: (R)-3 -(((2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4- yl)oxy)methyl)thietane 1,1 -dioxide.

Step A. (1,1-Dioxidothietan-3-yl)methyl 4-methylbenzenesulfonate. The title compound was prepared in a manner analogous to Intermediate 12, Step A, using 3- (hydroxymethyl)thietane 1,1-dioxide instead of (R)-(+)-1, 2- propanediol. MS (ESI): mass calcd. for C₁₁H₁₄O₅S₂, m/z found, 291.1 [M+H]⁺.

Step B. (R)-3-(((2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4- yl)oxy)methyl)thietane 1,1-dioxide. The title compound was prepared in a manner analogous to Intermediate 10, using ( 1,1-dioxidothietan-3-yl)methyl 4-methylbenzenesulfonate instead of 1- bromo-2-methoxyethane. MS (ESI): mass calcd. for C₁₄H₁₈BrNO₅S, 391.0; m/z found, 392.1 [M+H]⁺.

Intermediate 17: (S)-3 -(((2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4- yl)oxy)methyl)thietane 1 , 1 -dioxide.

The title compound was prepared in a manner analogous to Intermediate 10, except the reaction mixture was heated at 85 °C instead of 80 °C, using (1,1-dioxidothietan-3-yl)methyl 4- methylbenzenesulfonate (Intermediate 16 A) instead of 1-bromo-2-methoxy ethane and (S)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 9) instead of (R)-2-bromo- 6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 8). MS (ESI): mass calcd. for C₁₄H₁₈BrNO₅S, 391.0; m/z found, 392.1 [M+H]⁺.

Intermediate 18: 4-((1r,3r)-3-(Benzyloxy)cyclobutoxy)-2-bromo-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridine.

Step A. (1s,3s)-3-(Benzyloxy)cyclobutan-1-ol. To a solution of 3-(benzyloxy)cyclobutan- 1-one (1 g, 5.7 mmol) in ethanol (70 mL) at 0 °C was added sodium borohydride (214.7 mg, 5.675 mmol). The reaction was stirred for one hour at 0 °C. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO₄), filtered, and concentrated to afford the title compound as a light yellow oil (1 g, 98%, 95:5 cis:trans isomers by ¹H NMR). MS (ESI): mass calcd. for C₁₁H₁₄O₂, 178.1; m/z found, 179.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.41 - 7.21 (m, 5H), 5.02 (s, 1H), 4.33 (s, 2H), 3.72 - 3.64 (m, 1H), 3.54 (tt, J= 7.6, 6.4 Hz, 1H), 2.57 - 2.48 (m, 2H), 1.74 (dddd, J= 10.6, 8.9, 5.3, 2.7 Hz, 2H).

Step B. (1s,3s)-3-(Benzyloxy)cyclobutyl methanesulfonate. To a solution of (1s,3s)-3- (benzyloxy)cyclobutan-1-ol (900 mg, 5.1 mmol) and triethylamine (664.2 mg, 6.565 mmol) in dichloromethane (27 mL) at 0 °C was added methanesulfonyl chloride (694.2 mg, 5.565 mmol) dropwise. The reaction mixture was stirred for 2 hours at room temperature and quenched with saturated aqueous ammonium chloride. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to provide the title compound as a light yellow oil (700 mg, 54%). MS (ESI): mass calcd for C₁₂H₁₆O₄S, 256.1; m/z found, 257.2 [M+H]⁺.

Step C. 4-((1r,3r)-3-(Benzyloxy)cyclobutoxy)-2-bromo-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 10, except the reaction mixture was heated at 85 °C instead of 80 °C, using (1s,3s)-3-(benzyloxy)cyclobutyl methanesulfonate instead of 1-bromo-2-methoxyethane. Purification resulted in isolation of the trans diastereomer. MS (ESI): mass calcd. for C₂₁H₂₄BrNO₄, 433.1; m/z found, 434.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.27 (m, 5H), 7.05 (d, J= 2.0 Hz, 1H), 6.94 (d, J= 2.1 Hz, 1H), 5.04 (tt, J= 7.2, 3.9 Hz, 1H), 4.41 (s, 2H), 4.27 (tt, J= 7.2, 4.7 Hz, 1H), 3.98 (dd, J= 9.5, 1.1 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.77 (d, J = 9.6 Hz, 1H), 3.08 (s, 3H), 2.56 - 2.52 (m, 1H), 2.43-2.27 (m, 3H).

Intermediate 19: 4-((1r,3s)-3-(Benzyloxy)cyclobutoxy)-2-bromo-6-((S)-3- methoxytetrahy drofuran-3 -yl)pyridine.

The title compound was prepared in a manner analogous to Intermediate 10, except the reaction mixture was heated at 85 °C instead of 80 °C, using (1s,3s)-3-(benzyloxy)cyclobutyl methanesulfonate (Intermediate 18B) instead of 1-bromo-2-methoxy ethane and (S)-2-bromo-6- (3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 9) instead of (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 8). Purification resulted in isolation of the trans diastereomer MS (ESI): mass calcd. for C₂₁H₂₄BrNO₄, 433.1; m/z found, 434.1 [M+H]⁺.

Intermediate 20: (S)-6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-amine.

A 30 mL autoclave vessel was charged with (S)-2-bromo-6-(3-methoxytetrahydrofuran- 3-yl)-4-methylpyridine (Intermediate 3, 1 g, 3.7 mmol), Cu₂O (52.6 mg, 0.367 mmol), ethylene glycol (5 mL), and NH₄OH (10 mL). The autoclave vessel was sealed and heated at 110 °C for 19 hours. The autoclave was cooled to room temperature and the excess pressure released. The reaction was quenched with water (30 mL) and the resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to afford the title compound as a yellow solid (350 mg, 38%). MS (ESI): mass calcd. for C₁₁H₁₆N₂O₂, 208.1 ; m/z found, 209.1 [M+H]⁺.

Intermediate 21 : 6-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine.

To a solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1 g, 3.6 mmol) in 1,4- dioxane (16 mL) and H₂O (4 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (1.117 g, 5.367 mmol), potassium phosphate (1.5 g, 7.2 mmol), and Pd(dppf)Cl₂ (0.292 g, 0.358 mmol). The resulting mixture was heated at 80 °C under nitrogen for 3 h. The reaction mixture was cooled to room temperature and quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate in petroleum ether) afforded the title compound as a white solid (700 mg, 74%). MS (ESI): mass calcd. for C₁₀H₈CIN₅, 233.1; m/z found, 234.0 [M+H]⁺.

Intermediate 22: 6-Chloro-3-(furan-3-yl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 21, using furan- 3-ylboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole. MS (ESI): mass calcd. for C₁₀H₆CIN₃O, 219.0; m/z found, 220.0 [M+H]⁺.

Intermediate 23 : (R)-6-Chloro- 1 -(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine.

To a solution of 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21, 350 mg, 1.498 mmol) in 1,4-dioxane (20 mL) was added (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2, 489 mg, 1.80 mmol), cuprous bromide (107 mg, 0.749 mmol), DMEDA (118.8 mg, 1.348 mmol), and potassium carbonate (207 mg, 1.498 mmol). The resulting mixture was heated at 105 °C under N₂ for 3 h. After cooling to room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. Purification by silica gel chromatography (0-76% ethyl acetate in petroleum ether) afforded the title compound as a white solid (100 mg, 15%). MS(ESI): mass calcd. for C₂₁H₂₁CIN₆O₂, 424.1; m/z found, 425.2 [M+H]⁺.

Intermediate 24: (S)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using (S)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 3) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₁H₂₁CIN₆O₂, 424.1; m/z found, 425.1 [M+H]⁺.

Intermediate 25: (R)-6-Chloro-3-(furan-3-yl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-(furan-3-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 22) instead of 6-chloro-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21). MS (ESI): mass calcd. for C₂₁H₁₉CIN₄O₃, 410.1; m/z found, 411.1 [M+H]⁺.

Intermediate 26 : (S)-6-Chl oro-3 -(furan-3 -yl)- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-(furan-3-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 22) instead of 6-chloro-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 3) instead of (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₁H₁₉CIN₄O₃, 410.1; m/z found, 411.1 [M+H]⁺.

Intermediate 27: 6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine.

Step A. 4,6-Dichloro- N-methoxy- N-methylnicotinamide. To a stirred solution of 4,6- dichloronicotinic acid (5.0 g, 26 mmol) in N,N-dimethylformamide (75 mL) was added N,O- dimethyl hydroxylamine (3.181 g, 52.08 mmol), hydroxybenzotriazole (7.038 g, 52.08 mmol), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.984 g, 52.08 mmol), and N- ethyldiisopropylamine (10.078 g, 52.083 mmol) at room temperature. The mixture was stirred at 20 °C for 16 h and quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 250 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (50:1 to 5:1 petroleum ether: ethyl acetate) provided the title compound as a yellow oil (3.2 g, 52%). MS (ESI): mass calcd. for C₈H₈CI₂N₂O₂, 234.0; m/z found, 234.9 [M+H]⁺.

Step B. 1-(4,6-Dichloropyridin-3-yl)ethan-1-one. To a stirred solution of 4,6-dichloro-N- methoxy-N-methylnicotinamide (6.4 g, 27 mmol) in THF (100 mL) under N₂ was added methylmagnesium bromide (3 M in 2-methyltetrahydrofuran, 22.72 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After addition of saturated aqueous ammonium chloride (40 mL), the mixture was concentrated to ~20 mL and the remaining residue was extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried (Na₂SO₄), filtered, and concentrated to afford the title compound as a yellow oil (4.6 g, 80%). MS (ESI): mass calcd. for C₇H₅CI₂NO, 189.0; m/z found, 190.0 [M+H]⁺.

Step C. 6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine. 1-(4,6-Dichloropyridin-3- yl)ethan-1-one (2.3 g, 12 mmol) in hydrazine hydrate (50 mL) was stirred at 20 °C for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 150 mL). The combined organic layers were washed with water (2 x 50mL) and saturated aqueous sodium chloride (20 mL), then dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (30:1 to 3: 1 petroleum ether: ethyl acetate) afforded the title compound as a yellow solid (1.3 g, 63%). MS (ESI): mass calcd. for C₇H₆ClN₃, 167.0; m/z found, 168.1 [M+H]⁺.

Intermediate 28: 6-Chloro-3-methy1-1H-pyrrolo[3,2-c]pyridine.

To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (800 mg, 4.4 mmol) in tetrahydrofuran (10 mL) under N₂ was added 2 M lithium aluminum hydride in THF (6.0 mL, 11.96 mmol) dropwise at 0 °C. The reaction mixture was stirred for 4 hours at room temperature and quenched with water at room temperature. The solvent was removed under reduced pressure. Purification by reverse flash chromatography on a C 18 gel column (10-100% acetonitrile in water (0.05% ammonium bicarbonate)) provided the title compound as a light pink solid (400 mg, 55%). MS (ESI): mass calcd. for C₈H₇CIN₂, 166.0; m/z found, 167.2 [M+H]⁺.

Intermediate 29: (R)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3- methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21). MS (ESI): mass calcd. for C₁₈H₁₉CIN₄O₂, 358.1; m/z found, 359.0 [M+H]⁺. Intermediate 30: (S)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3- methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 3) instead of (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₈H₁₉CIN₄O₂, 358.1; m/z found, 359.0 [M+H]⁺.

Intermediate 31 : (R)-6-Chloro-1 -(4-(difluoromethyl)-6-(3 -methoxy tetrahy drofuran-3-y l)pyridin- 2-yl)-3 -methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-4- (difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 6) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₈H₁₇CIF₂N₄O₂. 394.1; m/z found, 395.0 [M+H]⁺.

Intermediate 32 : (S)-6-Chloro- 1 -(4-(difluoromethyl )-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin- 2-yl)-3 -methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-4- (difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 7) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₈H₁₇CIF₂N₄O₂. 394.1; m/z found, 395.2 [M+H]⁺.

Intermediate 33: (R)-6-Chloro-1-(4-(2-methoxy ethoxy )-6-(3 -methoxy tetrahy drofuran- 3- yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-4-(2- methoxy ethoxy )-6-(3 -methoxytetrahydrofuran-3-yl)pyridine (Intermediate 10) instead of (R)-2- bromo-6-(3 -methoxytetrahy drofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₀H₂₃CIN₄O₄, 418.1; m/z found, 419.2 [M+H]⁺.

Intermediate 34: (S)-6-Chloro-1-(4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-( 1-methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-4-(2- methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 11) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₀H₂₃CIN₄O₄, 418.1; m/z found, 419.2 [M+H]⁺.

Intermediate 35: 1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 2-bromo-4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 12) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₆H₃₇ClN₄O4Si, 532.2; m/z found, 533.3 [M+H]⁺. Intermediate 36: 1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-6-chloro-3 -methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 2-bromo-4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 13) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₆H₃₇ClN₄O₄Si. 532.2; m/z found, 533.5 [M+H]⁺.

Intermediate 37: (R)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3 -methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-cJpyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine (Intermediate 14) instead of (R)- 2-bromo-6-(3 -methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₁H₂₃CIN₄O₄, 430.1; m/z found, 431.1 [M+H]⁺.

Intermediate 38 : (S)-6-Chloro-1 -(6-(3 -methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine (Intermediate 15) instead of (R)- 2-bromo-6-(3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₁H₂₃CIN₄O₄, 430.1; m/z found, 431.3 [M+H]⁺.

Intermediate 39 : (R)-3 -(((2-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-(3- methoxytetrahy drofuran-3 -yl)pyridin-4-yl)oxy)methyl)thietane 1,1 -dioxide.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-3-(((2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1,1-dioxide (Intermediate 16) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₁H₂₃CIN₄O₅S, 478.1; m/z found, 479.2 [M+H]⁺.

Intermediate 40 : (S)-3 -(((2-(6-Chloro-3 -methyl-1H-pyrazolo[4,3-c]pyridin-1 -yl)-6-(3 - methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1, 1 -dioxide.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-3-(((2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1,1 -dioxide (Intermediate 17) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₁H₂₃CIN₄O₅S, 478.1; m/z found, 479.1 [M+H]⁺.

Intermediate 41 : (R)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3- methyl-1H-pyrrolo[3,2-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chl oro-3 -methyl- 1H-pyrrolo[3,2-c]pyridine (Intermediate 28) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21). MS (ESI): mass calcd. for C₁₉H₂₀CIN₃O₂, 357.1; m/z found, 358.2 [M+H]⁺

Intermediate 42: (S)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3- methyl-1H-pyrrolo[3,2-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrrolo[3,2-c]pyridine (Intermediate 28) instead of 6-chl oro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 3) instead of (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₉H₂₀CIN₃O₂, 357.1; m/z found, 358.1 [M+H]⁺.

Intermediate 43: (R)-6-Chl oro-1 -(6-(3 -methoxy tetrahy drofuran-3-y l)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrrolo[3,2-c]pyridine (Intermediate 28) instead of 6-chl oro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine (Intermediate 14) instead of (R)- 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₄CIN₃O₄, 429.2; m/z found, 430.3 [M+H]⁺.

Intermediate 44: (S)-6-Chl oro-1 -(6-(3 -methoxy tetrahy drofuran- 3 -y l)-4-(oxetan- 3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrrolo[3,2-c]pyridine (Intermediate 28) instead of 6-chl oro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine (Intermediate 15) instead of (R)- 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₄CIN₃O₄, 429.2; m/z found, 430.3 [M+H]⁺.

Intermediate 45 : (R)-3 -(((2-(6-Chl oro-3 -methyl - 1 H-pyrrol o[3 ,2-c]pyri din- 1 -yl )-6-(3 - methoxytetrahy drofuran-3 -yl)pyridin-4-yl)oxy)methyl)thietane 1 , 1 -dioxide.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chl oro-3 -methyl- 1H-pyrrolo[3,2-c]pyridine (Intermediate 28) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-3-(((2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1,1-dioxide (Intermediate 16) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₄CIN₃O₅S, 477.1; m/z found, 478.1 [M+H]⁺.

Intermediate 46 : (S)-3 -(((2-(6-Chloro-3 -methyl-1H-pyrrolo[3,2-c]pyridin- 1 -yl)-6-(3 - methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1, 1 -dioxide.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrrolo[3,2-c]pyridine (Intermediate 28) instead of 6-chl oro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-3-(((2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1,1 -di oxi de (Intermediate 17) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₄CIN₃O₅S, 477.1; m/z found, 478.1 [M+H]⁺.

Intermediate 47: Ethyl pyrrolo[1,2-c]pyrimidine-3-carboxylate.

To a solution of ethyl 2-isocyanoacetate (11.9 g, 105 mmol) and DBU (17.6 g, 116 mmol) in THF (60 mL) was added a solution of 1H-pyrrole-2-carbaldehyde (10 g, 105 mmol) in THF (40 mL) at room temperature. The resulting reaction mixture was stirred overnight at room temperature. The reaction was neutralized with 10% AcOH and the solvent was removed in vacuo. The resulting residue was dissolved in EtOAc/H₂O and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated. Purification by silica gel chromatography (30-70% EtOAc in hexanes) afforded the title compound (10 g, 50%). MS (ESI): mass calcd. for C₁₀H₁₀N₂O₂, 190.1; m/z found, 191.1 [M+H]⁺.

Intermediate 48: Ethyl 7-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate.

To a solution of ethyl pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 47, 5 g, 26 mmol) in CHCl₃ (100 mL) was added NCS (3.51 g, 26.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with H₂O (20 mL) and the resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (0-50% ethyl acetate in petroleum ether) afforded the title compound as a yellow solid (4 g, 68% yield). MS (ESI): mass calcd. for C₁₀H₉CIN₂O₂, 224.0; m/z found, 225.0 [M+H]⁺.

Intermediate 49: Ethyl 5-bromo-7-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 48, using ethyl 7-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 48) instead of ethyl pyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 47) andNBS instead of NCS. MS (ESI): mass calcd. for C₁₀H₈BrCIN₂O₂, 301.9; m/z found, 302.9 [M+H]⁺.

Intermediate 50: Ethyl 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate.

To a solution of ethyl 5-bromo-7-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 49, 10 g, 9.9 mmol) in 1,4-dioxane (200 mL) was added 4, 4,4', 4', 5,5,5', 5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (16.7 g, 65.9 mmol), KOAc (6.47 g, 65.9 mmol), and Pd(dppf)Cl₂ (1.345 g, 1.647 mmol). The reaction mixture was heated at 80 °C for 3 h. The reaction was cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (0-50% ethyl acetate in petroleum ether) afforded the title compound as a yellow solid (5.3 g, 46%). MS (ESI): mass calcd. for C₁₆H₂₀BCIN₂O₄, 350.1; m/z found, 351.1 [M+H]⁺. intermediate 51: Ethyl (R)-7-chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)pyrrolo[ 1 ,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 21, using (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2) instead of 6- chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine and ethyl 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 50) instead of 1-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): mass calcd. for C₂₁H₂₂CIN₃O₄: 415.1; m/z found, 416.1 [M+H]⁺.

Intermediate 52: Ethyl (S)-7-chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 21, using (S)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 3) instead of 6- chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine and ethyl 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 50) instead of 1 -methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): mass calcd. for C₂₁H₂₂CIN₃O₄, 415.1; m/z found, 416.1 [M+H]⁺.

Intermediate 53: Ethyl (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1- methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 21 , using ethyl (R)-7-chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 51) instead of 6-chloro-3-iodo-1H-pyrazolo[4,3- c]pyridine. MS (ESI): mass calcd. for C₂₅H₂₇N₅O₄: 461.2; m/z found, 462.2 [M+H]⁺.

Intermediate 54: Ethyl (S)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1- methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 21, using ethyl (S)-7-chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyrrolo[1,2- c]pyrimidine-3-carboxylate (Intermediate 52) instead of 6-chloro-3 -iodo-1H-pyrazolo [4,3- c]pyridine. MS (ESI): mass calcd. for C₂₅H₂₇N₅O₄: 461.2; m/z found, 462.2 [M+H]⁺. Intermediate 55 : (R)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine.

Step A. (R)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylic acid. To a solution of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 53, 900 mg, 1.95 mmol) in THF (10 mL) and H₂O (10 mL) was added LiOH (233.5 mg, 9.751 mmol). The resulting mixture was stirred at room temprature for 1.5 h. The solvent was removed under reduced pressure and reaction mixture was acidified to pH 6 with 1 M HCl. The precipitated solids were collected by filtration and rinsed with water to afford the title compound as a yellow solid (800 mg, 85%). MS (ESI): mass calcd. for C₂₃H₂₃N₅O₄, 433.2; m/z found, 434.2 [M+H]⁺.

Step B. tert-Butyl (R)-(5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1- methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)carbamate. To a solution of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylic acid (800 mg, 1.8 mmol) in tert-butanol (40 mL) was added DPP A (1.016 g, 3.691 mmol), and TEA (560 mg, 0.14 mmol). The resulting mixture was heated at 85 °C for 2.5 h. The solvent was removed under vacuum. Purification by silica gel chromatography (0-85% ethyl acetate in petroleum ether) afforded the title compound as a yellow solid (325 mg, 33%). MS (ESI): mass calcd. for C₂₇H₃₂N₆O₄, 504.2; m/z found, 505.2 [M+H]⁺.

Step C. (R)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -amine. To a solution of tert-butyl (R)-(5-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-7-( 1 -methyl-1H-pyrazol -4-y l)pyrrolo[ 1,2- c]pyrimidin-3-yl)carbamate (330 mg, 0.654 mmol) in DCM (5 mL) was added TFA (15 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was basified to pH 10 with saturated sodium bicarbonate solution and extracted with DCM (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (0-15% MeOH in DCM) afforded the title compound as a yellow solid (200 mg, 65%). MS (ESI): mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found, 405.1 [M+H]⁺.

Intermediate 56: (S)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 55, using ethyl (S)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2 -yl)-7-(1-methyl-1H-pyrazol-4- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 54) instead of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found, 405.2 [M+H]⁺.

Intermediate 57: Ethyl (R)-5-(6-(3-methoxytetrahydrofu ran-3-yl)-4-methylpyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidine-3 -carboxylate.

To a solution of ethyl (R)-7-chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 51,1 g, 2.4 mmol) in DMA (20 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (604 mg, 4.81 mmol), RuPhos (112 mg, 0.240 mmol), Pd(OAc)₂ (27 mg, 0.12 mmol), and Cs₂CO₃ (1.567 g, 4.809 mmol). The resulting mixture was heated at 80 °C overnight. After cooling to room temperature, the reaction was quenched with H₂O. The resulting mixture was extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (0-50% EtOAc in petroleum ether) afforded the title compound as a yellow solid (0.8 g, 84% yield).

Intermediate 58: Ethyl (S)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidine-3 -carboxylate.

The title compound was prepared in a manner analogous to Intermediate 57, using ethyl (S)-7-chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyrrolo[1,2- c]pyrimidine-3-carboxylate (Intermediate 52) instead of ethyl (R)-7-chloro-5-(6-(3- methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3 -carboxylate (Intermediate 51). MS (ESI): mass calcd. for C₂₂H₂₅N₃O₄, 395.2; m/z found, 396.2 [M+H]⁺.

Intermediate 59: (R)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 55, using ethyl (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methylpyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 57) instead of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3-carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₁₉H₂₂N₄O₂: 338.2, found: 339.1 [M+H]⁺.

Intermediate 60: (S)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3 -amine.

The title compound was prepared in a manner analogous to Intermediate 55, using ethyl (S)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methylpyrrolo[1,2- c]pyrimidine-3-carboxylate (Intermediate 58) instead of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₁₉H₂₂N₄O₂: 338.2; m/z found 339.1 [M+H]⁺.

Intermediate 61: Ethyl 7-methylpyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in manner analogous to Intermediate 57, using ethyl 7- chloropyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 48) instead of ethyl (R)-7-chloro-5- (6-(3 -methoxytetrahy drofuran-3 -yl)-4-methyIpyridin-2-yl)pyrrolo[1 ,2-c]pyrimidine-3 - carboxylate (Intermediate 51). MS (ESI): mass calcd. for C₁₁H₁₂N₂O₂, 204.1; m/z found, 205.1 [M+H]⁺.

Intermediate 62: tert-Butyl (7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate.

The title compound was prepared in a manner analogous to Intermediate 55B, using ethyl 7-methylpyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 61) instead of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₁₃H₁₇N₃O₂, 247.1; m/z found, 248.2 [M+H]⁺.

Intermediate 63 : (R)-5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[ 1 ,2-c]pyrimidin-3 -amine.

Step A. tert-Butyl (R)-(5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate. To a solution of tert-butyl (7- methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate (Intermediate 62, 150 mg, 0.607 mmol) in 1,4- dioxane (3 mL) under N₂ was added (R)-2-bromo-4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3-yl)pyridine (Intermediate 6, 279 mg, 0.910 mmol), palladium (II) acetate (20.4 mg, 0.091 mmol), tricyclohexyl phosphine (51.0 mg, 0.182 mmol), and cesium carbonate (395.2 mg, 1.213 mmol). The reaction mixture was heated at 130 °C for 16 h, then cooled to room temperature and the solvent was removed under reduced pressure. Purification by reverse flash chromatography on a C18 gel column (10-100% acetonitrile in water (0.04% ammonium hydroxide)) provided the title compound as a yellow solid (145 mg, 45%). MS (ESI): mass calcd. for C₂₄H₂₈F₂N₄O₄, 474.2; m/z found, 475.2 [M+H]⁺

Step B. (R)-5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3 -amine. To a solution of tert-butyl (R)-(5-(4-(difluoromethyl)-6- (3 -methoxy tetrahy drofuran-3 -yl)pyridin-2-yl)-7-methylpyrrolo[ 1 ,2-c]pyrimidin-3 -yl)carbamate (145 mg, 0.306 mmol) in dichloromethane (2 mL) was added TFA (1.5 mL). The reaction mixture was stirred for 1 h at room temperature, and the solvent was removed under reduced pressure. The crude residue was diluted with dichloromethane and the pH value was adjusted to 7~8 using triethylamine. Purification by silica gel chromatography (0-15% MeOH in DCM) provided the title compound as a yellow solid. MS (ESI): mass calcd. for C₁₉H₂₀F₂N₄O₂, 374.2; m/z found, 375.1 [M+H]⁺

Intermediate 64: (S)-5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[ 1 ,2-c]pyrimidin-3 -amine.

The title compound was prepared in a manner analogous to Intermediate 63, using (S)-2- bromo-4-(difluoromethyl)-6-(3 -methoxy tetrahy drofuran-3 -yl)pyridine (Intermediate 7) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 6) in Step A. MS (ESI): mass calcd. for C₁₉H₂₀F₂N₄O₂, 374.2; m/z found, 375.2 [M+H]⁺

Intermediate 65 : (R)-5-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[ 1 ,2-c]pyrimidin-3 -amine .

The title compound was prepared in a manner analogous to Intermediate 63, using (R)-2- bromo-4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 10) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine (Intermediate 6) in Step A. MS (ESI): mass calcd. for C₂₁H₂₆N₄O₄, 398.2; m/z found, 399.2 [M+H]⁺.

Intermediate 66: (S)-5-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)- 7-methylpyrrolo[ 1 ,2-c]pyrimidin-3 -amine.

The title compound was prepared in a manner analogous to Intermediate 63, using (S)-2- bromo-4-(2-methoxyethoxy )-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine (Intermediate 11) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 6) in Step A. MS (ESI): mass calcd. for C₂₁H₂₆N₄O₄, 398.2; m/z found, 399.2 [M+H]⁺.

Intermediate 67 : 5-(4-((R)-2-(( tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-7-methylpyrrolo[1 ,2-c]pyrimidin-3 -amine.

Step A. tert-Butyl (5-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate. The title compound was prepared in a manner analogous to Intermediate 63 A, using 2-bromo-4- ((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 12) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridine (Intermediate 6). MS (ESI): mass calcd. for C₃₂H₄₈N₄O₆Si, 612.3; m/z found, 613.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 8.83 (d, J= 1.5 Hz, 1H), 8.72 (d, J= 1.5 Hz, 1H), 7.22 (d, J= 1.0 Hz, 1H), 7.09 (d, J= 2.2 Hz, 1H), 6.70 (d, J= 2.2 Hz, 1H), 4.26-4.16 (m, 1H), 4.11-4.03 (m, 2H), 4.01-3.94 (m, 2H), 3.88 (d, J= 9.5 Hz, 1H), 3.14 (s, 3H), 2.86 (dt, J = 13.2, 8.7 Hz, 1H), 2.53 (d, J= 0.9 Hz, 3H), 2.42-2.31 (m, 1H), 1.50 (s, 9H), 1.27-1.17 (m, 4H), 0.87 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).

Step B. 5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine. A solution of tert-butyl (5-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate (200 mg, 0.32 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (0.2 mL) was subjected to microwave irradiation for 2 h at 120 °C. Purification by reverse flash chromatography on a C18 gel column (10-100% acetonitrile in water (0.04% ammonium hydroxide)) provided the title compound as a yellow solid. MS (ESI): mass calcd. for C₂₇H₄₀N₄O₄Si, 512.3; m/z found, 513.3 [M+H]⁺.

Intermediate 68: 5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine.

Step A. tert-Butyl (5-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate. The title compound was prepared in a manner analogous to Intermediate 63 A, using 2-bromo-4- ((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((S)-3 -methoxytetrahy drofuran-3 -y l)pyridine (Intermediate 13) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahy drofuran-3 - yl)pyridine (Intermediate 6). MS (ESI): mass calcd. for C₃₂H₄₈N₄O₆Si, 612.3; m/z found, 613.4 [M+H]⁺.

Step B. 5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine. The title compound was prepared in a manner analogous to Intermediate 67, Step B, using tert-butyl (5- (4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate instead of tert-butyl (5-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyri din-2 -yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate (Intermediate 67, Step A). MS (ESI): mass calcd. for C₂₇H₄₀N₄O₄Si, 512.3; m/z found, 513.3 [M+H]⁺.

Intermediate 69: 5-(4-(( 1r,3r)-3-(Benzyloxy)cyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 63, using 4- (( 1 r,3r)-3 -(benzyloxy )cyclobutoxy)-2-bromo-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridine (Intermediate 18) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridine (Intermediate 6) in Step A. MS (ESI): mass calcd. for C₂₉H₃₂N₄O₄, 500.2; m/z found, 501.1 [M+H]⁺.

Intermediate 70: 5-(4-(( 1r,3s)-3-(Benzyloxy)cyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 63, using 4- (( 1 r,3s)-3 - (benzyloxy )cyclobutoxy)-2-bromo-6-((S)- 3 -methoxytetrahy drofuran-3 -yl)pyridine (Intermediate 19) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridine (Intermediate 6) in Step A. MS (ESI): mass calcd. for C₂₉H₃₂N₄O₄, 500.2; m/z found, 501.1 [M+H]⁺.

Intermediate 71 : (S)-3-(((2-(3-Amino-7-methylpyrrolo[1 ,2-c]pyrimidin-5-yl)-6-(3- methoxytetrahy drofuran-3 -yl)pyridine-4-yl)oxy)methyl)thietane 1, 1 -dioxide.

The title compound was prepared in a manner analogous to Intermediate 63, using (S)-3- (((2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1,1-dioxide (Intermediate 17) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridine (Intermediate 6) in Step A. MS (ESI): mass calcd. for C₂₂H₂₆N₄O₅S, 458.2; m/z found, 459.3 [M+H]⁺

Intermediate 72 : (S)-6-Chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3 -methoxytetrahydrofuran-3 -yl)- 4-methylpyridine (Intermediate 3) instead of (R)-2 -bromo-6-(3 -meth oxy tetrahydrofuran- 3 -yl)-4- methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₇H₁₇CIN₄O₂, 344.1; m/z found, 345.1 [M+H]⁺.

Intermediate 73: (S)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)- 1H- pyrrolo[3,2-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-1H-pyrrolo[3,2-c]pyridine instead of 6-chloro-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3 -methoxytetrahy drofuran-3 -yl)- 4-methylpyridine (Intermediate 3) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₈H₁₈ClN₃O₂, 343.1; m/z found, 344.1 [M+H]⁺. Intermediate 74: (S)-N-(4-((6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-5- (methylamino)pyridin-2-yl)acetamide.

Step A. N-(4-Chloro-5-nitropyridin-2-yl)acetamide. To a solution of 4-chloro-5- nitropyridin-2-amine (5 g, 29 mmol) and acetyl chloride (3.39 g, 43.2 mmol) in DCM (50 mL) was added pyridine (4.56 g, 57.6 mmol) at room temperature. The reaction mixture was stirred for 3 h at room temperature and the solvent was removed under vacuum. Purification by reverse- phase flash chromatography on a C 18 gel column (5-50% MeCN in water (0.05% TFA)) afforded the title compound as a white solid (3.5 g, 53%). MS (ESI): mass calcd. for C₇H₆CIN₃O₃: 215.0; m/z found: 216.0 [M+H]⁺.

Step B. (S)-N-(4-((6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-5- nitropyridin-2-yl)acetamide. To a solution of N-(4-chloro-5-nitropyridin-2-yl)acetamide (543 mg, 2.52 mmol) in DMA (12 mL) was added (S)-6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-amine (Intermediate 20, 350 mg, 1.68 mmol), cesium carbonate (1.095 g, 3.361 mmol), Pd₂(dba)₃ (154 mg, 0.168 mmol), and XPhos (160 mg, 0.336 mmol). The reaction mixture was heated at 80 °C under N₂ for 2 h. The reaction was quenched with water (30 mL) and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. Purification by silica gel chromatography (0-50% ethyl acetate in petroleum ether) afforded the title compound as a white solid (300 mg, 36% yield). MS (ESI): mass calcd. for C₁₈H₂₁N₅O₅: 387.2; m/z found, 410.1 [M+Na]⁺.

Step C. (S)- N-(5-Amino-4-((6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)amino)pyridin-2-yl)acetamide. To a solution of (S)-N-(4-((6-(3-methoxytetrahydrofuran-3-yl)- 4-methylpyridin-2-yl)amino)-5-nitropyridin-2-yl)acetamide (300 mg, 0.77 mmol) in EtOH (10 mL) and H₂O (1 mL) was added Fe (432.5 mg, 7.744 mmol) and NH₄CI (103.6 mg, 1.936 mmol). The reaction mixture was heated at 80 °C for 1.5 h. The mixture was filtered, and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (0-15% MeOH in DCM) afforded the title compound as a black oil (215 mg, 76%). MS (ESI): mass calcd. for C₁₈H₂₃N₅O₃: 357.2; m/z found, 358.2 [M+H]⁺.

Step D. (S)- N-(4-((6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-5- (methylamino)pyridin-2-yl)acetamide. To a solution of (S)-N-(5-amino-4-((6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)pyridin-2-yl)acetamide (200 mg, 0.56 mmol) in ethanol (10 mL) at 0°C was added dropwise formaldehyde (42 mg, 1.4 mmol). The mixture was warmed to room temperature and stirred for 3 h. The mixture was cooled to 0°C and sodium borohydride (52.9 mg, 1.40 mmol) was added in three portions, keeping the temperature below 5°C. The reaction was stirred for 10 hours at room temperature and the solvent was removed under vacuum. Purification by silica gel chromatography (0-100% ethyl acetate in petroleum ether) afforded the title compound as a black solid (140 mg, 57%). MS (ESI): mass calcd. for C₁₉H₂₅N₅O₃, 371.2; m/z found, 372.2 [M+H]⁺.

Intermediate 75: 3-Chloro-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H- pyrrolo[2,3-c]pyridazine.

Step A. 3-Chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine. To a solution of 3-chloro-7H- pyrrolo[2,3-c]pyridazine (500 mg, 2.6 mmol) in DMF (5 mL) was added K₂CO₃ (545.5 mg, 3.947 mmol) and iodomethane (373.5 mg, 2.631 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (0-50% ethyl acetate in petroleum ether) afforded the title compound as a yellow oil (350 mg, 79%). MS (ESI): mass calcd. for C₇H₆CIN₃, 167.0; m/z found, 168.1 [M+H]⁺.

Step B. 5-Bromo-3-chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine. The title compound was prepared in a manner analogous to Intermediate 48, using 3-chloro-7-methyl-7H- pyrrolo[2,3-c]pyridazine instead of ethyl pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 47), NBS instead of NCS, and DMF instead of CHCh (100 mL). MS (ESI): mass calcd. for C₇H₅BrCIN₃, 245.0; m/z found, 246.0 [M+H]⁺.

Step C. 3-Chloro-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H- pyrrolo[2,3-c]pyridazine. The title compound was prepared in a manner analogous to Intermediate 50, using 5-bromo-3-chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine instead of ethyl 5-bromo-7-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 49) and

Pd(dppf)Cl₂ DCM instead of Pd(dppf)Cl₂. MS (ESI): mass calcd. for C₁₃H₁₇BCIN₃O₂, 293.1; m/z found, 294.1 [M+H]⁺.

Intermediate 76: (S)-3-Chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- methyl-7H-pyrrolo[2,3-c]pyridazine.

The title compound was prepared in a manner analogous to Intermediate 21, using 3- chloro-7-methyl-5-(4,4,5,.5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-c]pyridazine (Intermediate 75) instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole, (S)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 3) instead of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine, and Pd(dppf)Cl₂ DCM instead of Pd(dppf)Cl₂. MS (ESI): mass calcd. for C₁₈H₁₉CIN₄O₂, 358.1; m/z found, 359.1 [M+H]⁺.

Intermediate 77 : (S)-6-Chloro- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- imidazo[4,5-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-1H-imidazo[4,5-c]pyridine instead of 6-chloro-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2-bromo-6-(3-methoxy-tetrahydrofuran-3-yl)- 4-methylpyridine (Intermediate 3) instead of (R)-2-bromo-6-(3 -methoxy tetrahydrofuran- 3 -yl)-4- methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₇H₁₇CIN₄O₂, 344.1; m/z found, 345.1 [M+H]⁺.

Intermediate 78: 6-Chloro-3-(methyl-d₃)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 27, using methyl-d₃-magnesium iodide (1.0 M in diethyl ether) instead of methylmagnesium bromide in Step B. MS (ESI): mass calcd. for C₇H₃D₃CIN₃, 170.0; m/z found, 170.9 [M+H]⁺.

Intermediate 79: (R)-6-Chloro-1-(4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-3-(methyl-d₃)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-(methyl-d₃)-1H-pyrazolo[4,3-c]pyridine (Intermediate 78) instead of 6-chloro-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-4-(2- methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 10) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₀H₂₀D₃CIN₄O₄, 421.2; m/z found, 422.2 [M+H]⁺.

Intermediate 80: 6-Chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 27, using cyclopropylmagnesium bromide (1.0 M in THF) instead of methylmagnesium bromide in Step B and the reaction mixture was stirred at 25 °C instead of 20 °C in Step C. MS (ESI): mass calcd. for C₉H₈CIN₃, 193.0; m/z found, 194.1.

Intermediate 81: (R)-6-Chloro-3 -cyclopropyl- 1-(4-(2-methoxy ethoxy )-6-(3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 80) instead of 6-chloro-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo [4, 3 -c] pyridine (Intermediate 21) and (R)-2-bromo-4-(2- methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 10) instead of (R)-2- bromo-6-(3 -methoxy tetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₅CIN₄O₄, 444.2; m/z found, 445.2 [M+H]⁺.

Intermediate 82: 6-Chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine.

Step A. 6-Chloro-3-iodo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3- c]pyridine. To a solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2 g, 7 mmol) in DMF (30 mL) at 0 °C under N₂ was added NaH (60% dispersion in mineral oil, 344 mg, 8.60 mmol). The resulting mixture was stirred for 30 minutes at room temperature. (2- (Chloromethoxy)ethyl)trimethylsilane (2.38 g, 14.3 mmol) was added to the reaction mixture at room temperature. The resulting mixture was stirred at room temperature for 4 h, and the reaction was quenched with H₂O (4 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% EtOAc in petroleum ether) afforded the title compound as a colorless oil (1.5 g, 50%). MS (ESI): mass calcd. for C₁₂H₁₇ClIN₃OSi, 409.0; m/z found, 410.1 [M+H]⁺.

Step B. 6-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[4,3-c]pyridine. To a solution of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolo[4,3-c]pyridine (1.15 g, 2.81 mmol) and diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (2.27 g, 5.62 mmol) in DMF (12 mL) under N₂ was added copper (450 mg, 7.0 mmol). The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed sequentially with water (3 x 20 mL) and brine (2 x 20 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-2% EtOAc in petroleum ether) afforded the title compound (800 mg, 80%). MS (ESI): mass calcd. for C13H₁₇ClF₃N₃OSi, 351.1; m/z found, 352.0 [M+H]⁺.

Step C. 6-Chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine. To a solution of 6- chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (800 mg, 2 mmol) in dichloromethane (8 mL) was added TFA (8 mL). The solution was stirred for 2 h at room temperature. The pH of the reaction mixture was adjusted to pH 9 with 2 N NH₃ in water. The resulting mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. Purification by reverse-phase flash chromatography on a C 18 gel column (10- 100% MeCN in water (0.05% ammonium bicarbonate)) afforded the title compound as a white solid (400 mg, 80%). MS (ESI): mass calcd. for C₇H₃CIF₃N₃: 221.0; m/z found: 222.0 [M+H]⁺.

Intermediate 83 : (R)-6-Chloro-1-(4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3- y l)pyridin-2-yl)-3 -(trifluoromethyl)-1H-pyrazolo[4,3 -c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 82) instead of 6-chloro-3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-4- (2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 10) instead of (R)- 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₀H₂₀CIF₃N₄O₄, 472.1; m/z found, 473.2 [M+H]⁺.

Intermediate 84: (R)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 82) instead of 6-chloro-3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-6- (3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine (Intermediate 14) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₁H₂₀CIF₃N₄O₄. 484.1; m/z found, 485.2 [M+H]⁺.

Intermediate 85: 3-(6-Chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoxazole.

Step A. Isoxazole-3 -carbonyl chloride. To a solution of isoxazole-3-carboxylic acid (1 g, 9 mmol) in DCM (50 mL) was added DMF (65 mg, 0.88 mmol) and oxalyl chloride (2.25 g, 17.7 mmol). The resulting mixture was stirred for 1 h at 25 °C, then concentrated under vacuum to afford the title compound as a yellow oil (1.1 g, 95%).

Step B. (4,6-Dichloropyridin-3-yl)isoxazol-3-yl)methanone. To a solution of 5-bromo- 2,4-dichloropyridine (0.949 g, 4.18 mmol) in THF (20 mL) was added CuBr (0.15 g, 1.0 mmol). To the resulting mixture was added i-PrMgCl LiCl (1.3 M in THF, 4.18 mL, 5.44 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 25 °C. To the resulting mixture was added isoxazole-3-carbonyl chloride (1.1 g, 8.4 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred for 3 h at 25 °C. The reaction was quenched with saturated aqueous sodium bicarbonate solution and the resulting mixture was extracted with EtOAc. The organic layers were combined, dried (Na₂SO₄), filtered and concentrated. Purification by silica gel chromatography (0-30% EtOAc in petroleum ether) afforded the title compound as a yellow solid (0.9 g, 90% yield). MS (ESI): mass calcd. for C₉H₄CI₂N₂O₂, 242.0; m/z found, 243.0 [M+H]⁺.

Step C. 3-(6-Chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoxazole. To a solution of (4,6- dichloropyridin-3-yl)(isoxazol-3-yl)methanone (0.8 g, 3 mmol) in EtOH (20 mL) was added triethylamine (3.3 g, 33 mmol). To the resulting solution was added NH₂NH₂HCI (1.1 g, 16 mmol) at -78 °C. The resulting mixture was stirred at 25 °C overnight. The reaction was quenched with water and the resulting mixture was extracted with EtOAc. The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated. Purification by silica gel chromatography (0-80% EtOAc in petroleum ether) afforded the title compound as a yellow solid (0.6 g, 80%). MS (ESI): mass calcd. for C₉H₅CIN₄O, 220.0; m/z found, 221.1 [M+H]⁺. Intermediate 86 : (R)-3 -(6-Chloro- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H-pyrazolo[4,3-c]pyridin-3-yl)isoxazole.

The title compound was prepared in a manner analogous to Intermediate 23, except the reaction mixture was subjected to microwave irradiation at 130 °C instead of heating at 105 °C, using 3-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoxazole (Intermediate 85) instead of 6- chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21). MS (ESI): mass calcd. for C₂₀H₁₈CIN₅O₃, 411.1; m/z found, 412.1 [M+H]⁺.

Intermediate 87 : 3-(3-(Benzyloxy)cyclobutyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine.

Step A. 3-(Benzyloxy)cyclobutanecarbonyl chloride. A mixture of 3- (benzyloxy)cyclobutanecarboxylic acid (7.3 g, 35 mmol) and thionyl chloride (100 mL) was heated to 83 °C for 2 h. The resulting mixture was concentrated to afford the title compound.

Step B. (3-(Benzyloxy)cyclobutyl)(4,6-dichloropyridin-3-yl)methanone. The title compound was prepared in a manner analogous to Intermediate 85, Step B, using 3- (benzyloxy)cyclobutanecarbonyl chloride instead of isoxazole-3-carbonyl chloride (Intermediate 85A). MS (ESI): mass calcd. for C₁₇H₁₅CI₂NO₂, 335.1; m/z found, 336.2 [M+H]⁺.

Step C. 3-(3-(Benzyloxy)cyclobutyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine. The title compound was prepared in a manner analogous to Intermediate 27, Step C, using (3- (benzyloxy)cyclobutyl)(4,6-dichloropyridin-3-yl)methanone instead of 1-(4,6-dichloropyridin-3- yl)ethan-1-one (Intermediate 27B). MS (ESI): mass calcd. for C₁₇H₁₆CIN₃O, 313.1; m/z found, 314.1 [M+H]⁺.

Intermediate 88 : (R)-3 -(3 -(Benzyloxy)cyclobutyl)-6-chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 - yl)-4-methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 3-(3- (benzyloxy)cyclobutyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine (Intermediate 87) instead of 6- chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21). MS (ESI): mass calcd. for C₂₈H₂₉CIN₄O₃. 504.2; m/z found, 505.2 [M+H]⁺.

Intermedi ate 89 : (R)- 1 -(3 -(3 -Hydroxycyclobutyl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4- methylpyridin-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)-3 -(4-methoxybenzyl)urea.

Step A. (R)- 1 -(3 -(3 -(Benzyloxy)cyclobutyl)- 1 -(6-(3 -methoxy -tetrahydrofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea. To a sealed tube was added (R)-3 -(3 -(benzyloxy)cyclobutyl)-6-chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 88, 280 mg, 0.55 mmol), THF (5 mL), 1-(4-methoxybenzyl)urea (150 mg, 0.83 mmol), Cs₂CO₃ (452 mg, 1.39 mmol), and BrettPhos Pd G3 (100 mg, 0.1 mmol). The resulting mixture was heated to 70 °C for 3 h, then filtered and concentrated. Purification by reverse phase column chromatography on a C 18 gel column (10-80% MeCN in water) afforded the title compound (200 mg, 60%). MS (ESI): mass calcd. for C₃₇H₄₀N₆O₅, 648.3; m/z found, 649.3 [M+H]⁺.

Step B . (R)- 1 -(3 -(3 -Hydroxy cyclobutyl)- 1 -(6-(3 -methoxy -tetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea. To a solution of (R)- 1 -(3 -(3 -(benzyloxy )cyclobutyl)- 1 -(6-(3 -methoxy-tetrahy drofuran-3 -yl)-4-methylpyridin-2- yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea (200 mg, 0.3 mmol) in DCM (2 mL) was added BCl₃DCM (1 M in DCM, 1.85 mL, 1.85 mmol) at -78 °C. The resulting mixture was maintained under nitrogen and stirred at room temperature for 3 h. The reaction was quenched with MeOH (20 mL), and the resulting mixture was concentrated. Purification by reverse phase column chromatography on a C18 gel column (10-80% MeCN in water) afforded the title compound (150 mg, 87%). MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅, 558.3; m/z found: 559.2 [M+H]⁺.

Interm ediate 90 : (R)- 1 -(3 -(3 -Cyanocyclobutyl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4- methylpyri din-2 -yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea.

Step A. (R)-3 -(6-(3 -(4-Methoxybenzyl)ureido)- 1 -(6-(3 -methoxy tetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclobutyl methanesulfonate. A mixture of (R)- 1 -(3 -(3 -hydroxy cyclobutyl)- 1 -(6-(3 -methoxy -tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea (Intermediate 89, 150 mg, 0.27 mmol), methanesulfonic anhydride (56 mg, 0.32 mmol), triethylamine (81 mg, 0.81 mmol), and THF (2 mL) was stirred overnight at room temperature for 16 h. The reaction was quenched with water (2 mL). The resulting mixture was extracted with ethyl acetate (3 x 2 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated to provide the title compound. MS (ESI): mass calcd. for C₃₁H₃₆N₆O₇S, 636.2; m/z found, 637.2 [M+H]⁺.

Step B. (R)- 1 -(3 -(3 -Cyanocyclobutyl)- 1-(6-(3 -methoxytetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea. To a solution of (R)-3 -(6-(3 -(4-methoxybenzyl)ureido)- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2- yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclobutyl methanesulfonate (150 mg, 0.24 mmol) in DMF (2 mL) was added CsF (179 mg, 1.18 mmol) and trimethylsilyl cyanide (117 mg, 1.18 mmol). The resulting mixture was heated to 80 °C for 48 h. The reaction was quenched with water (10 mL) and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated. Purification by reverse phase column chromatography on a C18 gel column (10-80% MeCN in water) afforded the title compound as a white solid (60 mg, 45%). MS (ESI): mass calcd. for C₃₁H₃₃N₇O₄, 567.3; m/z found, 568.2 [M+H]⁺.

Intermediate 91 : (S)-3-(3-(Benzyloxy)cyclobutyl)-6-chloro- 1 -(6-(3-methoxytetrahydrofuran-3- yl)-4-methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 3-(3- (benzyloxy)cyclobutyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine (Intermediate 87) instead of 6- chloro-3 -(1-methyl- 1H-pyrazol -4-yl)- 1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (S)-2- bromo-6-(3 -methoxy tetrahy drofuran-3 -yl)-4-methylpyridine (Intermediate 3) instead of (R)-2- bromo-6-(3 -methoxy tetrahy drofuran-3 -yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₈H₂₉CIN₄O₃, 504.2; m/z found, 505.2 [M+H]⁺.

Intermediate 92 : (S)- 1 -(3 -(3 -Hydroxycyclobutyl)- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3 -(4-methoxybenzyl)urea.

The title compound was prepared in a manner analogous to Intermediate 89, using (S)-3- (3 -(benzyloxy)cyclobutyl)-6-chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2- yl)-1H-pyrazolo [4, 3 -c] pyridine (Intermediate 91) instead of (R)-3 -(3 -(benzyloxy )cyclobutyl)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 88) in Step A and stirring the reaction at -78 °C instead of room temperature in Step B. MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅. 558.3; m/z found, 559.2 [M+H]⁺.

Intermediate 93 : (S)-1 -(3-(3-Cyanocyclobutyl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3 -(4-methoxybenzyl)urea.

The title compound was prepared in a manner analogous to Intermediate 90, using (S)-1- (3 -(3 -hydroxy cyclobutyl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea (Intermediate 92) instead of (R)-1-(3-(3- hydroxy cyclobutyl)- 1 -(6-(3 -methoxy-tetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea (Intermediate 89) in Step A. MS (ESI): mass calcd. for C₃₁H₃₃N₇O₄, 567.3; m/z found, 568.2 [M+H]⁺.

Intermediate 94: (R)-2-Bromo-6-(3-ethoxytetrahydrofuran-3-yl)-4-methylpyridine.

Step A. (R,S)-2-Bromo-6-(3-ethoxytetrahydrofuran-3-yl)-4-methylpyridine. The title compound was prepared in a manner analogous to Intermediate 2 Step A, except the reaction mixture was heated at 50 °C instead of 25 °C, using iodoethane instead of CH₃I and THF instead of DMF. Step B. (R)-2-Bromo-6-(3-ethoxytetrahydrofuran-3-yl)-4-methylpyridine. The enantiomers of (R,S)-2-bromo-6-(3 -ethoxytetrahy drofuran-3 -yl)-4-methylpyridine were separated by SFC using an SFC column, such as a CHIRALPAK IC, 3.0 X 100 mm, 3 μm column (isocratic elution: 12:88 isopropanol (containing 0.1% N, N-diethyl aniline): supercritical CO₂) to obtain (R)-2-bromo-6-(3-ethoxytetrahydrofuran-3-yl)-4-methylpyridine as the first eluting enantiomer. The absolute configuration was determined by comparison to a standard prepared from a compound of known configuration. SFC R_t = 1.24 min. MS (ESI): mass calcd. for C₁₂H₁₆BrNO₂: 285.0, m/z found, 285.9 [M+H]⁺.

Intermediate 95 : (R)-6-Chloro- 1 -(6-(3 -ethoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 - methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chl oro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-6-(3- ethoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 94) instead of (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₉H₂₁CIN₄O₂: 372.1, m/z found, 373.1 [M+H]⁺.

Intermediate 96: 2 -Bromo-6-(3 -methoxytetrahydro-2H-pyran-3-y l)-4-(oxetan-3- ylmethoxy)pyridine.

Step A. 3-(6-Bromopyridin-2-yl)tetrahydro-2H-pyran-3-ol. The title compound was prepared in a manner analogous to Intermediate 1, using 2,6-dibromopyridine instead of 2,6- dibromo-4-methylpyridine and dihydro-2H-pyran-3(4H)-one instead of dihydrofuran-3(2H)-one. MS (ESI): mass calcd. for C₁₀H₁₂BrNO₂: 257.0, m/z found, 259.0 [M+H]⁺.

Step B. 2-Bromo-6-(3-methoxytetrahydro-2H-pyran-3-yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromopyridin-2- yl)tetrahydro-2H-pyran-3-ol instead of 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 1) and THF instead of DMF. MS (ESI): mass calcd. for C₁₁H₁₄BrNO₂: 271.0, m/z found, 273.0 [M+H]⁺.

Step C . 2-Bromo-6-(3 -methoxytetrahy dro-2H-py ran-3 -y l)-4-(4,4, 5 , 5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 8, Step C, using 2-bromo-6-(3-methoxytetrahydro-2H-pyran-3-yl)pyridine instead of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridine. MS (ESI): mass calcd. for C₁₇H₂₅BBrNO₄: 397.1, m/z found, 399.1 [M+H]⁺.

Step D. 2-Bromo-6-(3 -methoxytetrahydro-2H-pyran-3 -yl)pyridin-4-ol. The title compound was prepared in a manner analogous to Intermediate 8, Step D, using 2-bromo-6-(3- methoxytetrahydro-2H-pyran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine. MS (ESI): mass calcd. for C₁₁H₁₄BrNO₃: 287.0, m/z found, 289.0 [M+H]⁺.

Step E. 2-Bromo-6-(3 -methoxytetrahydro-2H-pyran-3 -yl)-4-(oxetan-3 - ylmethoxy)pyridine. The title compound was prepared in a manner analogous to Intermediate 14, using 2 -bromo-6-(3 -methoxytetrahydro-2H-pyran-3 -yl)pyridin -4-ol instead of (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 8). MS (ESI): mass calcd. for C₁₅H₂₀BrNO₄: 357.1, m/z found, 358.1 [M+H]⁺.

Intermediate 97: 6-Chl oro-1 -(6-(3 -methoxy tetrahydro-2H-pyran- 3 -yl)-4-(oxetan- 3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 2-bromo-6-(3- methoxytetrahydro-2H-pyran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine (Intermediate 96) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₅CIN₄O₄: 444.2, m/z found, 446.3 [M+H]⁺.

Intermediate 98: 2-Bromo-4-(1, 1-difluoroethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.

Step A. 1-(2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-ol. To a solution of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)isonicotinaldehyde (Intermediate 6A, 2.4 g, 8.4 mmol) in THF (24 mL), was added CH₃MgCl (3.0 M in THF, 4.2 mL) dropwise at -78 °C over 10 min. After 1 h, the solution is allowed to warm gradually to room temperature over 3 h. The reaction was quenched by the slow addition of saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to afford an oil. Purification by preparative HPLC on a C 18 column eluting with a mobile phase of water (0.05% ammonium bicarbonate) and acetonitrile afforded the title compound as a colorless oil (1.7 g, 67%). MS (ESI): mass calcd. for C₁₂H₁₆BrNO₃: 301.0 m/z found, 302.1 [M+H]⁺.

Step B. 1-(2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-one. To a solution of 1-(2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-ol (1.7 g, 5.6 mmol) in DCM (10 mL) at 0 °C was added Dess-Martin periodinane (3.58 g , 8.46 mmol). The reaction solution was stirred for 2 h at room temperature. The mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (20 mL) and saturated aqueous sodium thiosulfate (v/v, 1 : 1) twice. The organic phase was dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford the title compound.

Step C. 2-Bromo-4-(1,1-difluoroethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine. To a solution of 1-(2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-one (1.5 g, 5.0 mmol) in DCM (15 mL), with an inert atmosphere of nitrogen, was added diethylaminosulfur trifluoride (4.0 g, 25 mmol) dropwise at 0 °C. The reaction mixture was stirred for 4 h at 0 °C, carefully poured into ice water, then extracted with DCM. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride respectively. The organic phase was dried (Na₂SO₄), filtered and concentrated under reduced pressure. Purification by preparative HPLC on a C 18 column eluting with a mobile phase of water (0.05% ammonium bicarbonate) and acetonitrile afforded the title compound as a colorless oil (750 mg, 46%). MS (ESI): mass calcd. for C₁₂H₁₄BrF₂NO₂: 321.0 m/z found, 322.1 [M+H]⁺.

Intermediate 99: 6-Chloro-1-(4-(1,1-difluoroethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 2-bromo-4-(1,1- difluoroethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 98) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₉H₁₉CIF₂N₄O₂: 408.1, m/z found, 409.0 [M+H]⁺.

Intermediate 100 : 4-(4-(Benzyloxy)piperidin- 1 -yl)-2-bromo-6-(3 -methoxytetrahydrofuran-3 - yl)pyridine.

Step A. 4-(4-(Benzyloxy)piperidin-1-yl)-2,6-dibromopyridine. To a solution of NaH (0.714 g, 17.9 mmol) in DMF (25 mL) with an inert atmosphere of nitrogen, was added 4- (benzyloxy)piperidine (4.05 g, 17.9 mmol) dropwise maintaining the internal temperature below 0 °C. Then 2,6-dibromo-4-nitropyridine (5 g, 18 mmol) was added dropwise at 0 °C and the reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with water (20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine and dried (Na₂SO₄). After filtration, the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography with petroleum ether/ethyl acetate (2 - 25% ethyl acetate in petroleum ether) afforded the title compound as a yellow oil (3.55 g, 78%). MS (ESI): mass calcd. for C₁₇H₁₈Br₂N₂O: 423.98, m/z found, 424.97[M+H]⁺.

Step B. 3-(4-(4-(Benzyloxy)piperidin-1-yl)-6-bromopyridin-2-yl)tetrahydrofuran-3-ol. The title compound was prepared in a manner analogous to Intermediate 1, using 4-(4- (benzyloxy)piperidin-1-yl)-2,6-dibromopyridine instead of 2,6-dibromo-4-methylpyridine. MS (ESI): mass calcd. for C₂₁H₂₅BrN₂O₃, 432.1; m/z found 433.2 [M+H]⁺.

Step C . 4-(4-(Benzyloxy)piperidin- 1 -yl)-2-bromo-6-(3-methoxytetrahydrofuran-3 - yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(4-(4-(benzyloxy)piperidin-1-yl)-6-bromopyridin-2-yl)tetrahydrofuran-3-ol instead of 3- (6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 1). MS (ESI): mass calcd. for C₂₂H₂₇BrN₂O₃, 446.1; m/z found, 447.2 [M+H]⁺.

Intermediate 101 : 1-(4-(4-(Benzyloxy)piperidin-1-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 4-(4-(benzyloxy)piperidin- 1-yl)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 100) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₉H₃₂CIN₅O₃: 533.2, m/z found, 534.3 [M+H]⁺.

Intermediate 102: 3-(6-Bromo-4-methylpyridin-2-yl)-3-methoxytetrahydrothiophene 1,1- dioxide.

Step A. 3-(6-Bromo-4-methylpyridin-2-yl)tetrahydrothiophen-3-ol. The title compound was prepared in a manner analogous to Intermediate 1, using dihydrothiophen-3(2H)-one instead of dihydrofuran-3(2H)-one. MS (ESI): mass calcd. for C₁₀H₁₂BrNOS: 273.0, m/z found, 274.0 [M+H]⁺.

Step B. 2-Bromo-6-(3 -methoxytetrahydrothiophen-3-yl)-4-methylpyridine. The title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromo-4- methylpyridin-2-yl)tetrahydrothiophen-3-ol instead of 3-(6-bromo-4-methylpyridin-2- yl)tetrahydrofuran-3-ol (Intermediate 1) and THF instead of DMF. MS (ESI): mass calcd. for C₁₁H₁₄BrNOS: 287.0, m/z found, 288.0 [M+H]⁺.

Step C. 3 -(6-Bromo-4-methylpyridin-2-yl)-3 -methoxytetrahydrothiophene 1,1 -dioxide. To a solution of 2-bromo-6-(3-methoxytetrahydrothiophen-3-yl)-4-methylpyridine (1.5 g, 5.2 mmol) in MeOH (15 mL) was added potassium peroxymonosulfate (7.99 g, 13.1 mmol, dissolved in 4 mL of water) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The mixture was diluted with dichloromethane (200 mL) and the organic phase was washed with saturated aqueous sodium carbonate, brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (20: 1 to 10:1 DCM:MeOH) provided the title compound as a white solid (1 g, 60%). MS (ESI): mass calcd. for C₁₁H₁₄BrNO₃S: 319.0, m/z found, 320.0 [M+H]⁺. Intermediate 103: 3-(6-(6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-methylpyridin-2- yl)-3 -methoxytetrahy drothiophene 1 , 1 -dioxide.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3 -(1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 3-(6-bromo-4- methylpyridin-2-yl)-3 -methoxytetrahydrothiophene 1,1 -dioxide (Intermediate 102) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₈H₁₉CIN₄O₃S: 406.1, m/z found, 406.9 [M+H]⁺.

Intermediate 104: 3-(6-Bromo-4-methylpyridin-2-yl)-3-methoxytetrahydrothiophene 1 -oxide.

To a solution of 2-bromo-6-(3-methoxytetrahydrothiophen-3-yl)-4-methylpyridine (Intermediate 102B, 1.4 g, 4.9 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (15 mL) was added 30% hydrogen peroxide (493 mg, 5.37 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature, then purified by preparative HPLC on a C 18 silica gel column eluting a linear gradient of 10-100% acetonitrile in water (containing 0.05% ammonium bicarbonate) to afford the title compound as a pink solid (1.0 g, 74%). MS (ESI): mass calcd. for C₁₁H₁₄BrNO₂S: 303.0, m/z found, 304.0 [M+H]⁺.

Intermediate 105: 3 -(6-(6-Chloro-3 -methyl- 1H-pyrazolo[4, 3 -c]pyridin- 1 -yl)-4-methylpyridin-2- yl)-3-methoxytetrahydrothiophene 1 -oxide.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 3-(6-bromo-4- methylpyridin-2-yl)-3-methoxytetrahydrothiophene 1 -oxide (Intermediate 104) instead of (R)-2- bromo-6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₁₈H₁₉CIN₄O₂S: 390.1, m/z found, 390.9 [M+H]⁺.

Intermedi ate 106 : 2-Bromo-6-(3 -methoxytetrahydrofuran-3 -yl)-4-(piperidin- 1 -yl)pyridine.

Step A. 2,6-Dibromo-4-(piperidin-1-yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 100, Step A, using piperidine instead of 4- (benzyloxy)piperidine. MS (ESI): mass calcd. for C₁₀H₁₂Br₂N₂: 317.9, m/z found, 318.9 [M+H]⁺.

Step B. 3-(6-Bromo-4-(piperidin-1-yl)pyridin-2-yl)tetrahydrofuran-3-ol. The title compound was prepared in a manner analogous to Intermediate 1, using 2,6-dibromo-4- (piperidin-1-yl)pyridine instead of 2,6-dibromo-4-methylpyridine. MS (ESI): mass calcd. for C₁₄H₁₉BrN₂O₂, 326.1; m/z found 327.1 [M+H]⁺.

Step C. 2-Bromo-6-(3 -methoxytetrahydrofuran-3 -yl)-4-(piperidin-1-yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromo-4- (piperidin-1-yl)pyridin-2-yl)tetrahydrofuran-3-ol instead of 3-(6-bromo-4-methylpyridin-2- yl)tetrahydrofuran-3-ol (Intermediate 1). MS (ESI): mass calcd. for C₁₅H₂₁BrN₂O₂, 340.1; m/z found, 341.1 [M+H]⁺. Intermediate 107: 6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(piperidin-1-yl)pyridin-2- yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23 using 6- chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and 2-bromo-6-(3- methoxytetrahydrofuran-3-yl)-4-(piperidin-1-yl)pyridine (Intermediate 106) instead of (R)-2- bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₆CIN₅O₂: 427.2, m/z found, 428.2 [M+H]⁺.

Intermediate 108: Acetamide-2,2,2-d₃.

To a solution of ammonium chloride (1.19 g, 22.2 mmol) and KOH (1.76 g, 31.5 mmol) in water (4 mL) and acetonitrile (20 mL) was added acetyl-d₃ chloride (1.5 g, 19 mmol) dropwise at 0 °C. The reaction mixture was stirred for 8 h at room temperature. The reaction was quenched with methanol (5 mL) and the resulting mixture was concentrated. The crude residue was filtered through a plug of silica gel (4: 1 DCM:MeOH) and the fractions were concentrated under reduced pressure to afford the title compound (1.05 g, 91 %).

Intermedi ate 109 : 2-Bromo-4-((R)-2-methoxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 - yl)pyridine.

Step A: (R)-2-Methoxypropyl 4-methylbenzenesulfonate. To a solution of (R)-2- hydroxypropyl 4-methylbenzenesulfonate (Intermediate 12A, 6 g, 300 mmol) in acetonitrile (72 mL) under N₂, was added silver oxide (1.01 g, 4.38 mmol) and then CH₃I (6.18 g, 4.38 mmol) at room temperature. The reaction mixture was heated at 80 °C for 24 hours and kept in the dark. The reaction mixture was filtered and the solids were washed with acetonitrile (3 x 50 mL). The filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (0- 100% ethyl acetate in petroleum ether) afforded the title compound (2.5 g, 39%). MS (ESI): mass calcd. for C₁₁H₁₆O₄S: 244.1, m/z found, 245.1 [M+H]⁺.

Step B: 2-Bromo-4-((R)-2-methoxypropoxy)-6-((R)-3 -methoxytetrahy drofuran-3 - yl)pyridine. The title compound was prepared in a manner analogous to Intermediate 10, using (R)-2-methoxypropyl 4-methylbenzenesulfonate instead of 1-bromo-2-methoxy ethane and heating at 85 °C instead of 80 °C. MS (ESI): mass calcd. for C₁₄H₂₀BrNO₄, 345.1; m/z found, 346.0 [M+H]⁺.

Intermediate 110: 6-Chloro-1-(4-((R)-2-methoxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine.

The title compound was made in a manner analogous to Intermediate 23 using 2-bromo- 4-((R)-2-methoxypropoxy)-6-((R)-3 -methoxytetrahy drofuran-3 -yl)pyridine (Intermediate 109) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2) and 6-chloro-3 -methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 27) instead of 6-chloro-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21). MS (ESI): mass calcd. for C₂₁H₂₅CIN₄O₄: 432.2, m/z found, 433.2 [M+H]⁺.

Intermediate 111: (R)-1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-amine.

To a solution of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)-3 -methyl- 1H-py razol o [4, 3 -c] pyridine (Intermediate 29, 0.3 g, 0.8 mmol) in THF (10 mL) was added 1 M LiHMDS (1.672 mL, 1.672 mmol), Pd₂(dba)₃ (38 mg, 0.042 mmol), and XPhos (0.04 g, 0.08 mmol). The reaction mixture was heated at 70 °C for 3 h. The reaction was quenched with H₂O and the resulting mixture was extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate in petroleum ether) afforded the title compound as a yellow solid (90 mg, 32% yield). MS (ESI): mass calcd. for C₁₈H₂₁N₅O₂: 339.2, found: 340.1 [M+H]⁺ .

Intermediate 112: 5-(4-((R)-2-Methoxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 63, Steps A-B using 2-bromo-4-((R)-2-methoxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 109) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridine (Intermediate 6) in Step A. MS (ESI): mass calcd. for C₂₂H₂₈N₄O₄412.2; m/z found, 413.2 [M+H]⁺.

Intermediate 113: (R)-3-(((2-(3-Amino-7-methylpyrrolo[1,2-c]pyrimidin-5-yl)-6-(3- methoxytetrahydrofu ran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1, 1 -dioxide.

The title compound was made in a manner analogous to Intermediate 63 using (R)-3-(((2- bromo-6-(3 -methoxy tetrahy drofuran-3 -yl)pyridin-4-yl)oxy)methyl)thietane 1 , 1 -dioxide (Intermediate 16) instead of (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofu ran-3- yl)pyridine (Intermediate 6). MS (ESI): mass calcd. for C₂₂H₂₆N₄O₅S 458.2; m/z found, 459.3 [M+H]⁺.

Intermediate 114: 2-(4,5-Dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

To a solution of 4,4,4',4',5,5,5',5^,-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (36.2 g, 143 mmol) in octane (500 mL) was added 2,3-dihydrofuran (40.0 g, 571 mmol), [Ir(OMeXcod)]2 (1.41 g, 2.14 mmol), and dtbpy (1.15 g, 4.28 mmol). The resulting mixture was heated at 80 °C under nitrogen. Purification by silica gel chromatography (0-37% EtOAc in petroleum ether) afforded the title compound (4.2 g, 15% yield). MS (ESI): mass calcd. for C₁₀H₁₇BO₃: 196.1, found: 197.2 [M+H]⁺.

Intermediate 115: Ethyl 5-(6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate.

Step A: Ethyl (R)-7-(4,5-dihydrofuran-3-yl)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3 -carboxylate. To a solution of ethyl (R)-7-chloro- 5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3- carboxylate (Intermediate 51, 800 mg, 2 mmol) in 1,4-dioxane (16 mL) and H₂O (4 mL) was added 2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 114, 754 mg, 3.85 mmol), potassium phosphate (817 mg, 3.85 mmol), and Pd(dppf)Cl₂ (157 mg, 0.358 mmol). The resulting mixture was heated at 80 °C under nitrogen for 2.5 h. The reaction mixture was cooled to room temperature and the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. Purification by silica gel chromatography (0- 83% ethyl acetate in petroleum ether) afforded the title compound as a yellow solid (550 mg, 57%). MS (ESI): mass calcd. for C₂₅H₂₇N₃O₅: 449.2; m/z found, 450.2 [M+H]⁺.

Step B: Ethyl 5-(6-((R)-3-methoxytetrahydrofu ran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate. To a solution of ethyl (R)-7-(4,5- dihydrofuran-3-yl)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate (500 mg, 1.11 mmol, 1.0 eq.) in ethanol (20 mL) and THF (20 mL) was added 10% Pd/C (500 mg). The reaction mixture was stirred at room temperature under H₂ for 1 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound (490 mg, 89% yield). MS (ESI): mass calcd. for C₂₅H₂₉N₃O₅: 451.2, found: 452.2 [M+H]⁺.

Intermediate 116: 5-(6-((R)-3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahy drofuran-3-yl)pyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 55, Steps A-C using ethyl 5-(6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(tetrahydrofuran- 3-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 115) instead of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3-carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₂₄H₂₆N₆O₃: 394.2, found: 395.2 [M+H]⁺.

Intermediate 117: Ethyl 5-(6-((S)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3 -yl)pyrrolo[ 1 ,2-c]pyrimidine-3 -carboxylate.

The title compound was made in a manner analogous to Intermediate 115, Steps A-B using ethyl (S)-7-chloro-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 52) instead of ethyl (R)-7-chloro-5-(6- (3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 51) in Step A. MS (ESI): mass calcd. for C₂₅H₂₉N₃O₅: 451.2, found: 452.2 [M+H]⁺.

Intermediate 118: 5-(6-((S)-3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahy drofuran-3 -yl)pyrrolo[1,2-c]pyrimidin-3 -amine.

The title compound was prepared in a manner analogous to Intermediate 55, Steps A-C using ethyl 5-(6-((S)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(tetrahydrofuran- 3-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 117) instead of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3-carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₂₄H₂₆N₆O₃: 394.2, found: 395.3 [M+H]⁺.

Intermediate 119: Ethyl (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (methyl-d₃)pyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was made in a manner analogous to Intermediate 57, except the reaction mixture was heated at 100 °C instead of 80 °C, using 4,4,5,5-tetramethyl-2-(methyl-d₃)- 1,3,2-dioxaborolane instead of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, chloro[(tri-tert- butylphosphine)-2-(2-aminobiphenyl)]palladium(II) instead of Pd(OAc)₂ and RuPhos, potassium phosphate tribasic instead of Cs₂CO₃, and 1,4-dioxane/water instead of DMA. MS (ESI): mass calcd. for C₂₂H₂₂D₃N₃O₄: 398.2, found: 399.3 [M+H]⁺.

Intermediate 120: (R)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(methyl- d₃)pyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 55, Steps A-C using ethyl (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(methyl- d₃)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 119) instead of ethyl (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidine-3 -carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₁₉H₁₉D₃N₄O₂: 341.2, found: 342.3 [M+H]⁺.

Intermediate 121: Ethyl (R)- 7-chloro-5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate .

The title compound was prepared in a manner analogous to Intermediate 21 using ethyl 7- chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 50) instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole and (R)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 6) instead of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine. MS (ESI): mass calcd. for C₂₁H₂₀CIF₂N₃O₄: 451.1, found: 452.1 [M+H]⁺. Intermediate 122: Ethyl 5-(4-(difluoromethyl)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-7-(tetrahy drofuran-3 -yl)pyrrolo[1 ,2-c]pyrimidine-3 -carboxylate.

The title compound was prepared in a manner analogous to Intermediate 115, Steps A-B using ethyl (R)-7-chloro-5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 121) instead of ethyl (R)-7-chloro-5-(6- (3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 51) in Step A. MS (ESI): mass calcd. for C₂₅H₂₇F₂N₃O₅: 487.2, found: 488.2 [M+H]⁺.

Intermediate 123 : 5-(4-(Difluoromethyl)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- (tetrahydrofuran-3 -yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -amine.

The title compound was prepared in a manner analogous to Intermediate 55, Steps A-C using ethyl 5-(4-(difluoromethyl)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- (tetrahy drofuran-3 -yl)pyrrolo[1,2-c]pyrimidine-3 -carboxylate (Intermediate 122) instead of ethyl (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₂₂H₂₄F₂N₄O₃: 430.2, found: 431.2 [M+H]⁺.

Intermediate 124: Ethyl (S)-7-chloro-5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 21 using ethyl 7- chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 50) instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole and (S)-2-bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3 -yl)pyridine (Intermediate 7) instead of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine. MS (ESI): mass calcd. for C₂₁H₂₀CIF₂N₃O₄: 451.1, found: 452.1 [M+H]⁺.

Intermediate 125: Ethyl 5-(4-(difluoromethyl)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-7-(tetrahydrofuran-3-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate.

The title compound was prepared in a manner analogous to Intermediate 115, Steps A-B using ethyl (S)-7-chloro-5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 124) instead of ethyl (R)-7-chloro-5-(6- (3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)pyrrolo[ 1 ,2-c]pyrimidine-3 -carboxylate (Intermediate 51) in Step A. MS (ESI): mass calcd. for C₂₅H₂₇F₂N₃O₅: 487.2, found: 488.2 [M+H]⁺.

Intermediate 126: 5-(4-(Difluoromethyl)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- (tetrahydrofuran-3-yl)pyrrolo[1,2-c]pyrimidin-3-amine.

The title compound was prepared in a manner analogous to Intermediate 55, Steps A-C using ethyl-5-(4-(difluoromethyl)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- (tetrahy drofuran-3 -yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 125) instead of ethyl (R)-5- (6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4- yl)pyrrolo[1,2-c]pyrimidine-3 -carboxylate (Intermediate 53) in Step A. MS (ESI): mass calcd. for C₂₂H₂₄F₂N₄O₃: 430.2, found: 431.2 [M+H]⁺.

Intermediate 127: 6-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine.

To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine (1.5 g, 9.9 mmol) in DMF (20 mL) under N₂ was added potassium hydroxide (2.2 g, 39 mmol) at 0 °C. The reaction mixture was stirred for 30 min at room temperature, followed by the addition of iodine (2.5 g, 9.9 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with water (50 mL) and the solids were collected by filtration. The solids were dried under vacuum overnight to afford the title compound as a white solid (2 g, 73%). MS (ESI): mass calcd. for C₇H₄CIIN₂, 277.9; m/z found, 278.9 [M+H]⁺.

Intermediate 128: 6-Chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 82, using 6- chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (Intermediate 127) instead of 6-chloro-3 -iodo- 1H- pyrazolo[4,3-c]pyridine in Step A. MS (ESI): mass calcd. for C₈H₄CIF₃N₂, 220.0; m/z found, 221.0.

Intermediate 129: (R)-6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3 -(trifluoromethyl)- 1H-pyrrolo[3 ,2-c]pyridine.

The title compound was prepared in a manner analogous to Intermediate 23, using 6- chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (Intermediate 128) instead of 6-chloro-3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 21) and (R)-2-bromo-6- (3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine (Intermediate 14) instead of (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (Intermediate 2). MS (ESI): mass calcd. for C₂₂H₂₁CIF₃N₃O₄, 483.1; m/z found, 484.1 [M+H]⁺. EXAMPLES

Example 1 : (R)-1 -(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.

Step A. (R)-1-(4-Methoxybenzyl)-3-(1-(6-(3-methoxytetrahydrofuran-3-y])-4- methylpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea. To a solution of (R)-6-chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3-(1 - methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23, 90 mg, 0.212 mmol) in THF (10 mL) was added 1-(4-methoxybenzyl)urea (57.3 mg, 0.318 mmol), cesium carbonate (172 mg, 0.530 mmol), and BrettPhos Pd G3 (38 mg, 0.042 mmol). The resulting mixture was heated under nitrogen at 70 °C for 2 h. The organic solvent was removed under vacuum. Purification by silica gel chromatography (0-100% ethyl acetate in petroleum ether) afforded the title compound as a white solid (100 mg, 77%). MS (ESI): mass calcd. for C₃₀H₃₂N₈O₄, 568.3; m/z found, 569.2 [M+H]⁺.

Step B. 4. (R)-1-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea. A mixture of (R)-1-(4- methoxybenzyl)-3-(1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (100 mg, 0.176 mmol) and TFA (15 ml) was heated at 60 °C for 4 h. The organic solvent was removed under reduced pressure. Purification by reverse phase column chromatography on a C 18 gel column (10-60% acetonitrile in water (0.05% NH₄CO₃)) afforded the title compound as a white solid (42.7 mg, 54%). MS (ESI): mass calcd. for C₂₂H₂₄N₈O₃, 448.2; m/z found, 449.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.31 (s, 1H), 9.13 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.27 (s, 1H), 6.51 (br s, 2H), 4.27 - 4.30 (m, 1H), 3.90 - 4.08 (m, 6H), 3.13 (s, 3H), 2.66- 2.74 (m, 1H), 2.51 - 2.58 (m, 1H), 2.50 (s, 3H).

Example 2: (S)- 1 -( 1 -(6-(3 -Methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -( 1 -methyl- 1H- pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (S)-6- chloro- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3-( 1 -methyl- 1H-pyrazol-4- yl)-1 H-pyrazolo[4,3-c]pyridine (Intermediate 24) instead of (R)-6-chloro-1 -(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₄N₈O₃, 448.2; m/z found, 449.2 [M+H]⁺. ¹H HNMR (300 MHz, DMSO-d₆) δ: 9.31 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.63 (s, 1H ), 8.19 (s, 1H), 7.79 (s, 1H), 7.27 (s, 1H), 6.50 (s, 2H), 4.27 - 4.30 (m, 1H), 3.89 - 4.09 (m, 6H), 3.13 (s, 3H), 2.65- 2.75 (m, 1H), 2.50 - 2.58 (m, 1H), 2.48 (s, 3H).

Example 3: (R)- 1 -(3-(Furan-3-yl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)- 1H-pyrazolo[4, 3 -c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro-3-(furan-3-yl)- 1 -(6-(3 -methoxy-tetrahydrofuran-3-yl)-4-methylpyridin-2-yl)- 1H- pyrazolo [4, 3 -c] pyridine (Intermediate 25) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₂N₆O₄, 434.2; m/z found, 435.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.31 (s, 1H), 9.15 (s, 1H), 8.95 (s, 1H), 8.75 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 6.51 (s, 2H), 4.27 - 4.30 (m, 1H), 4.00 - 4.06 (m, 2H), 3.90 - 3.99 (m, 1H), 3.14 (s, 3H), 2.68 - 2.72 (m, 1H), 2.55 - 2.66 (m, 1H), 2.50 (s, 3H).

Example 4: (S)-1 -(3-(Furan-3-yl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (S)-6- chloro-3-(furan-3-yl)-1-(6-(3-methoxy-tetrahydrofuran-3-yl)-4-methy1pyridin-2-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 26) instead of (R)-6-chloro-1 -(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₂N₆O₄, 434.2; m/z found, 435.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.31 (s, 1H), 9.15 (s, 1H), 8.94 (s, 1H), 8.75 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 6.51 (s, 2H), 4.29 - 4.30 (m, 1H), 3.90 - 4.08 (m, 3H), 3.14 (s, 3H), 2.66 - 2.74 (m, 1H), 2.53 - 2.57 (m, 1H), 2.50 (s, 3H).

Example 5: (R)-1 -(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H- pyrazolo[4,3-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3- c]pyridine (Intermediate 29) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₁₉H₂₂N₆O₃, 382.2; m/z found, 383.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.81 (s, 1H), 8.80 (s, 1H), 7.69 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 4.27-4.24 (m, 1H), 4.05-3.87 (m, 3H), 3.11 (s, 3H), 2.69-2.58 (m, 5H), 2.53-2.44 (m, 3H).

Example 6: (S)-1-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H- pyrazolo[4,3-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1 , using (S)-6- chloro- 1 -(6-(3 -methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3 - c]pyridine (Intermediate 30) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methy lpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₁₉H₂₂N₆O₃, 382.2; m/z found, 383.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.23 (s, 1H), 8.81 (s, 1H), 8.80 (s, 1H), 7.69 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 4.27-4.24 (m, 1H), 4.05-3.87 (m, 3H), 3.11 (s, 3H), 2.72-2.62 (m, 5H), 2.59-2.44 (m, 3H). Example 7: (R)-1-(1-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3- methyl-1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro-1-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H- pyrazolo[4,3-c]pyridine (Intermediate 31) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo [4, 3 -c] pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₁₉H₂₀F₂N₆O₃, 418.2; m/z found, 419.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ: 9.32 (s, 1H), 8.85 (d, J= 4.0 Hz, 2H), 8.01 (s, 1H), 7.53 (s, 1H), 7.25 (s, 1H), 6.52 (s, 2H), 4.30 (d, J= 9.7 Hz, 1H), 4.14- 3.88 (m, 2H), 3.17 (s, 3H), 2.80-2.67 (m, 1H), 2.62 (s, 4H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ: - 114.92.

Example 8 : (S)- 1 -( 1 -(4-(Difluoromethyl )-6-(3 -methoxytetrahy drofuran-3 -y l)pyridine-2-yl)-3 - methyl- 1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1 , using (S)-6- chloro- 1 -(4-(difluoromethyl)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridine (Intermediate 32) instead of (R)-6-chl oro-1 -(6-(3- methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₁₉H₂₀F₂N₆O₃, 418.2; m/z found, 419.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.32 (s, 1H), 8.86 (d, J= 4.2 Hz, 2H), 8.02 (s, 1H), 7.54 (s, 1H), 7.44-7.08 (m, 1H), 6.52 (s, 2H), 4.32-4.29 (m, 1H), 4.12-3.92 (m, 3H), 3.18 (s, 3H), 2.79-2.74 (m, 1H), 2.64-2.58 (m, 4H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ: -114.9.

Example 9: (R)- 1 -(1 -(4-(2-Methoxyethoxy)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-y l)-3 - methyl -1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro- 1 -(4-(2-methoxy ethoxy )-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1 H- pyrazolo[4,3-c]pyridine (Intermediate 33) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl-1H-pyrazol -4-yl)- 1 H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₁H₂₆N₆O₅, 442.2; m/z found, 443.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.24 (s, 1H), 8.80 (s, 2H), 7.35 (d, J= 2.2 Hz, 1H), 6.92 (d, J= 2.2 Hz, 1H), 6.50 (s, 2H), 4.40-4.20 (m, 3H), 4.12-3.85 (m, 3H), 3.72 (d, J= 5.2 Hz, 2H), 3.54-3.35 (m, 3H), 3.13 (s, 3H), 2.79-2.53 (m, 5H).

Example 10 : (S)- 1 -( 1 -(4-(2-Methoxy ethoxy )-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-3 - methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (S)-6- chloro- 1 -(4-(2-methoxy ethoxy )-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H- pyrazolo [4, 3 -c] pyridine (Intermediate 34) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₁H₂₆N₆O₅, 442.2; m/z found, 443.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ: 9.26 (s, 1H), 8.84-8.78 (m, 2H), 7.36 (d, J= 2.2 Hz, 1H), 6.93 (d, J= 2.1 Hz, 1H), 6.52 (s, 2H), 4.35-4.27 (m, 2H), 4.25 (dd, J= 9.7, 1.4 Hz, 1H), 4.05 (m, 1H), 4.01-3.92 (m, 1H), 3.89 (d, J= 9.7 Hz, 1H), 3.75-3.69 (m, 2H), 3.34 (s, 3H),3.14 (s, 3H), 2.69 (m, 1H), 2.60 (s, 3H),2.55 (m, 1H).

Example 11: 1 -(1 -(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.

Step A. 1 -( 1 -(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3 - methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea. The title compound was prepared in a manner analogous to Example 1, using 1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-6-chloro- 3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 35) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl-1H-pyrazol -4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A.

Step B. 1 -( 1 -(4-((R)-2-Hy droxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridine- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea. To a solution of -(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (50 mg, 0.09 mmol) in dichloromethane (2 mL) under N₂ was added triethylamine trihydrofluoride (144.8 mg, 0.898 mmol) and triethylamine (181.8 mg, 1.796 mmol) in order at 0 °C. The resulting solution was stirred for 16 hours at 25 °C. The reaction mixture was concentrated under reduced pressure and then diluted with tetrahydrofuran. Purification by Flash-Prep-HPLC with a C18 gel column (10-100% acetonitrile in water (0.05% ammonium bicarbonate)) provided the title compound as a white solid (11.0 mg, 35%). MS (ESI): mass calcd. for C₂₁H₂₆N₆O₅, 442.2; m/z found, 443.3 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ: 8.76 (s, 1H), 8.54 (s, 1H), 7.47 (s, 1H), 7.02 (s, 1H), 4.28-4.03 (m, TH), 3.27 (s, 3H), 2.80-2.53 (m, 5H), 1.35-1.31 (m, 3H).

Example 12: 1 -( 1 -(4-((R)-2-Hy droxy propoxy )-6-((S)-3 -methoxytetrahydrofuran-3 -yl)pyridine-2- yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.

Step A. 1-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea. The title compound was prepared in a manner analogous to Example 1, using 1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-6-chloro- 3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 36) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl-1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₇H₄₀N₆O₅Si, 556.3; m/z found, 557.3 [M+H]⁺.

Step B. 1-(1-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridine- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea . The title compound was prepared in a manner analogous to Example 11, Step B, using 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₁H₂₆N₆O₅, 442.2; m/z found, 443.2 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ: 8.76 (s, 1H), 8.53-8.50 (m, 1H), 7.61-7.42 (m, 1H), 7.02-6.99 (m, 1H), 4.28-4.03 (m, 7H), 3.27-3.21 (m, 3H), 2.80-2.53 (m, 5H), 1.35-1.31 (m, 3H).

Example 13 : (R)- 1 -(1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridine-2-yl)-3 -methyl - 1H-pyrazolo[4,3-c]pyridine (Intermediate 37) instead of (R)-6-chloro-1 -(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₆N₆O₅, 454.2; m/z found, 455.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ: 9.24 (s, 1H), 8.81 (d, J= 2.1 Hz, 2H), 7.38 (d, J= 2.1 Hz, 1H), 6.93 (d, J= 2.1 Hz, 1H), 6.50 (s, 2H), 4.73 (dd, J= 7.9, 6.0 Hz, 2H), 4.57-4.36 (m, 4H), 4.24 (d, J= 9.7 Hz, 1H), 4.12-3.83 (m, 3H), 3.42 (dd, J= 14.9, 8.6 Hz, 1H), 3.14 (s, 3H), 2.76-2.53 (m, 5H).

Example 14 : (S)- 1 -( 1 -(6-(3 -Methoxytetrahydrofuran-3 -y l)4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (S)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine (Intermediate 38) instead of (R)-6-chloro-1-(6-(3- methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo [4,3 -c] pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₆N₆O₅, 454.2; m/z found, 455.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.24 (s, 1H), 8.84-8.77 (m, 2H), 7.38 (d, J= 2.2 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.50 (s, 2H), 4.73 (dd, J= 7.9, 6.1 Hz, 2H), 4.48 (t, J= 6.0 Hz, 2H), 4.42 (d, J= 6.6 Hz, 2H), 4.24 (d, J= 9.7 Hz, 1H), 4.09-3.83 (m, 3H), 3.45 (m, 1H), 3.14 (s, 3H), 2.69-2.60 (m, 5H).

Example 15 : (R)- 1 -( 1 -(4-(( 1 , 1 -Dioxidothietan-3-yl)methoxy)-6-(3 -methoxytetrahy drofuran-3 - yl)pyridine-2-yl)-3 -methyl- 1 H-pyrazolo[4,3 -c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-3-(((2- (6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine-1-yl)-6-(3-methoxytetrahydrofuran-3- yl)pyridine-4-yl)oxy)methyl)thietane 1,1 -dioxide (Intermediate 39) instead of (R)-6-chloro-1-(6- (3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₆N₆O₆S, 502.2; m/z found, 503.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₃) δ: 8.92-8.81 (m, 2H), 8.71 (d, J= 1.5 Hz, 1H), 7.68 (s, 1H), 7.29-7.19 (m, 2H), 7.00 (d, J= 55.3 Hz, 1H), 6.23 (s, 2H), 4.25 (d, J = 9.6 Hz, 1H), 4.13-3.86 (m, 3H), 3.14 (s, 3H), 2.85-2.68 (m, 1H), 2.54 (s, 3H), 2.40 (s, 1H).

Example 16 : (S)- 1 -( 1 -(4-(( 1 , 1 -Dioxidothietan-3 -yl)methoxy)-6-(3-methoxytetrahydrofuran-3 - yl)pyridine-2-yl)-3 -methyl- 1 H-pyrazolo[4,3 -c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (S)-3-(((2- (6-chloro-3 -methyl-1H-pyrazolo[4,3-c]pyridine- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 - yl)pyridine-4-yl)oxy)methyl)thietane 1,1-dioxide (Intermediate 40) instead of (R)-6-chloro-1-(6- (3 -methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23). MS (ESI): mass calcd. for C₂₂H₂₆N₆O₆S, 502.2; m/z found, 503.1 [M+H]⁺. ¹H NMR: (300 MHz, DMSO-d₆) δ: 9.24 (s, 1H), 8.81 (s, 2H), 7.37 (s, 1H), 6.93 (s, 1H), 6.49 (s, 2H), 4.38-4.30 (m, 4H), 4.25-4.13 (m, TH), 3.14-2.90 (m, 4H), 2.67- 2.60 (m, 4H).

Example 17 : (R)- 1 -(1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrrolo[3,2-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrrolo[3,2- c]pyridine (Intermediate 41) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃, 381.2; m/z found, 382.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 8.97 (s, 1H), 8.52-8.38 (m, 2H), 7.70 (d, J= 1.4 Hz, 1H), 7.43 (s, 1H), 7.24 (s, 1H), 6.66 (s, 2H), 4.19 (d, J= 9.6 Hz, 1H), 4.02-3.86 (m, 3H), 3.12 (s, 3H), 2.64-2.61 (m , 2H), 2.43 (s, 3H), 2.31 (d, J = 1.2 Hz, 3H). Example 18: (S)-1-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H- pyrrolo[3,2-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (S)-6- chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrrolo[3,2- c]pyridine (Intermediate 42) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃, 381.2; m/z found, 382.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 8.97 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 7.70 (d, J= 1.4 Hz, 1H), 7.44 (s, 1H), 7.24 (s, 1H), 6.65 (br s, 2H),4.25-4.11(m,1H) 3.98-3.89 (m, 3H), 3.12 (s, 3H), 2.62 (d, J= 13.4 Hz, 1H), 2.44 (s, 4H), 2.31 (d, J= 1.2 Hz, 3H).

Example 19 : (R)- 1 -(1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine-2-yl)-3-methyl- 1H-py rr ol o [3, 2-c] pyridine (Intermediate 43) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol -4-yl)- 1 H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₃H₂₇N₅O₅, 453.2; m/z found, 454.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ: 9.27 (s, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.19 (d, J= 1.9 Hz, 1H), 6.97 (d, J= 2.0 Hz, 1H), 6.72 (s, 2H), 4.75 (dd, J= 7.9, 6.1 Hz, 2H), 4.46 (dt, J= 6.0, 2.6 Hz, 4H), 4.18 (d, J = 9.7 Hz, 1H), 4.08 - 3.86 (m, 3H), 3.67 - 3.39 (m, 1H), 3.14 (s, 3H), 2.74 - 2.55 (m, 2H), 2.32 (s, 3H).

Example 20 : (S)- 1 -( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (S)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine-2-yl)-3-methyl- 1H-pyrrolo [3, 2-c] pyridine (Intermediate 44) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₃H₂₇N₅O₅, 453.2; m/z found, 454.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.51-8.40 (m, 2H), 7.77 (d, J= 1.4 Hz, 1H), 7.16 (d, J= 2.0 Hz, 1H), 6.94 (d, J= 1.9 Hz, 1H), 6.66 (s, 2H), 4.75 (dd, J= 7.9, 6.1 Hz, 2H), 4.46 (dd, J= 6.6, 4.7 Hz, 4H), 4.22-4.13 (m, 1H), 4.01-3.88 (m 3H), 3.47-3.43 (m, 1H), 3.14 (s, 3H), 2.64-2.57 (m, 2H), 2.31 (d, J = 1.2 Hz, 3H).

Example 21: (R)-1-(1-(4-((1,1-Dioxidothietan-3-yl)methoxy)-6-(3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-3-(((2- (6-chloro-3 -methyl-1H-pyrrolo[3,2-c]pyridine- 1 -yl)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine- 4-yl)oxy)methyl)thietane 1,1 -dioxide (Intermediate 45) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₃H₂₇N₅O₆S, 501.2; m/z found, 502.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.52-8.43 (m, 2H), 7.77 (d, J= 1.4 Hz, 1H), 7.15 (d, J= 2.0 Hz, 1H), 6.95 (d, J= 1.9 Hz, 1H), 6.66 (s, 2H), 4.37 (dd, J= 15.5, 8.3 Hz, 4H), 4.18 (d, J= 9.7 Hz, 1H), 4.09 (dd, J= 14.3, 6.0 Hz, 2H), 4.06- 3.86 (m, 3H), 3.14 (s, 3H), 3.10-2.98 (m,l H), 2.63 (dt, J= 13.3, 8.8 Hz, 1H), 2.43 (dd, J= 12.7, 5.5 Hz, 1H), 2.32 (d, J= 1.2 Hz, 3H).

Example 22 : (S)- 1 -( 1 -(4-((l , 1 -Dioxidothietan-3 -yl)methoxy)-6-(3 -methoxytetrahydrofuran-3 - yl)pyridine-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1 , using (S)-3-(((2- (6-chloro-3 -methyl-1H-pyrrolo[3,2-c]pyridine- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine- 4-yl)oxy)methyl)thietane 1,1 -dioxide (Intermediate 46) instead of (R)-6-chloro-1 -(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₃H₂₇N₅O₆S, 501.2; m/z found, 502.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.48-8.45 (m, 2H), 7.76 (s, 1H), 7.14 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 1.5 Hz, 1H), 6.65 (s, 2H), 4.40-4.38 (m, 4H), 4.25-3.85 (m, 7H), 3.14-2.92 (m, 4H), 2.62-2.56 (m, 1H), 2.31 (s, 3H).

Example 23 : (R)-1-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)urea.

To a solution of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1- methyl-1H-pyrazol -4 -yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 55, 100 mg, 0.25 mmol) in DCM (10 mL) was added 2,2,2-trichloroacetyl isocyanate (51.2 mg, 0.272 mmol) at 0 °C. The reaction mixture was warmed to room temperature, stirred at 1.5 h at room temperature, and solvent was removed under vacuum. The residue was charged with saturated sodium bicarbonate solution (5 mL) and methanol (5 mL) at 0 °C and the mixture was stirred for 2 h at room temperature. The reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by reverse-phase preparative HPLC on a C18 column (26- 46% MeCN in 10 mM aq. NH₄HCO₃) afforded the title compound as a yellow solid (38.6 mg, 33%). MS (ESI): mass calcd. for C₂₃H₂₅N₇O₃: 447.2; m/z found: 448.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 8.97 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 8.27 (s, 1H ), 7.90 (s, 1H), 7.48 - 7.49 (m, 2H), 7.03 (s, 1H), 6.22 (s, 2H), 4.21 - 4.25 (m, 1H), 3.97 - 4.02 (m, 2H), 3.87- 3.97 (m, 4H), 3.10 (s, 3H), 2.60 - 2.80 (m, 1H), 2.42 - 2.50 (m, 1H), 2.36 (s, 3H).

Example 24 : (S)- 1 -(5-(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (S)-5-(6- (3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4- yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 56) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₃H₂₅N₇O₃: 447.2; m/z found: 448.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 8.27 (s 1H), 7.90 (s, 1H), 7.48 - 7.49 (m, 2H), 7.03 (s, 1H), 6.22 (s, 2H), 4.22 - 4.24 (m, 1H), 4.00 - 4.08 (m, 1H), 3.88 - 3.95 (m, 5H), 3.10 (s, 3H), 2.66 - 2.75 (m, 1H), 2.48 - 2.50 (m, 1H), 2.36 (s, 3H).

Example 25: (R)-1-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (R)-5-(6- (3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3- amine (Intermediate 59) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃: 381.2; m/z found, 382.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 5: 8.82 (s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 7.38 (s, 1H), 7.10 (s, 1H), 6.98 (s, 1H), 6.19 (s, 2H), 4.19 - 4.22 (m, 1H), 3.92 - 4.04 (m, 2H), 3.85 - 3.88 (m, 1H), 3.09 (s, 3H), 2.67 - 2.75 (m, 1H), 2.51 (s, 3H), 2.46 - 2.50 (m, 1H), 2.34 (s, 3H).

Example 26: (S)-1-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (S)-5-(6- (3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3- amine (Intermediate 60) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃, 381.2; m/z found, 382.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.76 - 8.82 (m, 2H), 8.67 (s, 1H), 7.38 (s, 1H), 7.11 (s, 1H ), 6.98 (s, 1H), 6.20 (s, 2H), 4.20 - 4.22 (m, 1H), 3.96 - 4.04 (m, 2H), 3.86 - 3.94 (m, 1H), 3.09 (s, 3H), 2.63 - 2.75 (m, 1H), 2.52 (s, 3H), 2.43 - 2.50 (m, 1H), 2.35 (s, 3H).

Example 27: (R)-1-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (R)-5-(4- (difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 63) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55). MS (ESI): mass calcd. for C₂₀H₂₁F₂N₅O₃, 417.2; m/z found, 418.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 - 8.81 (m, 2H), 8.71 (d, J= 1.5 Hz, 1H), 7.68 (s, 1H), 7.29 - 7.19 (m, 2H), 7.28 - 6.91 (m, 1H), 6.23 (s, 2H), 4.25 (d, J= 9.6 Hz, 1H), 4.13 - 3.86 (m, 3H), 3.14 (s, 3H), 2.85 - 2.68 (m, 1H), 2.54 (s, 3H), 2.40 (s, 1H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ - 114.344.

Example 28: (S)-1-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1 ,2-c]pyrimidin-3 -yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (S)-5-(4- (difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3-amine (Intermediate 64) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C2QH₂₁F₂N₅O₃, 417.2; m/z found, 418.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.74 (d, J = 1.2 Hz, 1H), 8.52 (d, J = 1.2 Hz, 1H), 7.63 (s, 1H), 7.34 (s, 1H), 7.13 (d, J= 0.8 Hz, 1H), 6.99-6.71 (m, 1H), 4.31-4.30 (m, 1H), 4.28-4.12 (m, 3H), 3.27 (s, 3H), 2.93-2.88 (m, 1H), 2.57-2.51 (m, 4H). ¹⁹F NMR (400 MHz, CD₃OD): -116.583.

Example 29: (R)-1-(5-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)- 7-methylpyrrolo[1,2-c]pyrimidin-3 -yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (R)-5-(4- (2-methoxy ethoxy )-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 65) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55). MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J= 1.5 Hz, 1H), 8.77 (s, 1H), 8.66 (d, J= 1.5 Hz, 1H), 7.18 (d, J= 1.2 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 6.19 (s, 2H), 4.31- 4.14 (m, 3H), 4.07-3.84 (m, 3H), 3.73-3.67 (m, 2H), 3.33 (s, 3H), 3.11 (s, 3H), 2.78-2.66 (m, 1H), 2.50 (s, 3H), 2.48-2.37 (m, 1H).

Example 30 : (S)- 1 -(5-(4-(2-Methoxyethoxy)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (S)-5-(4- (2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3-amine (Intermediate 66) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methy lpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4-yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.85 - 8.74 (m, 2H), 8.66 (d, J= 1.5 Hz, 1 H), 7.18 (d, J= 1.1 Hz, 1H), 7.10 (d, J= 2.2 Hz, 1H), 6.71 (d, J= 2.2 Hz, 1H), 6.20 (s, 2H), 4.30 - 4.22 (m, 2H), 4.18 (dd, J= 9.7, 1.3 Hz, 1H), 4.09 - 3.82 (m, 3H), 3.75 - 3.66 (m, 2H), 3.28 (s, 3H), 3.11 (s, 3H), 2.80 - 2.67(m, 1H), 2.55 - 2.33 (m, 1H).

Example 31 : 1-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

Step A. 1-(5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. The title compound was prepared in a manner analogous to Example 23, using 5-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 67) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₈H₄₁N₅O₅Si, 555.3; m/z found, 556.4 [M+H]⁺.

Step B. 1-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. The title compound was prepared in a manner analogous to Example 11, Step B, using 1-(5-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6- ((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea instead of 1 -( 1 -(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3 - methoxytetr ahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.2. ¹H NMR (300 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.84 (d, J= 15.0 Hz, 2H), 7.21 - 6.50 (m, 5H), 4.96 (s, 1H), 4.17 (d, J= 9.7 Hz, 1H), 4.06 - 3.73 (m, 6H), 3.13 (s, 3H), 2.79-2.65 (m, 1H), 2.48-2.3 l(m, 4H), 1.17 (d, J= 6.3 Hz, 3H).

Example 32: 1 -(5-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

Step A. 1 -(5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. The title compound was prepared in a manner analogous to Example 23, using 5-(4-( (R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 68) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3-amine (Intermediate 55). MS (ESI): mass calcd. for C₂₈H₄₁N₅O₅Si, 555.3; m/z found, 556.3[M+H]⁺.

Step B. 1-(5-(4-((R)-2-hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. The title compound was prepared in a manner analogous to Example 11, Step B, using 1-(5-(4-((R)-2-((tert-butyldiinethylsilyl)oxy)propoxy)-6- ((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea instead of 1 -( 1 -(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3 - methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.2. ¹H NMR (300 MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.85-8.79 (m, 2H), 6.96-6.54 (m, 5H), 4.91 (s, 1H), 4.18- 4.13 (m, 1H), 3.93-3.79 (m, 6H), 3.12 (s, 3H), 2.73-2.68 (m, 1H), 2.49-2.47 (m, 4H), 1.15 (d, J= 6.3 Hz, 3H).

Example 33 : 1-(5-(4-((1r,3r)-3-Hydroxycyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

Step A. 1-(5-(4-((1r,3r)-3-(Benzyloxy)cyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. The title compound was prepared in a manner analogous to Example 23, using 5-(4-((1r,3r)-3-(benzyloxy)cyclobutoxy)-6-((R)-3- methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 69) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55). MS (ESI): mass calcd. for C₃₀H₃₃N₅O₅, 543.3; m/z found, 544.2 [M+H]⁺.

Step B. 1-(5-(4-((1r,3r)-3-Hydroxycyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. To a solution of 1-(5-(4-((1r,3r)-3- (benzyloxy)cyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea (25 mg, 0.044 mmol) in dichloromethane (0.5 mL) at- 78 °C under N₂ was added boron trichloride (1 M in dichloromethane, 0.176 mL), dropwise. The reaction mixture was stirred at -78 °C for 1 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated. Purification by Flash-Prep-HPLC with a C18 gel column (20-60% MeCN in water (0.05% ammonium bicarbonate)) afforded the title compound as a yellow solid (10.1 mg, 51%). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₅, 453.2; m/z found, 454.3. ¹H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J= 1.5 Hz, 1H), 8.77 (s, 1H), 8.64 (d, J = 1.5 Hz, 1H), 7.14 (d, J= 1.1 Hz, 1H), 6.91 (d, J= 2.2 Hz, 1H), 6.58 (d, J= 2.1 Hz, 1H), 6.19 (s, 2H), 5.23 (s, 1H), 5.02 (t, J= 5.2 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.16 (d, J= 9.6 Hz, 1H), 4.08 - 3.90 (m, 2H), 3.86 (d, J= 9.7 Hz, 1H), 3.11 (s, 3H), 2.74 (dt, J= 13.3, 8.8 Hz, 1H), 2.50 (s, 3H), 2.37 (t, J= 5.7 Hz, 5H).

Example 34: 1-(5-(4-((1r,3s)-3-Hydroxycyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

Step A. 1-(5-(4-((1r,3s)-3-(Benzyloxy)cyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. The title compound was prepared in a manner analogous to Example 23, using 5-(4-((1r,3s)-3-(benzyloxy)cyclobutoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 70) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55).

Step B. 1-(5-(4-((1r,3s)-3-Hydroxycyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea. The title compound was prepared in a manner analogous to Example 33, Step B, using 1-(5-(4-((1r,3s)-3- (benzyloxy)cyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea instead of 1-(5-(4-((1r,3r)-3-(benzyloxy)cyclobutoxy)- 6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea (Example 33, Step A). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₅, 453.2; m/z found, 454.1. ¹H NMR (300 MHz, DMSO-d₆) 8 8.96 - 8.73 (m, 2H), 8.64 (d, J= 1.4 Hz, 1H), 7.14 (s, 1H), 6.91 (d, J= 2.1 Hz, 1H), 6.58 (d, J= 2.1 Hz, 1H), 6.19 (s, 2H), 5.23 (d, J= 5.4 Hz, 1H), 5.02 (t, J= 5.4 Hz, 1H), 4.40 (d, J= 5.9 Hz, 1H), 4.16 (d, J= 9.5 Hz, 1H), 4.07 - 3.92 (m, 2H), 3.86 (d, J= 9.6 Hz, 1H), 3.11 (s, 3H), 2.56 (s, 3H), 2.80-2.68 (m, 1H), 2.37 (t, J= 5.7 Hz, 5H).

Example 35: (S)-1-(5-(4-((1, 1 -Dioxidothietan-3 -yl)methoxy)-6-(3 -methoxy tetrahydrofuran- 3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was prepared in a manner analogous to Example 23, using (S)-3-(((2- (3-amino-7-methylpyrrolo[1,2-c]pyrimidin-5-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-4- yl)oxy)methyl)thietane 1,1-dioxide (Intermediate 71) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₆S, 501.2; m/z found, 502.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆): δ 8.86-8.75 (m, 2H), 8.67 (d, J= 1.5 Hz, 1H), 7.18-7.12 (m, 2H), 6.72 (d, J= 2.1 Hz, 1H), 6.20 (s, 2H), 4.43-4.30 (m, 4H), 4.31 (s, 1H), 4.23-4.14 (m, 4H), 4.14-3.82 (m, 1H), 3.12 (s, 3H), 2.83-2.67 (m, 1H), 2.79-2.75 (m, 1H), 2.48- 2.32 (m, 3H), 2.08-1.67 (m, 1H).

Example 36 : 1 -(6-(3 -Methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridine-6-yl)acetamide.

To a solution of (R)-6-chloro-1-(6-(3-methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 29, 100 mg, 0.28 mmol) in DMA (3 mL) was added acetamide (24.7 mg, 0.418 mmol), Pd₂(dba)₃ (25.5 mg, 0.0279 mmol), XPhos (22.9 mg, 0.0557 mmol), and cesium carbonate (182 mg, 0.557 mmol). The resulting mixture was heated at 130 °C under nitrogen for 2 h. The reaction mixture was cooled to room temperature and quenched with H₂O (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. Purification by reverse phase preparative HPLC on a C 18 column (38-60% acetonitrile in 10 mM NH₄HCO₃ (aq.)) afforded the title compound as a white solid (25 mg, 23% yield). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃, 381.4; m/z found, 382.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.66 (s, 1H), 9.23 (s, 1H), 8.91 (s, 1H), 7.72 (s, 1H), 7.26 (s, 1H), 4.24-4.27 (m, 1H), 3.96-4.09 (m, 2H), 3.90 (d, J= 10.0 Hz, 1H), 3.13 (s, 3H), 2.69-2.77 (m, 1H), 2.63 (s, 3H), 2.51-2.55 (m, 1H), 2.48 (s, 3H), 2.15 (s, 3H).

Example 37 : (S)-N-( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1 H- pyrazolo[4,3-c]pyridine-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 36, using (S)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3- c]pyridine (Intermediate 30) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 29). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃, 381.2; m/z found, 382.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ: 10.67 (s, 1H), 9.24 (s, 1H), 8.93 (s, 1H), 7.74 (s, 1H), 7.27 (s, 1H), 4.25-4.28 (m, 1H), 3.99-4.09 (m, 2H), 3.90 (d, J= 10.0 Hz, 1H), 3.14 (s, 3H), 2.70-2.75 (m, 1H), 2.64 (s, 3H), 2.50-2.56 (m, 1H), 2.47 (s, 3H), 2.16 (s, 3H).

Example 38 : (R)-N-( 1 -(4-(Difluoromethyl)-6-(3 -methoxytetrahydrofuran-3 -y l)pyridine-2-y l)-3 - methyl -1H-pyrazolo[4,3 -c]pyridine-6-yl)acetamide.

To a solution of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 31, 50 mg, 0.13 mmol) in 1,4-dioxane (1.5 mL) under N₂ was added acetamide (15 mg, 0.25 mmol), BrettPhos Pd G3 (23 mg, 0.025 mmol), and cesium carbonate (82.6 mg, 0.254 mmol), successively. The resulting solution was heated at 110 °C for 2 h. The reaction mixture was then cooled to 25 °C with an ice water bath. Purification by Flash-Prep-HPLC on a C 18 column (5-100% acetonitrile in water (0.05% ammonium bicarbonate)) and lyophilization afforded the title compound as a white solid (15.3 mg, 28%). MS (ESI): mass calcd. for C₂₀H₂₁F₂N₅O₃, 417.2; m/z found, 418.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.74 (s, 1H), 9.25 (d, J= 1.1 Hz, 1H), 8.95 (d, J= 1.1 Hz, 1H), 8.03 (d, J= 1.2 Hz, 1H), 7.55 (d, J= 1.2 Hz, 1H), 7.26 (s, 1H), 4.28 (dd, J= 9.7, 1.3 Hz, 1H), 4.19-3.97 (m, 2H), 3.93 (d, J= 9.7 Hz, 1H), 3.18 (s, 3H), 2.80 (dt, J= 13.3, 8.8 Hz, 1H), 2.65 (s, 3H), 2.63-2.52 (m, 1H), 2.17 (s, 3H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ -114.94.

Example 39: (S)-N-(1-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3- methyl- 1H-pyrazolo[4,3 -c]pyridine-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 38, using (S)-6- chloro- 1 -(4-(difluoromethyl)-6-(3 -methoxy tetrahy drofuran-3 -yl)pyri dine-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridine (Intermediate 32) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridine (Intermediate 31). MS (ESI): mass calcd. for C₂₀ H₂₁F₂N₅O₃, 417.2; m/z found, 418.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), 9.24 (s, 1H), 8.94 (d, J= 1.2 Hz, 1H), 8.02 (s, 1H), 7.55 (s, 1H), 7.39-7.12 (m, 1H), 4.29-4.27 (m, 1H), 4.12-4.02 (m, 2H), 3.94-3.91 (m, 1H), 3.18 (s, 3H), 2.81-2.78 (m, 1H), 2.65 (s, 3H), 2.51-2.50 (m, 1H), 2.16 (s, 3H). ¹⁹F NMR (300 MHz, DMSO- d₆): -114.9.

Example 40 : (R)-N-( 1 -(4-(2-Methoxy ethoxy )-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine-2-yl)- 3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (R)-6-chloro-1 -(4-(2- m ethoxy ethoxy )-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4,3 - c]pyridine (Intermediate 33) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 -c]pyridine (Intermediate 31) and THF instead of 1,4-dioxane. MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 9.23 (s, 1H), 8.91 (s, 1H), 7.38 (s, 1H), 6.95 (d, J = 2.0 Hz, 1H), 4.38-4.28 (m, 2H), 4.23 (dd, J = 9.7, 1.3 Hz, 1H), 4.12-3.95 (m, 2H), 3.89 (d, J= 9.7 Hz, 1H), 3.76-3.68 (m, 2H), 3.34 (s, 3H), 3.15 (s, 3H), 2.74 (dt, J= 13.3, 8.8 Hz, 1H), 2.63 (s, 3H), 2.53 (d, J= 8.3 Hz, 1H), 2.15 (s, 3H).

Example 41 : (S)-N-(1-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)- 3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (S)-6-chloro-1-(4-(2- methoxyethoxy)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4,3 - c]pyridine (Intermediate 34) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridine (Intermediate 31) and THF instead of 1,4-dioxane. MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.21 (d, J= 1.3 Hz, 1H), 8.90 (s, 1H), 7.37 (d, J= 2.2 Hz, 1H), 6.95 (d, J= 2.1 Hz, 1H), 4.35-4.28 (m, 2H), 4.23 (dd, J= 9.8, 1.4 Hz, 1H), 4.07 (m, 1H), 4.03-3.93 (m, 1H), 3.89 (d, J= 9.7 Hz, 1H), 3.75-3.69 (m, 2H), 3.34 (s, 3H), 3.15 (s, 3H), 2.78-2.66 (m, 1H), 2.62 (d, J= 1.6 Hz, 3H), 2.15 (s, 3H).

Example 42 : N-( 1 -(4-((R)-2-hydroxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.

Step A. N-(1-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6- yl)acetamide. The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using 1-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 35) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine (Intermediate 31). MS (ESI): mass calcd. for C₂₈H₄₁N₅O₅Si, 555.3; m/z found, 556.3 [M+H]⁺.

Step B. N-(1-(4-((R)-2-hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide. The title compound was prepared in a manner analogous to Example 11, Step B, using N-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.3 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 9.24 (s, 1H), 8.78 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.03 (d, J= 2.1 Hz, 1H), 4.29-4.02 (m, TH), 3.32-3.31 (m, 3H), 2.94-2.84 (m, 1H), 2.65-2.50 (m, 4H), 2.21 (s, 3H), 1.37-1.31 (m, 3H).

Example 43 : N-(1-(4-((R)-2-Hydroxypropoxy)-6-( (S)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.

Step A. N-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide. The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 100 °C instead of 110 °C, using 1-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-6-chloro-3 -methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 36) instead of (R)- 6-chl oro- 1 -(4-(difluoromethyl)-6-(3 -methoxytetrahy drofuran-3 -y l)pyridine-2-y l)-3 -methyl - 1H- pyrazolo[4,3-c]pyridine (Intermediate 31). MS (ESI): mass calcd. for C₂₈H₄₁N₅O₅Si, 555.3; m/z found, 556.3 [M+H]⁺. Step B. N-(1-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 -c]pyridine-6-yl)acetamide. The title compound was prepared in a manner analogous to Example 11, Step B, using N-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₂H₂₇N₅O₅, 441.2; m/z found, 442.2 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 9.21 (s, 1H), 8.75 (d, J= 0.6 Hz, 1H), 7.45 (d, J= 2.1 Hz, 1H), 7.01 (d, J= 2.1 Hz, 1H), 4.29-4.02 (m, TH), 3.32- 3.31 (m, 3H), 2.92-2.83 (m, 1H), 2.65-2.50 (m, 4H), 2.21 (s, 3H), 1.37-1.31 (m, 3H).

Example 44 : (S)-N-( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- pyrazolo[4,3-c]pyridine-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 36, using (S)-6- chloro- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H-pyrazolo[4,3 -c]pyridine (Intermediate 72) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 29). Also obtained from this reaction mixture was Example 45. MS (ESI): mass calcd. for C₁₉H₂₁N₅O₃, 367.2; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.68 (s, 1H), 9.28 (s, 1H), 8.94 (s, 1H), 8.53 (s, 1H ), 7.79 (s, 1H), 7.31 (s, 1H), 4.25 - 4.28 (m, 1H), 3.99- 4.07 (m, 2H), 3.89 - 3.92 (m, 1H), 3.14 (s, 3H), 2.72 - 2.75 (m, 1H), 2.50 - 2.51 (m, 1H), 2.47 (s, 3H), 2.15 (s, 3H).

Example 45 : (S)-N-(3-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H- pyrazolo[4,3-c]pyridine-6-yl)acetamide.

The title compound was obtained from the reaction described in Example 44. MS (ESI): mass calcd. for C₁₉H₂₁N₅O₃, 367.2; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 8: 10.67 (s, 1H), 9.53 (s, 1H), 8.58 (s, 1H), 8.50 (s, 1H ), 7.01 (s, 1H), 6.93 (s, 1H), 3.93 - 3.97 (m, 1H), 3.82- 3.86 (m, 3H), 3.08 (s, 3H), 2.49 - 2.51 (m, 1H), 2.33 (s, 3H), 2.18 - 2.29 (m, 1H), 2.09 (s, 3H).

Example 46 : (S)-N-(1-(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrrolo[3,2-c]pyridine-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 36, using (S)-6- chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrrolo[3,2- c]pyridine (Intermediate 42) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 29). MS (ESI): mass calcd. for C₂₁H₂₄N₄O₃, 380.2; m/z found, 381.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.05 (s, 1H), 8.60 (s, 1H), 7.81 (s, 1H ), 7.49 (s, 1H), 7.28 (s, 1H), 4.19 - 4.22 (m, 1H), 3.91- 4.04 (m, 3H), 3.15 (s, 3H), 2.64 - 2.72 (m, 1H), 2.43 - 2.48 (m, 4H), 2.34 (s, 3H), 2.11 (s, 3H).

Example 47 : (R)-N-(5-(6-(3 -Methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-7-(1 -methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)acetamide.

To a solution of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1- methyl-1H-pyrazol -4-yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 55, 100 mg, 0.25 mmol) in DCM (5 mL) was added pyridine (58.7 mg, 0.742 mmol) and acetyl chloride (21.3 mg, 0.272 mmol) at room temperature. The mixture was stirred for 2 h and the solvent was removed under vacuum. Purification by reverse-phase preparative HPLC on a C 18 column (22-52% MeCN in 10 mM NH₄HCO₃ (aq.)) provided the title compound as a yellow solid (38.4 mg, 34% yield). MS(ESI): mass calcd. for C₂₄H₂₆N₆O₃, 446.2; m/z found, 447.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₃) δ: 10.35 (s, 1H), 9.01 - 9.06 (m, 2H), 8.30 (s, 1H), 7.92 (s, 1H ), 7.54 (s, 2H), 7.07 (s, 1H), 4.21 - 4.25 (m, 1H), 3.88 - 4.05 (m, 6H), 3.11 (s, 3H), 2.71- 2.81 (m, 1H), 2.41 - 2.48 (m, 1H), 2.38 (s, 3H), 2.12 (s, 3H).

Example 48: (S)-N-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-rnethylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)acetamide.

The title compound was prepared in a manner analogous to Example 47, using (S)-5-(6- (3 -methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4- yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 56) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₄H₂₆N₆O₃, 446.2; m/z found, 447.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₃) δ 10.36 (s, 1H), 9.02 - 9.06 (m, 2H), 8.30 (s, 1H), 7.93 (s, 1H), 7.54 - 7.55 (m, 2H), 7.08 (s, 1H), 4.23 - 4.25 (m, 1H), 4.02 - 4.05 (m, 2H), 3.90 - 4.00 (m, 4H), 3.12 (s, 3H), 2.75 - 2.78 (m, 1H), 2.48 - 2.49 (m, 1H), 2.38 (s, 3H), 2.38 (s, 3H), 2.13 (s, 3H).

Example 49: (S)-N-(5-(6-(3-MethoxytetrahydrofLiran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3 -yl)acetamide.

The title compound was prepared in a manner analogous to Example 47, using (S)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3-amine (Intermediate 60) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4-yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₁H₂₄N₄O₃, 380.1; m/z found, 381.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H), 7.02 (s, 1H), 4.19 - 4.22 (m, 1H), 3.96 - 4.04 (m, 2H), 3.88 (d, J= 10.0 Hz, 1H), 3.10 (s, 3H), 2.65 - 2.79 (m, 1H), 2.54 (s, 3H), 2.42 - 2.50 (m, 1H), 2.35 (s, 3H), 2.10 (s, 3H).

Example 50: (R)-N-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1 ,2-c]pyrimidin-3 -yl)acetamide.

The title compound was prepared in a manner analogous to Example 47, using (R)-5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 63) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55) and triethylamine instead of pyridine. MS (ESI): mass calcd. for C₂₁H₂₂F₂N₄O₃, 416.2; m/z found, 417.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.05 - 8.85 (m, 2H), 7.70 (s, 1H), 7.37-7.19 (m, 2H), 7.27-6.90 (m, 1H), 4.23 (d, J= 9.7 Hz, 1H), 4.13-3.84 (m, 3H), 3.13 (s, 3H), 2.87-2.73 (m, 2H), 2.55 (s, 3H), 2.11 (s, 3H). 1⁹F NMR (300 MHz, DMSO-d₆) δ -114.414.

Example 51 : (S)-N-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[ 1 ,2-c]pyrimidin-3-yl)acetamide.

The title compound was prepared in a manner analogous to Example 47, using (S)-5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 64) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4-yl)pyrrolo[1 ,2-c]pyrimidin-3 -amine (Intermediate 55) and triethylamine instead of pyridine. MS (ESI): mass calcd. for C₂₁H₂₂F₂N₄O₃, 416.2; m/z found, 417.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.99 (s, 1H), 8.71 (d, J= 1.2 Hz, 1H), 7.63 (d, J= 0.8 Hz, 1H), 7.34 (s, 1H), 7.13 (d, J= 0.8 Hz, 1H), 6.97- 6.70 (m, 1H), 4.31-4.28 (m, 1H), 4.27-4.24 (m, 1H), 4.23-4.21 (m, 1H), 4.20-4.12 (m, 1H), 3.24 (s, 3H), 2.96-2.89 (m, 1H), 2.59-2.54 (m, 4H), 2.18 (s, 3H). ¹⁹FNMR (400 MHz, CD₃OD): - 116.633.

Example 52: (R)-N-(5-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.

The title compound was prepared in a manner analogous to Example 47, using (R)-5-(4- (2-methoxyethoxy )-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 65) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 55) and triethylamine instead of pyridine. MS (ESI): mass calcd. for C₂₃H₂₈N₄O₅, 440.2; m/z found, 441.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.96 (s, 1H), 8.88 (d, J= 1.5 Hz, 1H), 7.24 (d, J= 1.0 Hz, 1H), 7.14 (d, J= 2.3 Hz, 1H), 6.74 (d, J= 2.2 Hz, 1H), 4.32-4.23 (m, 2H), 4.18 (dd, J= 9.7, 1.2 Hz, 1H), 4.07- 3.92 (m, 2H), 3.87 (d, J= 9.7 Hz, 1H), 3.75-3.67 (m, 2H), 3.32 (s, 3H), 3.11 (s, 3H), 2.82-2.73 (m, 1H), 2.54 (s, 3H), 2.43 (ddd, J= 12.6, 6.7, 4.8 Hz, 1H), 2.10 (s, 3H).

Example 53 : (S)-N-(5-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[ 1 ,2-c]pyrimidin-3 -yl)acetamide.

The title compound was prepared in a manner analogous to Example 47, using (S)-5-(4- (2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 66) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 55) and triethylamine instead of pyridine. MS (ESI): mass calcd. for C₂₃H₂₈N₄O₅, 440.2; m/z found, 441.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.96 (d, J=

1.5 Hz, 1H), 8.88 (d, J= 1.5 Hz, 1H), 7.24 (d, J= 1.1 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.74 (d, J= 2.2 Hz, 1H), 4.30 - 4.23 (m, 2H), 4.18 (dd, J= 9.7, 1.3 Hz, 1H), 4.03 (m, 2H), 3.87 (d, J=

9.6 Hz, 1H), 3.73 - 3.67 (m, 2H), 3.33 (s, 3H), 3.11 (s, 3H), 2.76 (dt, J= 13.2, 8.8 Hz, 1H), 2.54 (d, J= 1.0 Hz, 3H), 2.47 - 2.38(m, 1H), 2.10 (s, 3H).

Example 54 : N-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridin-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.

Step A. N-(5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide. The title compound was prepared in a manner analogous to Example 47, using 5-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 67) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55) and triethylamine instead of pyridine. MS (ESI): mass calcd. for C₂₉H₄₂N₄O₅Si, 554.3; m/z found, 555.2[M+H]⁺.

Step B. N-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide. The title compound was prepared in a manner analogous to Example 11, Step B, using N-(5-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₃H₂₈N₄O₅, 440.2; m/z found, 441.2. ¹H NMR (300 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.95 (s, 1H), 8.87 (s, 1H), 7.31 - 7.02 (m, 2H), 6.73 (d, J= 2.2 Hz, 1H), 4.92 (s, 1H), 4.17 (d, J= 9.6 Hz, 1H), 4.10 - 3.82 (m, 6H), 3.11 (s, 3H), 2.76 (dt, J= 13.0, 8.7 Hz, 1H), 2.54 (s, 3H), 2.43 (dd, J= 12.5, 6.2 Hz, 1H), 2.10 (s, 3H), 1.18 (d, J= 5.4 Hz, 3H).

Example 55 : N-(5-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.

Step A. N-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide. The title compound was prepared in a manner analogous to Example 47, using 5-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 68) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-7-( 1 -methyl- 1 H-pyrazol -4-y l)pyrrolo[ 1,2- c]pyrimidin-3 -amine (Intermediate 55) and triethylamine instead of pyridine. MS (ESI): mass calcd. for C₂₉H₄₂N₄O₅Si, 554.3; m/z found, 555.2 [M+H]⁺.

Step B. N-(5-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide. The title compound was prepared in a manner analogous to Example 11, Step B, using N-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₃H₂₈N₄O₅, 440.2; m/z found, 441.2 [M+H]^{+ 1}H NMR (300 MHz, DMSO-d₆) δ: 10.29 (s, 1H), 8.97-8.89 (m, 2H), 7.26 (s, 1H), 7.13 (d, J= 2.1 Hz, 1H), 6.74 (d, J= 2.1 Hz, 1H), 4.95 (d, J= 4.5 Hz, 1H), 4.21-4.18 (m, 1H), 4.02-3.97 (m, 5H), 3.90-3.87 (m, 1H), 3.13 (s, 3H), 2.75-2.70 (m, 1H), 2.55-2.52 (m, 3H), 2.48-2.46 (m, 1H), 2.12 (s, 3H), 1.19 (d, J= 5.7 Hz, 3H).

Example 56 : (S)-N-( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2 -yl)-1H- pyrrolo[3,2-c]pyridin-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 36, using (S)-6- chloro- 1 -(6-(3 -methoxy -tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1 H-pyrrolo[3 ,2-c]pyridine (Intermediate 73) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methyIpyridin-2-yl)-3 -methyl -1H-pyrazolo [4, 3 -c] pyridine (Intermediate 29). MS (ESI): mass calcd. for C₂₀H₂₂N₄O₃, 366.2; m/z found, 367.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.05 (s, 1H), 8.63 (s, 1H), 8.01 (d, J= 4.4 Hz, 1H), 7.55 (s, 1H), 7.32 (s, 1H), 6.82 (s, 1H), 4.19-4.21 (m, 1H), 3.91-4.00 (m, 3H), 3.14 (s, 3H), 2.63-2.72 (m, 1H), 2.46-2.50 (m, 4H), 2.10 (s, 3H).

Example 57 : (S)-N-( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl-2- oxo-2, 3 -dihydro- 1H-imidazo[4, 5-c]pyridin-6-yl)acetamide.

To a solution of (S)-77-(4-((6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)amino)-5-(methylamino)pyridin-2-yl)acetamide (Intermediate 74, 100 mg, 0.27 mmol) in THF (10 mL) at 0 °C under N₂ was added DIPEA (87 mg, 0.67 mmol) dropwise, followed by the addition of a solution of triphosgene (32 mg, 0.11 mmol) in THF (2 mL). The resulting mixture was warmed to room temperature, stirred for 1.5 h at room temperature, and the solvent was removed under vacuum. Purification by reverse-phase preparative HPLC on a C18 column (21- 30% ACN in 10 mM NH₄HCO₃ (aq.)) afforded the title compound as a white solid (27.3 mg, 25%). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₄, 397.2; m/z found, 398.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ: 10.40 (s, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 7.77 (s, 1H ), 7.39 (s, 1H), 4.14 - 4.17 (m, 1H), 3.87 - 3.97 (m, 3H), 3.43 (s, 3H), 3.13 (s, 3H), 2.58 - 2.69 (m, 2H), 2.46 (s, 3H), 2.07 (s, 3H).

Example 58: (S)-N-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methyl-7H- pyrrolo[2,3 -c]pyridazin-3 -yl)acetamide.

The title compound was prepared in a manner analogous to Example 36, using (S)-3- chloro-5-(6-(3 -methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-7-methyl-7H-pyrrolo[2, 3 - c]pyridazine (Intermediate 76) instead of (R)-6-chloro-1-(6-(3 -methoxy tetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 29). MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃: 381.2, found: 382.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO -d₆) δ 10.90 (s, 1H), 9.30 (s, 1H), 8.64 (s, 1H), 7.61 (s, 1H), 7.17 (s, 1H), 4.17 - 4.20 (m, 1H), 3.95 - 4.09 (m, 5H), 3.89 (d, J= 9.6 Hz, 1H), 3.10 (s, 3H),

Example 59: (S)-N-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H- imidazo[4,5-c]pyridin-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 36, using (S)-6- chloro- 1 -(6-(3 -methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H-imidazo[4,5-c]pyridine (Intermediate 77) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methyIpyridin-2-y l)-3 -methyl -1H-py razolo [4, 3 -c] pyridine (Intermediate 29). MS (ESI): mass calcd. for C₁₉H₂₁N₅O₃, 367.2; m/z found, 368.4 [M+H]⁺. ¹HNMR (300 MHz, Methanol-d₄ ) δ 8.99 (s, 1H), 8.87 (s, 1H), 8.71 (s, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 4.23 - 4.27 (m, 1H), 4.04 - 4.16 (m, 3H), 3.23 (s, 3H), 2.71 - 2.82 (m, 1H), 2.49 - 2.57 (m, 4H), 2.20 (s, 3H).

Example 60: (R)-1-(1-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3- (methyl-d₃ )- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro- 1 -(4-(2-methoxy ethoxy )-6-(3 -methoxy tetrahy drofuran-3 -yl)pyri din-2-y l)-3 -(methyl-d₃ )- 1H-pyrazolo[4,3-c]pyridine (Intermediate 79) instead of (R)-6-chloro-1-(6-(3- methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo [4, 3 -c] pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₁H₂₃D₃N₆O₅, 445.2; m/z found, 446.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.80 (s, 2H), 7.33 (s, 1H), 6.92 (s, 1H), 6.53 (s, 2H), 4.30-4.23 (m, 3H), 4.09-3.87 (m, 3H), 3.72 (s, 2H), 3.35 (s, 3H), 3.16 (s, 3H), 2.74-2.63 (m, 1H), 2.54-2.27 (m, 1H). Example 61 : (R)-1-(3-Cyclopropyl-1-(4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro-3 -cyclopropyl- 1 -(4-(2-methoxyethoxy)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)- 1H-pyrazolo[4,3-c]pyridine (Intermediate 81) instead of (R)-6-chloro-1 -(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₃H₂₈N₆O₅, 468.2; m/z found, 469.1. ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 7.31 (d, J= 1.8Hz, 1H), 6.92 (d, J= 1.8Hz, 1H), 6.50 (s, 2H), 4.32-4.22 (m, 3H), 4.07-3.86 (m, 3H), 3.73-3.70 (m, 2H), 3.34 (s, 3H), 3.13 (s, 3H), 2.73-2.63 (m, 1H), 2.50-2.41 (m, 2H), 1.21-1.05 (m, 4H).

Example 62 : (R)- 1 -( 1 -(4-(2 -Methoxyethoxy )-6-(3 -methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3- (trifluoromethyl)-1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro- 1 -(4-(2-methoxyethoxy)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 - (trifluoromethyl)- 1H-pyrazolo[4,3-c]pyridine (Intermediate 83) instead of (R)-6-chloro-1 -(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₆O₅, 496.2; m/z found, 497.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 9.03 (s, 1H), 8.95 (s, 1H), 7.40 (s, 1H), 7.09 (s, 1H), 6.48 (s, 2H), 4.36 (d, J = 4.0 Hz, 2H), 4.24 (d, J = 9.6 Hz, 1H), 4.06-3.89 (m, 3H), 3.72 (d, J= 4.0 Hz, 2H), 3.31 (s, 3H), 3.15 (s, 3H), 2.70-2.65 (m, 1H), 2.60-2.50 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ-60.36.

Example 63 : (R)- 1 -( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyri din-2-yl)- 3 -(trifluoromethyl)- 1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)-3- (trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 84) instead of (R) -6 -chloro-1 -(6 -(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₃F₃N₆O₅, 508.2; m/z found, 509.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 9.04 (s, 1H), 8.96 (s, 1H), 7.42 (d, J= 2.0 Hz, 1H), 7.11 (d, J= 2.1 Hz, 1H), 6.48 (s, 2H), 4.75-4.72 (m, 2H), 4.52-4.47 (m, 4H), 4.25 (d, J= 9.6 Hz, 1H), 4.07-3.90 (m, 3H), 3.47-3.44 (m, 1H), 3.17 (s, 3H), 2.71-2.68 (m, 1H), 2.57-2.50 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ-60.34.

Example 64 : (R)- 1 -(3 -(Isoxazol-3 -yl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2- yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1 , using (R)-3-(6- chloro- 1 -(6-(3 -methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H-pyrazolo[4,3 -c]pyridin-

3-yl)isoxazole (Intermediate 86) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-

4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₁H₂₁N₇O₄, 435.2; m/z found: 436.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 1H), 9.23 (s, 1H), 9.17 (s, 1H), 9.01 (s, 1H), 7.88 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.50 (s, 2H), 4.28 - 4.31 (m, 1H), 3.91 - 4.08 (m, 3H), 3.15 (s, 3H), 2.66 - 2.76 (m, 1H), 2.50 - 2.60 (s, 4H).

Example 65 : (R)- 1 -(3 -(3 -Hydroxycyclobutyl)- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)- 1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1 Step B, using R)- 1 -(3 -(3 -hydroxy cyclobutyl)- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea (Intermediate 89) instead of (R)-1-(4- methoxybenzyl)-3 -( 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3-( 1 -methyl - 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 1, Step A). MS (ESI): mass calcd. for C₂₂H₂₆N₆O₄: 438.2; m/z found: 439.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.82 - 8.88 (m, 2H), 7.72 - 7.75 (m, 1H), 7.26 (s, 1H), 6.51 (s, 2H), 5.26 (d, J= 7.2 Hz, 1H), 4.26 - 4.29 (m, 2H), 3.99 - 4.21 (m, 2H), 3.89 - 3.97 (m, 1H), 3.34 - 3.37 (m, 1H), 3.13 (s, 3H), 2.72 - 2.79 (m, 2H), 2.65 - 2.70 (m, 1H), 2.50 - 2.56 (m, 1H), 2.47 (s, 3H), 2.29 - 2.33 (m, 2H).

Example 66 : (R)- 1 -(3 -(3 -Cyanocyclobutyl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4- methylpyridin-2 -yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1 Step B, using (R)- 1-(3-(3-cyanocyclobutyl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea (Intermediate 90) instead of (R)-1-(4- methoxybenzyl)-3-(1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 1, Step A). MS (ESI): mass calcd. for C₂₃H₂₅N₇O₃: 447.2; m/z found: 448.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.83 - 8.84 (m, 2H), 7.77 (s, 1H), 7.26 (s, 1H), 6.50 (s, 2H), 4.25 - 4.30 (m, 2H), 3.96 - 4.05 (m, 2H), 3.89 (d, J= 10.0 Hz, 1H), 3.56 - 3.58 (m, 1H), 3.12 (s, 3H), 2.83 - 2.87 (m, 4H), 2.66 - 2.69 (m, 1H), 2.54 - 2.58 (m, 1H), 2.47 (s, 3H).

Example 67: (S)-1-(3-(3-Cyanocyclobutyl)-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)- 1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1 Step B, using (S)- 1 -(3 -(3 -cyanocyclobutyl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea (Intermediate 93) instead of (R)-1-(4- methoxybenzyl)-3-(1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 1, Step A). MS (ESI): mass calcd. for C₂₃H₂₅N₇O₃: 447.2; m/z found: 448.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.84 (s, 2H), 7.77 (s, 1H), 7.27 (s, 1H), 6.51 (s, 2H), 4.24 - 4.29 (m, 2H), 3.87 - 4.07 (m, 3H), 3.56 - 3.60 (m, 1H), 3.12 (s, 3H), 2.81 - 2.88 (m, 4H), 2.63 - 2.73 (m, 1H), 2.50 - 2.57 (m, 1H), 2.47 (s, 3H).

Example 68 : (S)-3 -( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-6-ureido- 1H- pyrazolo[4,3-c]pyridin-3-yl)cyclobutane- 1 -carboxamide.

The title compound was obtained from the reaction described in Example 67. MS (ESI): mass calcd. for C₂₃H₂₇N₇O₄: 465.2; m/z found: 466.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.79 - 8.84 (m, 2H), 7.76 (s, 1H), 7.26 - 7.29 (m, 2H), 6.84 (s, 1H), 6.52 (s, 2H), 4.27 - 4.29 (m, 1H), 3.89 - 4.07 (m, 4H), 3.17 - 3.25 (m, 1H), 3.13 (s, 3H), 2.65 - 2.72 (m, 3H), 2.58 - 2.62 (m, 3H), 2.48 (s, 3H).

Example 69 : (R)- 1 -(1 -(6-(3 -Ethoxytetrahydrofuran-3 -yl)-4-methylpyri din-2 -yl)-3 -methyl- 1H- pyrazolo[4,3 -c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6- chloro- 1 -(6-(3 -ethoxytetrahy drofuran-3 -y l)-4-methylpyridin-2-y l)-3 -methyl- 1H-pyrazolo[4,3 - c]pyridine (Intermediate 95) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methy lpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)- 1H-pyrazolo[4,3 -c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₀H₂₄N₆O₃, 396.2; m/z found, 397.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.08 (s, 2H), 7.69 (s, 1H), 7.24 (s, 1H), 6.51 (s, 2H), 4.20 (d, J= 9.0Hz, 1H), 4.08-4.95 (m, 2H), 3.87 (d, J= 9.6Hz, 1H), 3.40-3.35 (m, 1H), 3.28-3.25 (m, 1H), 2.77-2.63 (m, 5H), 2.51 (s, 3H), 1.15-1.05 (m, 3H).

Example 70 : (*S)- 1 -( 1 -(6-(3 -Methoxytetrahydro-2H-pyran-3-yl)-4-(oxetan-3 -ylmethoxy)pyridin- 2-yl)-3 -methyl -1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.

Step A. (R,S)-1-(1-(6-(3-Methoxytetrahydro-2H-pyran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. The title compound was prepared in a manner analogous to Example 1, using 6-chloro-1 -(6-(3 -methoxytetrahydro- 2H- pyran-3-yl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 97) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A.

Step B. (*S)-1-(1-(6-(3-Methoxytetrahydro-2H-pyran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. The enantiomers of (R,S)- 1 -( 1 -(6-(3 -methoxy tetrahy dro-2H-pyran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-y l)-3 - methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea were separated by Prep-chiral -HPLC using a chiral HPLC column, such as a CHIRALPAK IG-3, 4.6 x 50 mm, 3 um, eluting with an isocratic mobile phase of 80:20 (3:1 n-hexane:DCM containing 0.1% DEA):IPA, yielding as a first eluting enantiomer, (*S)-1-(1-(6-(3 -methoxy tetrahy dro-2H-pyran-3 -yl)-4-(oxetan-3 - ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea and as a second eluting enantiomer (*R)- 1 -( 1 -(6-(3 -methoxytetrahy dro-2H-pyran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (Example 71). The fractions containing (*S)- 1 -(1 -(6-(3 -methoxytetrahydro-2H-pyran-3 -y l)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)-3 - methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea were collected and concentrated under reduced pressure to afford the title compound as a white solid (55.1 mg, 17%). R_t=2.79 min. MS (ESI): mass calcd. for C₂₃H₂₈N₆O₅, 468.2; m/z found, 469.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.87 (s, 1H), 8.79 (s, 1H), 7.33 (s, 1H), 6.92 (s, 1H), 6.45 (s, 2H), 4.75-4.70 (m, 2H), 4.50-4.39 (m, 4H), 3.95 (s, 2H), 3.83-3.69 (m, 2H), 3.65-3.41 (m, 1H), 3.16 (s, 3H), 2.59 (s, 3H), 2.40-2.31 (m, 1H), 2.12-2.03 (m, 1H), 2.00-1.80 (m, 1H), 1.60-1.45 (m, 1H).

Example 71 : (*R)- 1 -(1 -(6-(3 -Methoxytetrahydro-2H-pyran-3 -yl)-4-(oxetan-3 - ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The chiral separation described for Example 70 provided (*R)- 1-(1-(6-(3- methoxytetrahydro-2H-pyran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridin-6-yl)urea as a white solid (55.1 mg, 18%). R_t=3.80 min. MS (ESI): mass calcd. for C₂₃H₂₈N₆O₅, 468.2; m/z found, 469.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.87 (s, 1H), 8.79 (s, 1H), 7.32 (d, J= 2.1 Hz, 1H), 6.92 (d, J= 2.1 Hz, 1H), 6.45 (s, 2H), 4.75-4.70 (m, 2H), 4.50-4.39 (m, 4H), 3.95 (s, 2H), 3.90-3.65 (m, 2H), 3.51-3.42 (m, 1H), 3.16 (s, 3H), 2.59 (s, 3H), 2.39-2.33 (m, 1H), 2.04 -1.83(m, 2H), 1.60-1.40 (m, 1H).

Example 72 : (*R)- 1 -(1 -(4-( 1 , 1 -Difluoroethyl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 - methyl- 1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.

Step A. (R,S)-1-(1-(4-(1,1-Difluoroethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. The title compound was prepared in a manner analogous to Example 1, using 6-chloro-1-(4-(1,1-difluoroethyl)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 99) instead of (R)-6-chloro- 1-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A.

Step B . (*R)- 1 -( 1 -(4-(l , 1 -Difluoroethyl)-6-(3 -methoxy tetrahydrofuran-3 -yl)pyridin-2-yl)- 3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. The enantiomers of (R,S)-1-(1-(4-(1,1- difluoroethyl)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 - c]pyridin-6-yl)urea were separated by SFC utilizing a SFC column, such as a CHIRAL ART Cellulose-SB 4.6 x 100 mm, 3 μm column eluting with an isocratic mobile phase of 50% MeOH (containing 0.1% DEA) in CO₂ yielding as a first eluting enantiomer, (*R)-1-(1-(4-(1,1- difluoroethyl)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3 -methyl- 1H-pyrazolo[4,3 - c]pyridin-6-yl)urea and as a second eluting enantiomer, (*S)-1-(1-(4-(1,1-difluoroethyl)-6-(3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (Example 73). The fractions containing (*R)-1-(1-(4-(1,1-difluoroethyl)-6-(3- methoxytetr ahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea were collected and concentrated under reduced pressure to afford the title compound as a white solid (55 mg, 29%). SFC R_t = 1.92 min. MS (ESI): mass calcd. for C₂₀H₂₂F₂N₆O₃: 432.17; m/z found, 433.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.86-8.85 (m, 2H), 7.96 (s, 1H), 7.50 (s, 1H), 6.52 (s, 2H), 4.33-4.30 (m, 1H), 4.14-3.92 (m, 3H), 3.18 (s, 3H), 2.80-2.70 (m, 1H), 2.63-2.5 (m, 4H), 2.08 (t, J= 19.3 Hz, 3H).

Example 73 : (*S)- 1 -( 1 -(4-( 1 , 1 -Difluoroethyl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 - methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The chiral separation described for Example 72 provided (*S)-1-(1-(4-(1,1- difluoroethyl)-6-(3-methoxytetrahydrofuran-3 -yl )pyridin-2-y l)-3 -methyl -1H-pyrazolo[4,3 - c]pyridin-6-yl)urea (50.4 mg, 28%) as a white solid. R_t = 2.03 min. MS (ESI): mass calcd. for C₂₀H₂₂F₂N₆O₃. 432.2; m/z found, 433.1 [M+H]⁺.

Example 74 : (*R)- 1 -(1 -(4-(4-Hy droxypi peridin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin- 2-yl)-3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea.

Step A. 1-(1-(4-(4-(Benzyloxy)piperidin-1-yl)-6-(3 -methoxytetrahydrofuran-3 - yl)pyridin-2-yl)-3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea. The title compound was prepared in a manner analogous to Example 1, using 1-(4-(4-(benzyloxy)piperidin-1-yl)-6-(3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-6-chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 101) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3 -c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₃₀H35N₇O₄: 557.3; m/z found, 558.3 [M+H]⁺.

Step B . 1 -( 1 -(4-(4-Hydroxypiperidin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. To a solution of 1-(1-(4-(4- (benzyloxy)piperidin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 -methyl- 172- pyrazolo[4,3-c]pyridin-6-yl)urea (0.3 g, 0.538 mmol) in DCM (9 mL) was added BCh (1 M in dichloromethane, 2.1 m1, 2.1 mmol) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred for 1 h at -78 °C. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phase was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC utilizing a C 18 silica gel column eluting with 10-100% acetonitrile in H₂O (0.05% NH₄HCO₃) afforded 150 mg of the title compound as a white solid.

Step C . (*R)-1-( 1 -(4-(4-Hy droxypiperidin- 1 -yl)-6-(3 -methoxytetrahy drofuran-3 - yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. The enantiomers of (R,S)-1-(1- (4-(4-hy droxypiperidin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridin-6-yl)urea were separated by chiral HPLC using a chiral HPLC column, such as a CHIRALPAK IG-3, 4.6x50 mm, 3 um column (isocratic elution: 70:30 tert-butyl methyl ether (containing 0.1% N,N-diethylaniline): EtOH) yielding as a first eluting enantiomer (*R)- 1 -( 1 -(4-(4-hydroxypiperidin- 1 -yl)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3 - methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea and as a second eluting enantiomer, (*S)-1-(1-(4-(4- hy droxypiperidin- 1 -yl)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridin-6-yl)urea (Example 75). The fractions containing (*R)- 1-(1-(4-(4- hydroxypiperidin-1-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H- pyrazolo[4,3-c]pyridin-6-yl)urea were collected and concentrated under reduced pressure to afford the title compound as a white solid (59 mg, 23%). R_t=1.29 min. MS (ESI): mass calcd. for C₂₃H₂₉N₇O₄: 467.2; m/z found, 468.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.76 (d, J= 4.8 Hz, 2H), 7.20 (s, 1H), 6.83 (s, 1H), 6.53 (s, 2H), 4.76 (d, J= 3.9 Hz, 1H), 4.21 (d, J= 9.6 Hz, 1H), 4.05-3.68 (m, 6H), 3.19-3.13 (m, 5H), 2.72-2.62 (m, 1H), 2.59 (s, 3H), 2.47- 2.42 (m, 1H), 1.86-1.83 (m, 2H), 1.53-1.404 (m, 2H). Example 75: (*S)-1-(1-(4-(4-Hydroxypiperidin-1-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The chiral separation described for Example 74 provided (*S)- 1 -( 1-(4-(4- hydroxypiperidin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridin-6-yl)urea (58 mg, 22%) as a white solid. R_t=2.42 min MS (ESI): mass calcd. for C₂₃H₂₉N₇O₄: 467.2; m/z found, 468.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.76 (d, J= 3.0 Hz, 2H), 7.19 (s, 1H), 6.83 (s, 1H), 6.53 (s, 2H), 4.77 (d, J= 4.2 Hz, 1H), 4.21 (d, J= 9.9 Hz, 1H), 4.05-3.68 (m, 6H), 3.19-3.13 (m, 5H), 2.72-2.62 (m, 2H), 2.59 (s, 3H), 1.86-1.83 (m, 2H), 1.53-1.34 (m, 2H).

Example 76: 1-(1 -(6-(3 -Methoxy- 1,1 -dioxidotetrahydrothiophen-3 -yl)-4-methylpyridin-2-yl)-3 - methyl-1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using 3-(6-(6- chloro-3-methyl-1H-pyrazolo[4, 3-c]pyridin-1 -yl)-4-methylpyridin-2-yl)-3- methoxytetrahydrothiophene 1,1-dioxide (Intermediate 103) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -( 1 -methyl- 1 H-pyrazol -4-yl)-1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₁₉H₂₂N₆O₄S: 430.1; m/z found, 431.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.82 (s, 1H), 8.70 (s, 1H), 7.75 (s, 1H), 7.34 (s, 1H), 6.66 (s, 2H), 4.08-4.04 (m, 1H), 3.62 (d, J= 14.0 Hz, 1H), 3.41-3.32 (m, 2H), 3.09 (s, 3H), 3.06-3.02 (m, 1H), 2.76-2.67 (m, 1H), 2.60 (s, 3H), 2.51- 2.50 (m, 3H).

Example 77 : 1 -( 1 -(6-(3 -Methoxy- 1 -oxidotetrahydrothiophen-3 -yl)-4-methylpyridin-2-yl)-3 - methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using 3-(6-(6- chloro-3-methyl-1H-pyrazolo[4,3 -c]pyridin- 1 -yl)-4-methylpyridin-2-yl)-3 - methoxytetrahydrothiophene 1 -oxide (Intermediate 105) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl-1H-pyrazol -4-yl)- 1 H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₁₉H₂₂N₆O₃S: 414.2; m/z found, 415.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.28-9.14 (m, 1H), 8.80- 8.73 (m, 2H), 7.71-7.68 (m, 1H), 7.33-7.30 (m, 1H), 6.79 (s, 1H), 6.59 (s, 1H), 4.34-3.78 (m, 1H), 3.73-3.32 (m, 1H), 3.21-2.93 (m, 6H), 2.86-2.80 (m, 1H), 2.59 (s, 3H), 2.47 (s, 3H).

Example 78: 1-(1 -(6-(3-Methoxytetrahydrofuran-3-yl)-4-(piperidin-1-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using 6-chloro-1- (6-(3 -methoxytetrahy drofuran-3 -yl)-4-(piperidin- 1 -yl)pyridin-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 - c]pyridine (Intermediate 107) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₃H₂₉N₇O₃: 451.2; m/z found, 452.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.85 (s, 1H), 8.69 (s, 1H), 7.19 (s, 1H), 6.83 (s, 1H), 6.65 (hr s, 2H), 4.24 (d, J= 9.6 Hz, 1H), 3.92 - 4.05 (m, 2H), 3.87 (d, J= 9.6 Hz, 1H), 3.35 - 3.44 (m, 4H), 3.13 (s, 3H), 2.59 - 2.73 (m, 5H), 1.55 - 1.62 (m, 6H).

Example 79 : 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)-

3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy )pyridin-2-yl)-3 -methyl-1H-pyrazolo[4, 3 - c]pyridine (Intermediate 37) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 -c]pyridine (Intermediate 31), and THF instead of 1,4-dioxane. MS (ESI): mass calcd. for C₂₃H₂₇N₅O₅, 453.2; m/z found, 454.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.66 (s, 1H), 9.23 (d, J= 0.6 Hz, 1H), 8.92 (d, J= 0.6 Hz, 1H), 7.41 (d, J= 2.1 Hz, 1H), 6.97 (d, J= 2.2 Hz, 1H), 4.76 - 4.71 ( m, 2H), 4.52 - 4.43 (m, 4H), 4.25 - 4.23 (m, 1H), 4.14 - 3.95 (m, 2H), 3.91 - 3.88 (m, 1H), 3.48 - 3.43 (m, 1H), 3.16 (s, 3H), 2.83 - 2.67 (m, 1H), 2.64 (s, 3H), 2.54 (s, 1H), 2.16 (s, 3H).

Example 80 : (R)-N-( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)- 3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)acetamide-2,2,2-d₃.

The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3- c]pyridine (Intermediate 37) instead of (R)-6-chl oro-1 -(4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 31), acetamide-2,2,2-d₃ (Intermediate 108) instead of acetamide and THF instead of 1, 4- dioxane. MS (ESI): mass calcd. for C₂₃H₂₄D₃N₅O₅, 456.2; m/z found, 457.3 [M+H]⁺. NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 9.23 (d, J= 0.8 Hz, 1H), 8.92 (d, J= 0.8 Hz, 1H), 7.40 (d, J= 2.0 Hz, 1H), 6.96 (d, J= 2.0 Hz, 1H), 4.75 - 4.71 (m, 2H), 4.52 - 4.45 (m, 2H), 4.43 - 4.42 (m, 2H), 4.24 - 4.22 (m, 1H),4.12 - 4.04 (m, 1H), 4.01 - 3.97 (m, 1H), 3.95 - 3.87 (m, 1H), 3.51 - 3.41 (m, 1H), 3.16 (s, 3H), 2.75 - 2.74 (m, 1H), 2.63 (s, 3H), 2.54 (s, 1H).

Example 81 : (R)-N-( 1 -(4-(( 1 , 1 -Dioxidothietan-3 -yl)methoxy)-6-(3 -methoxytetrahydrofuran-3 - yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (R)-3-(((2-(6-chloro-3-methyl-1H- pyrazolo[4,3-c]pyridin-1-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)methyl)thietane 1,1-dioxide (Intermediate 39) instead of ((R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 31). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₆S, 501.2; m/z found, 457.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 9.23 (s, 1H), 8.92 (s, 1H), 7.40 (d, J = 1.8 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 4.40 - 4.32 (m, 4H), 4.25 - 3.96 (m, 5H), 3.91 - 3.87 (m, 1H), 3.17 (s, 3H), 3.09 - 2.98 (m, 1H), 2.85 - 2.75 (m, 1H), 2.64 (s, 3H), 2.52 (s, 1H), 2.16 (s, 3H). Example 82: N-(1-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridin-6-yl)acetamide-2,2,2-d₃.

Step A: N-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide- 2,2,2-d₃. The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 100 °C instead of 110 °C, using 1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-6-chloro- 3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 35) instead of (R)-6-chloro-1-(4- (difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3- c]pyridine (Intermediate 31) and acetamide-2,2,2-d₃ (Intermediate 108) instead of acetamide. MS (ESI): mass calcd. for C₂₈H₃₈D₃N₅O₅Si, 558.3; m/z found, 559.4 [M+H]⁺.

Step B : N-( 1 -(4-((R)-2-Hy droxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridin- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide-2,2,2-d₃ . The title compound was prepared in a manner analogous to Example 11, Step B using N-(1-(4-((R)-2-((tert- utyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide-2,2,2-d₃ instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A). MS (ESI): mass calcd. for C₂₂H₂₄D₃N₅O₅, 444.2; m/z found, 445.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) 8 10.66 (s, 1H), 9.23 (s, 1H), 8.92 (s, 1H), 7.38 (d, J= 2.1 Hz, 1H), 6.95 (d, J= 2.1 Hz, 1H), 4.97 (d, J= 3.9 Hz, 1H), 4.25 - 4.22 (m, 1H), 4.11 - 3.98 (m, 5H), 3.96 - 3.88 (m, 1H), 3.16 (s, 3H), 2.81 - 2.64 (m, 5H), 1.20 (s, 3H).

Example 83: (R)-2-Hydroxy-N-(1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3 -methyl-1H-pyrazolo[4,3 -c]pyridin-6-y l)acetamide.

To a solution of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 37, 160 mg, 0.37 mmol) in 1,4-dioxane (1.6 mL) was added 2-hydroxyacetamide (55.8 mg, 0.743 mmol), Pd(OAc)₂ (8.4 mg, 0.037 mmol), XPhos (35 mg, 0.074 mmol), and cesium carbonate (242 mg, 0.743 mmol). The resulting mixture was heated at 80 °C under nitrogen for 16 h. The reaction mixture was cooled to room temperature and the reaction was quenched with H₂O (10 mL). Purification by reverse phase preparative HPLC on a C 18 column (5-100% acetonitrile in 10 mM NH₄HCO₃ (aq.)) afforded the title compound (57 mg, 32% yield). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₆, 469.2; m/z found, 470.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.24 (s, 1H), 8.94 (s, 1H), 7.42 (d, J= 2.0 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 5.87 (t, J= 6.0 Hz, 1H), 4.76 - 4.72 (m, 2H), 4.51 - 4.48 (m, 2H), 4.45 - 4.43 (m, 2H), 4.26 - 4.23 (m, 1H), 4.11 - 4.05 (m, 3H), 4.02 - 3.98 (m, 1H), 3.91 - 3.89 (m, 1H), 3.47 - 3.43 (m, 1H), 3.16 (s, 3H), 2.76 - 2.73 (m, 1H), 2.64 (s, 3H), 2.51 - 2.50 (m, 1H).

Example 84 : 1 -( 1 -(4-((R)-2-Methoxypropoxy)-6-((R)-3 -methoxytetrahy drofuran-3 -yl)pyridin-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.

The title compound was made in a manner analogous to Example 1 using 6-chloro-1-(4- ((R)-2-methoxypropoxy)-6-((R)- 3 -methoxytetrahydrofuran-3 -yl)pyridin-2-y l)-3 -methyl- 1H- pyrazolo [4, 3 -c] pyridine (Intermediate 110) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -(1 -methyl- 1H-pyrazol-4-yl)- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₂H₂₈N₆O₅ 456.2; m/z found, 457.3 [M+H]⁺. NMR (400 MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.81 (d, J = 2.4 Hz, 2H), 7.35 (d, J=1.6 Hz, 1H), 6.93 (d, J= 2.0 Hz, 1H), 6.51 (s, 2H), 4.26 - 4.10 (m, 3H), 4.06 - 3.87 (m, 3H), 3.75 - 3.71 (m, 1H), 3.38 (s, 3H), 3.14 (s, 3H), 2.73 - 2.68 (m, 5H), 1.22 (d, J= 6.4 Hz, 3H).

Example 85: (R)- N-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H- pyrazolo[4,3 -c]pyridin-6-yl)acetamide-2,2,2-d₃ .

The title compound was made in a manner analogous to Example 47 using (R)-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6- amine (Intermediate 111) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55) and acetyl chloride-d₃ instead of acetyl chloride. MS (ESI): mass calcd. for C₂₀H₂₀D₃N₅O₃: 384.2, found: 385.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.23 (s, 1H), 8.91 (s, 1H), 7.72 (s, 1H), 7.26 (s, 1H), 4.24 - 4.27 (m, 1H), 3.99 - 4.07 (m, 2H), 3.89 - 3.91 (m, 1H), 3.14 (s, 3H), 2.72 - 2.75 (m, 1H), 2.63 (s, 3H), 2.50 - 2.51 (m, 1H), 2.46 (s, 3H).

Example 86 : 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridin-6-yl)cyclopropanecarboxamide.

The title compound was made in a manner analogous to Example 1, Step A using (R)-6- chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrazolo[4, 3 - c]pyridine (Intermediate 29) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)- 1H-pyrazolo[4,3 -c]pyridine (Intermediate 23) and cyclopropanecarboxamide instead of 1-(4-methoxybenzyl)urea in Step A. MS(ESI): mass calcd. for C₂₂H₂₅N₅O₃: 407.2, found: 408.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.97 (s, 1H), 9.21 (s, 1H), 8.92 (s, 1H), 7.71 (s, 1H), 7.25 (s, 1H), 4.16 - 4.19 (m, 1H), 3.95 - 4.07 (m, 2H), 3.82 - 3.84 (m, 1H), 3.14 (s, 3H), 2.74 - 2.82 (m, 1H), 2.63 (s, 3H), 2.51- 2.53 (m, 1H), 2.46 (m, 3H), 2.04 - 2.10 (m, 1H), 0.81 - 0.86 (m, 4H).

Example 87 : (R)- 1 -( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3 -c]pyridin-6-yl)-3 -methylurea.

The title compound was made in a manner analogous to Example 1, Step A using (R)-6- chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -y l)-4-methylpyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3 - c]pyridine (Intermediate 29) instead of (R)-6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)-1H-pyrazolo[4,3 -c]pyridine (Intermediate 23) and 1 -methylurea instead of 1-(4-methoxybenzyl)urea in Step A. MS(ESI): mass calcd. for C₂₀H₂₄N₆O₃: 396.2, found: 397.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.37 (s, 1H), 8.79 (s, 1H), 8.67 (s, 1H), 7.69 (s, 1H), 7.22 - 7.24 (m, 2H), 4.25 - 4.27 (m, 1H), 4.10 - 4.12 (m, 1H), 3.97 - 4.09 (m, 1H), 3.82- 3.89 (m, 1H) 3.14 (s, 3H), 2.70 - 2.78 (m, 4H), 2.59 (s, 3H), 2.52 - 2.54 (m, 1H), 2.45 (m, 3H).

Example 88: N-(5-(4-((R)-2-Methoxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-7-methylpyrrolo[ 1 ,2-c]pyrimidin-3-yl)acetamide.

The title compound was prepared in a manner analogous to Example 47 using 5-(4-((R)- 2-methoxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2- c]pyrimidin-3-amine (Intermediate 112) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methy lpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4-yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -amine (Intermediate 55) and TEA instead of pyridine. MS (ESI): mass calcd. for C₂₄H₃₀N₄O₅, 454.2; m/z found, 455.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 6.74 (s, 1H), 4.20 - 3.92 (m, 5H), 3.88 (d, J= 9.6 Hz, 1H), 3.71 - 3.70 (m, 1H), 3.31 (s, 3H), 3.12 (s, 3H), 2.80 - 2.73 (m, 1H), 2.55 (s, 3H), 2.41 (s, 1H), 2.11 (s, 3H), 1.21 (d, J= 6.0 Hz, 3H).

Example 89: (R)-N-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.

The title compound was prepared in a manner analogous to Example 47 using (R)-5-(6- (3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3- amine (Intermediate 59) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55) and TEA instead of pyridine. MS (ESI): mass calcd. for C₂₁H₂₄N₄O₃, 380.2; m/z found, 381.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.97 (s, 1H), 8.89 (s, 1H), 7.43 (s, 1H), 7.17 (s, 1H), 7.03 (s, 1H), 4.20 (d, J= 9.6Hz, 1H), 4.05-3.96 (m, 2H), 3.87 (d, J= 9.9Hz, 1H), 3.11 (s, 3H), 2.78-2.70 (m, 1H), 2.65-2.50 (m, 4H), 2.36 (s, 3H), 2.06 (s, 3H). Example 90: (R)-1-(5-(4-((1,1-Dioxidothietan-3-yl)methoxy)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was made in a manner analogous to Example 23 using (R)-3-(((2-(3- amino-7-methylpyrrolo[1,2-c]pyrimidin-5-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4- yl)oxy)methyl)thietane 1,1 -dioxide (Intermediate 113) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₆S, 501.2; m/z found, 502.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J= 1.6 Hz, 1H), 8.77 (s, 1H), 8.67 (d, J= 1.2 Hz, 1H), 7.17 (s, 1H), 7.11 (d, J= 2.4 Hz, 1H), 6.71 (d, J= 2.0 Hz, 1H), 6.20 (s, 2H), 4.39-4.31 (m, 4H), 4.19-4.17 (m, 1H), 4.10-4.06 (m, 2H), 4.03-4.02 (m, 1H), 4.02-3.94 (m, 1H), 3.87-3.85 (m, 1H), 3.11 (s, 3H), 3.04 - 2.96 (m, 1H), 2.75-2.72 (m, 1H), 2.51 (s, 3H), 2.50- 2.49 (m, 1H).

Example 91 : N-(5-(6-((R)-3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl)acetamide.

The title compound was prepared in a manner analogous to Example 47 using 5-(6-((R)- 3 -methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-7-(tetrahy drofuran-3 -yl)pyrrolo[ 1 ,2- c]pyrimidin-3 -amine (Intermediate 116) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl-1H-pyrazol-4-yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₄H₂₈N₄O₄: 436.2, found: 437.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.30 (s, 1H), 9.06 (s, 1H), 8.99 (s, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.03 (s, 1H), 4.18 - 4.23 (m, 2H), 3.85 - 4.03 (m, 6H), 3.74 - 3.79 (m, 1H), 3.09 (s, 3H), 2.72 - 2.75 (m, 1H), 2.43 - 2.49 (m, 2H), 2.35 (s, 3H), 2.05- 2.11 (m, 4H).

Example 92: 1-(5-(6-((R)-3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was made in a manner analogous to Example 23 using 5-(6-((R)-3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(tetrahydrofuran-3-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 116) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4-yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₄: 437.2, found: 438.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.99 (s, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 6.99 (s, 1H), 6.20 (br s, 2H), 4.17 - 4.23 (m, 2H), 3.84 - 4.01 (m, 6H), 3.74 - 3.78 (m, 1H), 3.08 (s, 3H), 2.67 - 2.72 (m, 1H), 2.42 - 2.47 (m, 2H), 2.34 (s, 3H), 2.04- 2.05 (m, 1H).

Example 93 : N-(5-(6-((S)-3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3 -yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -yl)acetamide.

The title compound was prepared in a manner analogous to Example 47 using 5-(6-((S)- 3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-7-(tetrahy drofuran-3 -yl)pyrrolo[ 1 ,2- c]pyrimidin-3-amine (Intermediate 118) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)-7-( 1 -methyl- 1H-pyrazol-4-yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₄H₂₈N₄O₄: 436.2, found: 437.1. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.31 (s, 1H), 9.06 (s, 1H), 8.99 (s, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.03 (s, 1H), 4.18 - 4.23 (m, 2H), 3.74 - 4.04 (m, TH), 3.10 (s, 3H), 2.72 - 2.76 (m, 1H), 2.43 - 2.48 (m, 2H), 2.36 (s, 3H), 2.05- 2.11 (m, 4H).

Example 94: 1 -(5-(6-((S)-3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3 -yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -yl)urea.

The title compound was made in a manner analogous to Example 23 using 5-(6-((S)-3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(tetrahydrofuran-3-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 118) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2 -yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55). MS (ESI): mass calcd. for C₂₃H₂₇N₅O₄: 437.2, found: 438.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 6.99 (s, 1H), 6.20 (hr s, 2H), 4.17 - 4.23 (m, 2H), 3.84 - 4.01 (m, 6H), 3.73 - 3.78 (m, 1H), 3.08 (s, 3H), 2.69 - 2.72 (m, 1H), 2.42 - 2.47 (m, 2H), 2.34 (s, 3H), 2.04 - 2.07 (m, 1H).

Example 95: (R)-1-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(methyl- d3)pyrrolo[1,2-c]pyrimidin-3-yl)urea.

The title compound was made in a manner analogous to Example 23 using (R)-5-(6-(3- methoxytetrahydrofu ran-3-yl)-4-methylpyridin-2-yl)-7-(methyl-d3)pyrrolo[1,2-c]pyrimidin-3- amine (Intermediate 120) instead of (R)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 55). MS (ESI): mass calcd. for C₂₀H₂₀D₃N₅O₃: 384.2, found: 385.0 [M+H]^{+ 1}H NMR (400 MHz, DMSO- d₆) δ 8.81 (s, 1H), 8.75 (s, 1H), 8.67 (s, 1H), 7.37 (s, 1H), 7.10 (s, 1H), 6.98 (s, 1H), 6.19 (s, 2H), 4.27 - 4.20 (m, 1H), 4.04 - 3.92 (m, 2H), 3.89 - 3.86 (m, 1H), 3.09 (s, 3H), 2.75 - 2.68 (m, 1H), 2.50 - 2.43 (m, 1H), 2.34 (s, 3H).

Example 96: 1-(5-(4-(Difluoromethyl)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- (tetrahydrofuran-3 -yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -yl)urea.

The title compound was made in a manner analogous to Example 23 using 5-(4- (difluoromethyl)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-7-(tetrahydrofuran-3 - yl)pyrrolo[1,2-c]pyrimidin-3-amine (Intermediate 123) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55). MS (ESI): mass calcd. for C₂₃H₂₅F₂N₅O₄: 473.2, found:

474.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.86 (s, 1H), 8.73 (s, 1H), 7.78 (s, 1H), 7.39 (s, 1H), 7.25 (s, 1H), 7.08 (t, J= 110.8 Hz, 1H), 6.24 (br s, 2H), 4.17 - 4.26 (m, 2H), 4.03 - 4.07 (m, 1H), 3.84 - 4.00 (m, 5H), 3.75 - 3.80 (m, 1H), 3.12 (s, 3H), 2.74 - 2.78 (m, 1H), 2.42 - 2.47 (m, 2H), 2.02- 2.08 (m, 1H).

Example 97: 1-(5-(4-(Difluoromethyl)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- (tetrahy drofuran-3 -yl)pyrrolo[ 1 ,2-c]pyrimidin-3 -yl)urea.

The title compound was made in a manner analogous to Example 23 using 5-(4- (difluoromethyl)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-(tetrahydrofuran-3- yl)pyrrolo[1,2-c]pyrimidin-3 -amine (Intermediate 126) instead of (R)-5-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2- c]pyrimidin-3 -amine (Intermediate 55). MS(ESI): mass calcd. for C₂₃H₂₅F₂N₅O₄: 473.2, found: 474.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.97 (s, 1H), 8.66 (s, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.24 (s, 1H), 7.03 (t, J= 110.8 Hz, 1H), 4.21 - 4.23 (m, 1H), 4.13 - 4.17 (m, 1H), 4.01 - 4.04 (m, 1H), 3.82 - 3.97 (m, 5H), 3.75 - 3.79 (m, 1H), 3.09 (s, 3H), 2.69 - 2.72 (m, 1H), 2.43 - 2.45 (m, 2H), 1.99- 2.08 (m, 1H).

Example 98 : (R)- N-( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrrolo[3,2-c]pyridin-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated to 70 °C instead of 110 °C, using (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine (Intermediate 41) instead of (R)-6-chloro-1 -(4-(difluoromethyl)-6-(3 -methoxytetrahydrofuran-3- yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 31) and THF instead of 1,4-dioxane. MS (ESI): mass calcd. for C₂₁H₂₄N₄O₃, 380.2; m/z found, 381.2 [M+H]^{+ 1}H NMR (300 MHz, Methanol-d₄ ) δ 8.97 (s, 1H), 8.55 (s, 1H), 7.67 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 4.29-4.26 (m, 1H), 4.17- 4.08 (m, 3H), 3.27 (s, 3H), 2.84-2.74 (m, 1H), 2.59-2.46 (m, 4H), 2.41 (s, 3H), 2.22 (s, 3H).

Example 99: (R)- N-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)- 3-methyl-LS-pyrrolo[3,2-c]pyridin-6-yl)acetamide.

The title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated to 70 °C instead of 110 °C, using (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrrolo[3,2- c]pyridine (Intermediate 43) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 31) and THF instead of 1,4-dioxane. MS (ESI): mass calcd. for C₂₄H₂₈N₄O₅, 452.2; m/z found, 453.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.05 (s, 1H), 8.59 (s, 1H), 7.88 (s, 1H), 7.20 (s, 1H), 6.97 (s, 1H), 4.78-4.74 (m, 2H), 4.55-4.45 (m, 4H), 4.17 (d, J= 9.3 Hz, 1H), 4.02-3.90 (m, 3H), 3.51-3.42 (m, 1H), 3.17 (s, 3H), 2.74-2.61 (m, 1H), 2.54 (s, 1H), 2.35 (s, 3H), 2.11 (s, 3H).

Example 100 : (R)- 1 -( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2- yl)-3-(trifluoromethyl)- 1H-pyrrolo[3,2-c]pyridin-6-yl)urea.

The title compound was prepared in a manner analogous to Example 1, using (R)-6-chloro- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)-3 -(trifluoromethyl)- 1H-pyrrolo [3, 2-c] pyridine (Intermediate 129) instead of (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol -4-yl )- 1H- pyrazolo[4,3-c]pyridine (Intermediate 23) in Step A. MS (ESI): mass calcd. for C₂₃H₂₄F₃N₅O₅, 507.2; m/z found, 508.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.65 - 8.61 (m, 3H), 7.41 (d, J= 1.6 Hz, 1H), 7.09 (d, J= 1.6 Hz, 1H), 6.55 (s, 2H), 4.78-4.74 (m, 2H), 4.50-4.45 (m, 4H), 4.17 (d, J= 9.6 Hz, 1H), 4.02 - 3.92 (m, 3H), 3.52-3.44 (m, 1H), 3.16 (s, 3H), 2.67-2.59 (m, 1H), 2.50-2.48 (m, 1H).¹⁹F NMR (376 MHz, DMSO-d₆) δ -56.14.

IN VITRO BIOLOGICAL ASSAYS AND DATA

Probe Displacement Assay

The probe displacement assay is conducted as follows: In a 384-well plate, test compound along with recombinantly expressed His-tagged protein corresponding to amino acids 556-871 of human TYK2 (sequence shown below) at 5 nM, 33 nM probe (BB, preparation described below) and 0.33 mg/mL Yttrium oxide (YOx) His-capture SPA beads (PerkinElmer, RPNQ0276) in IX PBS containing 10 mM MgCl₂, 0.1 mg/mL BSA, 0.1 mM TCEP, 0.005% Tween-20, and 1% DMSO (final concentration) were incubated for 10 hours at room temperature. The amount of radiolabeled probe bound to TYK2 was then quantified using a ViewLux Microplate Imager, and the fraction bound by the test compound calculated by comparison to wells containing scale references for 0% and 100% probe displacement. The IC₅₀ value is defined as the concentration of test compound required to inhibit radiolabeled probe binding by 50%.

The radiolabeled probe (BB) mentioned above was prepared by treating (R)-N-(1-(3-(8- methyl-5-(methylamino)-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2- (methylsulfonyl)benzamide (AA) with tritium (1.0 equiv) and Crabtree’s catalyst (CAS# 64536- 78-3, 0.6 equiv) in DCM (0.005M) as shown below.

Protein sequence of recombinant His-tagged Tyk2 (556-871):

Human PBMC IL-23 stimulation assay Interleukin 23 exerts its effects in the human peripheral blood monocytic cells (PBMCs) by interacting with its receptor and signaling through the JAK2/TYK2-STAT4 pathway. Upon receptor activation JAK2/TYK2 are auto-phosphorylated. This initiates a downstream phosphorylation of STAT4 (pSTAT4). Intracellular levels of pSTAT4 are measured using the AlphaLISA® SureFire® Ultra™ p-STAT4 (Tyr693) Kit from Perkin Elmer. The time-resolved fluorescence signal generated by the assay is acquired on a fluorescent plate reader. As cells are exposed to increasing concentrations of each test compound, the percentage of IL-23 -dependent pSTAT4 inhibition is determined at each concentration. Therefore, this assay evaluates the test compound effect elicited by Tyk2 inhibition.

The assay is performed as follows: Ciyopreserved human PBMCs (BioSpecialty) are thawed, washed and resuspended in complete growth media (RPMI-1640 containing 10% FBS, 1% Pen/Strep, 1% Na Pyruvate, 55uM b-ME). Human T-Activator CD3/CD28 Dynabeads (Thermo Scientific, 11161D) are washed and resuspended in complete growth media supplemented with 30U/ml of IL-2 (R&D Systems, 202- IL). The PBMC cells and Dynabeads are then mixed together in a T75 flask for 5 days at 37 °C, 5% CO₂, with a final bed-to-cell ratio of 1 :2, and a final cell density of 0.6x10⁶ cells/ml at 50ml total volume. After 5 days of culture, the Dynabeads are removed and the cells are resuspended in RPMI-1640 containing 0.1% BSA to perform serum/cytokine starvation for 4 hours (kept in T75 flask at 37°C, 5% CO₂). Upon completion of starvation, cells are resuspended in HBSS containing 0.1% BSA at 2x10⁶ cells/ml, and seeded at 40,000cells/well in PerkinElmer OptiPlate-384 pre-spotted with 72 nL of compounds. The assay plate is incubated for 30 minutes at 37°C, 5% CO₂. IL-23 is resuspended in HBSS containing 0.1% BSA and is added to the assay plate at 4μl/well, yielding a dosage of EC₉₀ determined empirically per donor, except for the low control wells which receive only HBSS containing 0.1% BSA. Assay plate is incubated for additional 30 minutes at 37°C, 5% CO₂. 5X lysis buffer provided by the AlphaLISA® SureFire® Ultra™ p-STAT4 (Tyr693) kit is added to the plate and incubated for 20 minutes on plate shaker at ~350 RPM. Per instructions of the AlphaLISA kit, the acceptor and donor mix are prepared and added to the assay plate. After 2 h of incubation at room temperature, the assay plate is read on fluorescent plate readers using AlphaLISA settings. The fluorescent signal is plotted against the compound concentration and the data is fitted to 4-parameters logistical fit model to yield IC₅₀ of the compound. The assay is accepted based on the performance of the reference compound, Tofacitinib Citrate (Sigma- Aldrich; Catalog No. PZ0017), of the expected IC₅₀ value of O.24μM. The IC₅₀ will fall within a 3-fold window of the value reported above.

Human PBMC IL-12 stimulation assay

Interleukin 12 (IL-12) exerts its effects in the human peripheral blood monocytic cells (PBMCs) by interacting with its receptor and signaling through the JAK2/TYK2-STAT4 pathway. Upon receptor activation, JAK2/TYK2 are auto-phosphorylated. This initiates a downstream phosphorylation of STAT4 (pSTAT4). Intracellular levels of pSTAT4 are measured using the AlphaLISA® SureFire® Ultra™ p-STAT4 (Tyr693) Kit from PE. The time-resolved fluorescence signal generated by the assay is acquired on a fluorescent plate reader. As cells are exposed to increasing concentrations of each test compound, the percentage of IL-12-dependent pSTAT4 inhibition is determined at each concentration. Therefore, this assay evaluates the test compound effect elicited by Tyk2 inhibition.

The assay is performed as follows: Cryopreserved human PBMCs (BioSpecialty) are thawed, washed and resuspended in complete growth media (RPMI-1640 containing 10% FBS, 1% Pen/Strep, 1% Na Pyruvate) containing 10μ g/ml of anti-CD28 (Biolegend #302934). Cells are plated at a final volume of 15 mL, 2.0x10⁶ cells/ml in petri dish pre-coated with anti-CD3 (Biolegend #300332), and incubated overnight at 37 °C, 5% CO₂. After overnight incubation, the cells are resuspended in HBSS containing 0.1% BSA at 2x10⁶ cells/ml and seeded at 40,000 cells/well in PerkinElmer OptiPlate-384 pre-spotted with 72 nL of compounds. The assay plate is incubated for 30 minutes at 37 °C, 5% CO₂. IL-12 (R&D Systems, #219-IL) is resuspended in HBSS containing 0.1% BSA and is added to the assay plate at 4μ l/well, yielding a dosage of EC₉0 determined empirically per donor, except for the low control wells which receive only HBSS containing 0.1% BSA. The assay plate is incubated for additional 30 minutes at 37 °C, 5% CO₂. 5X lysis buffer provided by the AlphaLISA® SureFire® Ultra™ p-STAT4 (Tyr693) kit is added to the plate and it is incubated for 20 minutes on plate shaker at ~350 RPM. Per instructions of the AlphaLISA kit, the acceptor and donor mix are prepared and added to the assay plate. After 2 h of incubation at room temperature, the assay plate is read on fluorescent plate readers using AlphaLISA settings. The fluorescent signal is plotted against the compound concentration and the data is fitted to 4- parameters logistical fit model to yield IC₅₀ of the compound. The assay is accepted based on the performance of the reference compound, Tofacitinib Citrate (Sigma-Aldrich; Catalog No.

PZ0017), of the expected IC₅₀ value of 2.06 pM. The IC₅₀ will fall within a 3-fold window of the value reported above.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

All documents cited herein are incorporated by reference.

Claims

We claim

1. A compound of Formula I’:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O, S(O) or SO₂; m is 1 or 2;

R^1a independently for each occurrence is H or -C_(1-2)alkyl;

R^1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3; X is -O-, -NH-, -SO₂-, or -C_(1-4)alkyl- that is unsubstituted or substituted with -OH or -CN;

Y is -CH₂-, or -CH(OH)-;

U is 0 or 1;

R³ is H;

R⁴ is H or -C_(1-2)alkyl; and R⁵ is -C_(1-4)alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Z is O, S(O) or SO₂; m is 1 or 2; R¹ is -C_(1-2)alkyl unsubstituted or substituted with one to three fluorine atoms; -OCH₃, -

R^1a independently for each occurrence is H or -C_(1-2)alkyl;

R^1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3;

X is -O- or -SO₂-;

Y is -CH₂-, or -CH(OH)-;

U is 0 or 1;

R³ is H;

R⁴ is H or -C_(1-2)alkyl; and R⁵ is -C_(1-4)alkyl.

3. The compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-3)alkyl, -O(CH₂)₂OCH₃,

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -CH₃, -CHF₂, -CF₃, -CF₂CH₃, -O(CH₂)₂OCH₃,

5 The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

R² is -NH₂, -NH(CH₃), -C₃-C₄ cycloalkyl or -C_(1-2)alkyl that is unsubstituted or substituted with -OH.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

R² is -NH₂, -NH(CH₃), -CH₃, -CD₃, -CH₂OH, or

7. The compound of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R³ is H;

R⁴ is -C_(1-2)alkyl.

8. The compound of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R³ is H, -CH₃, -CD₃, -CF₃, -C₃-C₄ cycloalkyl that is unsubstituted or substituted with one or two R^3a groups; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5- membered heteroaryl having 1 to 2 heteroatoms selected from N and O, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-2)alkyl.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R³ is H, -CH₃, -CD₃, -CF₃,

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R³ is H, -CH₃, -CD₃, -CF₃,

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R³ is H, -CH₃, -CD₃, -CF₃,

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is a compound of Formula I’a:

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is a compound of Formula I’b:

14. The compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

16. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-4)alkyl, -O(CH₂)₂OC_(1-4)alkyl,

X is O, NH, SO₂, or -C_(1-4)alkyl that is unsubstituted or substituted with -OH or CN.

R² is -NH₂ or -C_(1-4)alkyl; and

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-4) alkyl, -O(CH₂)₂OCH₃,

X is O, SO₂, or -C_(1-4)alkyl that is unsubstituted or substituted with -OH;

R² is -NH₂ or -C_(1-4)alkyl; and

18. The compound of any one of claims 16 to 17, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-4)alkyl, -O(CH₂)₂OCH₃,

R² is -NH₂ or -C_(1-4)alkyl; and

19. The compound of any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. The compound of any one of claims 16 to 19, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -C_(1-3)alkyl, -O(CH₂)₂OCH₃,

21. The compound of any one of claims 16 to 20, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -CH₃, -CHF₂, -CF₃, -O(CH₂)₂OCH₃,

22. The compound of claims 16 to 21, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is -O(CH₂)₂OCH₃,

23. The compound of any one of claims 16 to 22, or a pharmaceutically acceptable salt thereof, wherein:

R² is -NH₂, -CH₃, or -CH₂CH₃.

24. The compound of any one of claims 16 to 23, or a pharmaceutically acceptable salt thereof, wherein:

R² is -NH₂, or -CH₃.

25. The compound of any one of claims 16 to 24, or a pharmaceutically acceptable salt thereof, wherein:

R³ is H, -C_(1-3)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1-4)alkyl.

26. The compound of any one of claims 16 to 25, or a pharmaceutically acceptable salt thereof, wherein:

R³ is H, -C_(1-3)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1- ₂₎alkyl.

27. The compound of any one of claims 16 to 26, or a pharmaceutically acceptable salt thereof, wherein: R³ is H, -C_(1-3)alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N or O, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C_(1- ₂₎alkyl.

28. The compound of any one of claims 16 to 27, or a pharmaceutically acceptable salt thereof, wherein: R³ is H, -C_(1-3)alkyl,

R⁴ is -C_(1-2)alkyl.

29. The compound of any one of claims 16 to 28, or a pharmaceutically acceptable salt thereof, wherein:

R³ is H, -CH₃,

30. The compound of any one of claims 16 to 29, or a pharmaceutically acceptable salt thereof, which is a compound of Formula la:

31. The compound of any one of claims 16 to 29, or a pharmaceutically acceptable salt thereof, which is a compound of Formula la:

32. The compound of any of claims 16 to 31, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

34. A pharmaceutical composition, comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35 A pharmaceutical composition made by mixing a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

36. The pharmaceutical composition of claim 34 or 35, or a pharmaceutically acceptable salt thereof, which is administered orally.

37. The pharmaceutical composition of claim 36, or a pharmaceutically acceptable salt thereof, which is administered as a tablet or a capsule.

38. A process for making a pharmaceutical composition comprising mixing a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. A method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.

41. The method of claim 40, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriasis.

42. The method of claim 40, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

43. The method of claim 40, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.