EA035568B1 - SUBSTITUTED PYRAZOLO[1,5-a]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS - Google Patents

Abstract

Provided herein are compounds of the Formula Iand stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X, X, X, X, ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Description

Cross-reference to related claims

This patent application claims priority to US Provisional Application No. 62/566093, filed September 29, 2017; No. 62/554817, filed September 6, 2017; No. 62/491164, filed April 27, 2017; No. 62/447850, filed January 18, 2017; and No. 62/406252, filed October 10, 2016, each of which is incorporated herein in its entirety by reference.

State of the art

The present invention relates to novel compounds that inhibit rearranged during transfection (RET) kinase, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and the use of the compounds in therapy. More specifically, the present disclosure relates to substituted pyrazolo ^^^ pyridines that can be used to treat and prevent diseases that can be treated with a RET kinase inhibitor, including diseases and disorders associated with RET.

RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is required for the normal development, maturation, and maintenance of certain tissues and cell types (Mulligan, L.M., Nature Reviews Cancer, 2014, 14, 173-186). The extracellular part of RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding, and a near-membrane region rich in cysteine, which is necessary for the correct folding of the extracellular domain of RET, while the cytoplasmic part of the receptor includes two subdomains of tyrosine kinase.

RET signaling is mediated by the binding of a group of soluble glial cell line neurotrophic factor (GDNF) proteins, family ligands (GFL), which also include neuroturin (NTRN), artemin (ARTN) and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev ., 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RET does not bind directly to GFL and requires an additional coreceptor, i.e. one of four members of the α (GFRa) family of receptors of the GDNF family, which are linked to the cell surface through a glycosyl phosphatidylinositol bond Family members GFL and GFRa form binary complexes that in turn bind to RET and recruit it into cholesterol-rich membrane subdomains, known as lipid rafts, where RET signaling occurs. Upon binding of the ligand-coreceptor complex, RET dimerization and autophosphorylation of intracellular tyrosine residues recruit adapter and signaling proteins to stimulate multiple downstream signaling pathways. Binding of the adapter protein to these binding sites leads to activation of the RasMAPK and PI3K-Akt / mTOR signaling pathways or to the recruitment of the CBL ubiquitin ligase family, which are involved in RET-dependent suppression of RET-mediated functions.

Abnormal RET expression and / or activity have been identified in various cancers and gastrointestinal disorders such as irritable bowel syndrome (IBS).

The essence of the invention

It has been found that substituted pyrazolo P ^^ pyridine compounds are RET kinase inhibitors and can be used for the treatment of diseases such as proliferative diseases, including cancer. Accordingly, provided herein is a compound of Formula I

I or a pharmaceutically acceptable salt or solvate thereof, wherein A, B, X ¹ , X ² , X ³ , X ⁴ and ring D are as defined herein. In addition, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

In addition, provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

In addition, provided herein is a method of treating an RET-associated disease or disorder in a patient in need of such treatment, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined in this document.

In addition, provided herein is a method of treating cancer and / or inhibiting metastasis associated with a particular cancer in a patient in need of such treatment, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof , or a solvate, or a pharmaceutical composition thereof, as defined herein.

In addition, provided herein is a method of treating irritable bowel syndrome (IBS) and / or pain associated with IBS in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a solvate, or a pharmaceutical composition thereof, as defined herein. In addition, there is provided a method of providing supportive care to a patient with cancer, including preventing or minimizing gastrointestinal disorders such as diarrhea associated with treatment, including chemotherapy, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof , or a pharmaceutical composition thereof, as defined herein.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of cancer and / or inhibition of metastasis associated with a particular cancer.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the maintenance of cancer patient care, including the prevention or minimization of gastrointestinal disorders such as diarrhea associated with treatment, including chemotherapy.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting RET kinase activity.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of an RET-associated disease or disorder.

In addition, this document provides a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for the manufacture of a medicament for the treatment of cancer and / or inhibition of metastasis associated with a particular type of cancer.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, for the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

In addition, this document provides a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, for the manufacture of a medicament for the maintenance of a cancer patient, including preventing or minimizing gastrointestinal disorders such as diarrhea associated with treatment, including chemotherapy.

In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, for the manufacture of a medicament for inhibiting RET kinase activity. In addition, provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, for the manufacture of a medicament for the treatment of an RET-associated disease or disorder.

Also provided herein is a method for treating cancer in a patient in need thereof, comprising (a) determining whether the cancer is associated with dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them (e.g., RET- associated cancer); and (b) in the case of determining cancer as associated with dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them (for example, RET-associated cancer), administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate, or a pharmaceutical composition thereof.

Also provided herein is a pharmaceutical combination for the treatment of cancer (e.g., RET-associated cancer, such as RET-associated cancer having one or more RET inhibitor resistance mutations) in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, wherein

- 2 035568 a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and an additional drug are formulated as separate compositions or dosages for simultaneous, separate or sequential use for the treatment of cancer, wherein the amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and an additional the therapeutic agent is together effective in treating cancer. Also provided herein is a pharmaceutical composition containing such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of cancer. Also provided herein is a commercial package or product containing such a combination as a combination preparation for simultaneous, separate or sequential use; and for carrying out a method of treating cancer in a patient in need thereof. Also provided herein is a method for reversing or preventing acquired resistance to an anti-cancer drug, comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a patient at increased risk of developing resistance to an anti-cancer drug or already having acquired resistance. In some embodiments of the invention, a dose of an anti-cancer drug is administered to the patient (eg, at substantially the same time as the dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof).

Also provided herein is a method of slowing and / or preventing the development of cancer resistant to an anti-cancer drug in an individual, comprising administering to the individual an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, before, during or after administration of an effective amount of an anti-cancer drug ...

Also provided herein is a method of treating an individual with cancer who has an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual (a) an effective amount of a compound of Formula I before, during, or after administration of (b) an effective amount of an anticancer drug.

Also provided are methods of treating an individual with RET-associated cancer who has one or more RET inhibitor resistance mutations that increase the cancer's resistance to the first RET inhibitor (e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E, and / or one or more RET inhibitor resistance mutations listed in Tables 3 and 4), which include administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, before, during, or after the administration of another cancer drug (e.g., a second RET kinase inhibitor ).

Also provided are methods of treating an individual with RET-associated cancer, which comprise administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anti-cancer drug (eg, a first RET kinase inhibitor).

Also provided herein is a method of treating irritable bowel syndrome (IBS) in a patient in need thereof, comprising (a) determining if IBS is associated with dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them ; and, (b) in the case of determining CPK as associated with dysregulation of the RET, RET kinase gene or their expression, or their activity, or the level of any of them, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or its pharmaceutical composition. Also provided herein is a pharmaceutical combination for the treatment of irritable bowel syndrome (IBS) in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent and, (c) optionally, at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in the treatment of IBS, wherein the amounts of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent together are effective in the treatment of IBS. Also provided herein is a pharmaceutical composition containing such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of IBS. Also provided herein is a commercial package or product containing such a combination as a combination preparation for simultaneous, separate or sequential use; and for carrying out a method of treating IBS in a patient in need thereof.

Also provided herein is a method for preparing a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, prepared by a process for preparing a compound as defined herein.

Unless otherwise indicated, all technical and scientific terms used in this document have the same meanings as commonly understood by a person skilled in the art, to which

- 3 035568 relates to this invention. This document describes methods and materials for use in this invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database values, and other references cited herein are incorporated by reference in their entirety. In case of conflict, this description, including definitions, prevails.

Other features and advantages of the invention will become apparent from the following detailed description and claims.

Detailed description of the essence of the invention

Provided herein is a compound of Formula I

( ^D /

I and its pharmaceutically acceptable salts and solvates, where

X ¹ , X ² , X ³ and X4 are independently CH, CF, CCH _3, or N, where zero, one, or two of X ¹ , X ² , X ³ and X4 are N;

A is H, CN, Cl, CH ₃ -, CH ₃ CH ₂ -, cyclopropyl, —CH2 CN, or —CH (CN) CH ₃ ;

B represents:

(a) hydrogen, (b) Ci-C ₆ -okuh, optionally substituted with 1-3 fluorine atoms, (c) hydroxy-C ₂ -C ₆ -alkyl-, where the alkyl moiety is optionally substituted with 1-3 fluorine atoms or C ₃ -C ₆ -cycloalkylidene ring, (d) dihydroxy-C ₃ -C ₆ -alkyl, where the alkyl moiety is optionally substituted with a C3-C6-cycloalkylidene ring, (e) (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ - alkyl optionally substituted with 1 to 3 fluorine atoms, (f) (R ¹ R ² N) C1-C6 alkyl-, wherein said alkyl moiety is optionally substituted with OH and wherein R ¹ and R ^{2 are} independently H or CrC ₆ -OKUH (optionally substituted with 1-3 fluorine atoms);

(g) het-Ar ¹ C ₁ -C ₃ -alkyl, where het-Ar ¹ is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, and is optionally substituted with one or more independently selected ^ - ^ - alkyl substituents;

(h) (C ₃ -C ₆ -cycloalkyl) C ₁ -C ₃ -alkyl, wherein said cycloalkyl is optionally substituted with OH, (i) (het-Cyc ^a ) C ₁ -C ₃ -alkyl-, (j) het- Cyca-;

(k) C ₃ -C ₆ -cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH, (l) (C ₁ -C ₄ -alkyl) C (= O) OC ₁ -C ₆ -alkyl-, where each of ^ - ^ -alkyl and ^ - ^ - alkyl fragments are optionally and independently substituted by 1-3 fluorine atoms, or (m) (R ¹ R ² N) C (= O) C1-C6 -alkyl-, where R ¹ and R ² independently are H or Ci-C6-okuh (optionally substituted with 1-3 fluorine atoms);

het -Cyca- is a 4-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O, and optionally substituted with one or more substituents independently selected from OH, C ₁ -C ₆ -alkyl (optionally substituted by 1-3 fluorine atoms), hydroxy-C ₁ -C ₆ -alkyl-, ^ - ^ - alkoxy, (QQ-okuh ^^ O) -, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ - alkyl and fluoro or where het-Cyca is substituted with oxo;

ring D is (i) a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, where each of said rings is optionally substituted with (a ) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) cycloalkylidene ring C ₃ -C ₆ or (c) oxo;

E represents:

(a) hydrogen, (b) Ci-C ₆ -okuh optionally substituted with 1 to 3 fluorine atoms, (c) (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms , (d) (C ₁ -C ₆ -alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted by 1-3 atoms

- 4 035568 fluorine or a substituent R ^g R ^b N, where R ^g and R ^h independently represent H or C1-Cb-alkyl, (e) (hydroxy-C ₂ -C ₆ -alkyl) C (= O) -, optionally substituted with 1-3 fluorine atoms, (f) (C1-C ₆ -alkoxy) C (= O) -, (g) (C ₃ -C ₆ cycloalkyl) C (= O) -, wherein said cycloalkyl is optionally substituted one or more substituents independently selected from C.'iC.'6-alkyl, C.'iC.'6-alkoxy, OH and (C-C-alkoxy ^ -C alkyl, or said cycloalkyl is substituted with 5-6 -membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N and O, (h) AFCj-C. ^ km-, (i) Ar1 (C1-C ₆ ^ Kra) C (= O) -, where said alkyl moiety is optionally substituted with OH, hydroxy _C1-C6 alkyl, C-C-alkoxy. R ^m R ⁿ N- or R ^m R ⁿ N-CH2-, where each R ^m and R ⁿ independently represents H or C1-C ₆ -alkyl, (j) het-Ag2S1-C ₆ -alkyl-, wherein said alkyl moiety is optionally substituted with 1-3 fluorine atoms, (k) het-Ar2 _(C1-C6 alkyl) C (= O) -, where said alkyl moiety is optionally substituted with OH, _{hydroxy-C1-C6} alkyl or _C1-C6 alkoxy, (l) het-Ag2S (= O) -, (m) het-Sus1S (= O) -, (n) Sus1S1-het-C ₆ - alkyl-, (o) R ³ R ⁴ NC (= O) -, (p) Ar1N (R ³ ) C (= O) -, (q) het-Ar2Zh ³ ) C (= O) -, (d) _(C1-C6 alkyl ^ O ₂ - wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, (s) Ar1SO2-, (t ) het-Ar ^ O2, (u) № (C1-C ₆ alkyl ) pyridinonyl, (v) Ar1C (= O) -, (w) Ar1O-C (= O) -, (x) (C ₃ -C ₆ -cycloalkyl) (C1-C ₆ -alkyl) C (= O) -, (y) (C ₃ -C ₆ -cycloalkyl) (C1-C ₆ -alkyl ^ O ₂ -, where the alkyl fragment is optionally substituted with 1-3 fluorine atoms, (z) ArkCj-C. ^ K ^^ O ^ , (aa) het-Cus ¹ -O-C (= O) -, (bb) het-Cus1CH ₂ C (= O) -, (cc) het-Ar ² , or (dd) C ₃ -C ₆ - cycloalkyl;

Ar ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms), R ^e R ^f N-, where R ^e and R ^f independently represent H, C1-C6-alkyl; ^^ F) _C1-C6 alkoxy, where R ^p and R ^q are independently H or C1-C6-alkyl, and (het-AH ^a) C1-C ₆ alkyl, wherein het-Ar ³ represents is a 5-6 membered heteroaryl ring containing 1-2 ring nitrogen atoms, or Ar ¹ is a phenyl ring fused to a 5-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O;

het-Ar ² is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl ring containing 1-3 ring nitrogen atoms, where het -Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms) , (Ci-C6 alkoxy) C1-C6-alkyl- (optionally substituted by 1-3 fluorine atoms), R ^e R ^f N-, where R ^e and R ^f independently represent H or C1-C6-alkyl, OH, (C1 —C ₆ alkoxy) C1 — C ₆ alkoxy and C ₃ —C ₆ cycloalkyl;

het-Cus ¹ is a 4-6 membered saturated heterocyclic ring containing 1-2 ring heteroatoms independently selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C ₆ - alkoxy and halogen;

R ³ represents H or C1-C ₆ -alkyl; and

R ⁴ represents a _C1-C6 alkyl.

For complex chemical names used in this document, the substituent group is named before the group to which it is attached. For example, methoxyethyl includes an ethyl group in the main chain with a methoxy group as a substituent.

The term halogen means —F (sometimes referred to herein as fluorine), —Cl, —Br, and —I.

The terms _C1-C3 alkyl, C1-C ₆ alkyl, C ₂ -C ₆ -alkyl and C ₃ -C ₆ alkyl, in the context of this document, refers to saturated monovalent hydrocarbon radicals with a linear or branched

- 5,035,568 chain containing from one to three, from one to six, from two to six or from three to six carbon atoms, respectively. Examples include, without limitation, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

The term C ₁ -C ₆ alkoxy, as used herein, refers to a straight or branched chain saturated monovalent alkoxy radical containing from one to six carbon atoms, where the radical is attached to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy.

The terms (CpC ^ alkoxy ^ CpC ^ alkyl- and (C ₁ -C ₆ -alkoxy) C ₂ -C ₆ -alkyl-, as used herein, refer to saturated straight or branched chain monovalent radicals containing from one to six atoms . carbon or from two to six carbon atoms, respectively, wherein one of the carbon atoms substituted by (C1-C ₆ -alkoxy), as defined herein, examples include methoxymethyl (CH ₃ OCH ₂ -) and methoxymethyl (CH ₃ OCH ₂ CH ₂ -).

The terms hydroxy-C ₁ -C ₆ -alkyl and hydroxy-C ₂ -C ₆ -alkyl, as used herein, refer to saturated straight-chain or branched saturated monovalent radicals containing from one to six carbon atoms or from two up to six carbon atoms, respectively, with one of the carbon atoms replaced by a hydroxy group.

The term dihydroxy-C ₃ -C ₆ -alkyl - as used herein, refers to a saturated, straight or branched chain saturated monovalent radical of three to six carbon atoms, two of the carbon atoms being replaced by a hydroxy group.

The terms (R ¹ R ² N) C1-C6-alkyl, and (R ¹ R ² N) C2-C ₆ -alkyl, in the context of this document, refer to refer to radicals of _C1-C6 alkyl or C2-C6 respectively as defined herein, wherein one of the carbon atoms is substituted with an R1R2N— group, where R ¹ and R ² are as defined herein.

The term Ar ¹ C ₁ -C ₆ -alkyl-, in the context of this document, refers to a C1-C ₆ -alkyl radical as defined herein, wherein one of the carbon atoms is replaced by a het-Ar ¹ group, while het-Ar ^{1 is} defined in this document.

The term C ₃ -C ₆ -cycloalkyl, as used herein, refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The terms (C ₃ -C ₆ -cycloalkyl) C ₁ -C ₃ -alkyl- and (C ₃ -C ₆ -cycloalkyl) C ₁ -C ₆ -alkyl, as used herein, refer to C1-C ₃ - alkyl or C1-C6 radicals, respectively, as defined herein, wherein one of the carbon atoms is substituted by C ₃ -C ₆ cycloalkyl ring as defined herein.

The term C3-C6 cycloalkylidene ring, as used herein, refers to a divalent carbocyclic ring containing three to six carbon atoms. The suffix ylidine refers to a divalent radical derived from a saturated hydrocarbon by removing two hydrogen atoms from the same carbon atom.

The term (het-Cyc ^a ) C ₁ -C ₃ -alkyl, in the context of this document, refers to a C _g C ₃ -alkyl radical as defined herein, wherein one of the carbon atoms is substituted by a het-Cus ^a group, while get-Cyca is as defined herein.

The term Ag1S1-C ₆ -alkyl, in the context of this document, refers to a C1-C ₆ -alkyl radical as defined herein, wherein one of the carbon atoms is substituted with Ar ¹ group wherein Ar ¹ is defined herein.

The terms het SRS-A ^ ^ alkyl-, in the context of this document, refer to a C1-C ₆ -alkyl radical as defined herein, wherein one of the carbon atoms substituted het-Ar ² group, wherein het-Ar ² defined in this document.

The term het-Sus1S1-C ₆ -alkyl, in the context of this document, refers to a C1-C ₆ -alkyl radical as defined herein, wherein one of the carbon atoms substituted het-Cyc ¹ group, wherein het-Cyc ¹ is as defined in this document.

The term № _(C1-C6 alkyl) pyridinone, as used herein, refers to a ring pyridin-2 (1H) -one, and the ring nitrogen atom is substituted with C1-C ₆ -alkyl substituent, and wherein the radical may be connected with any of the ring carbon atoms other than the carbon atom bonded to the oxo group. Examples include the structures (C 1 -Cd alkyl) (C _ G 's alkyl) (C 1 -C 3 alkyl) (C 1 -C3 alkyl)

The term heterospirocyclic, as used herein, refers to a group containing two rings linked by a spirocyclic bond through a carbon atom, where each ring contains from 4 to 6 ring atoms (with one ring carbon being common to both rings), and wherein two of the ring atoms are nitrogen atoms.

- 6 035568

The term oxo or oxo, as used herein, refers to an oxygen atom that is double bonded to a carbon atom, t.c. = O. For example, in one embodiment, when considering ring D, a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms can be, for example, a piperazinyl ring substituted with an oxo group (for example, a piperazinonyl ring), and it can be represented by the structure

about

The term compound, in the context of this document, refers to all stereoisomers, geometric isomers, tautomers and isotopes of the indicated structures. Compounds identified herein by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

The term tautomer, in the context of this document, refers to compounds whose structures differ markedly in the arrangement of atoms, but which exist in easy and rapid equilibrium, and it should be understood that the compounds provided herein can be depicted as different tautomers, and when the compounds are in tautomeric forms, all tautomeric forms are intended to be included within the scope of the invention, and the name of the compounds does not exclude any tautomer. Typical tautomerizations include, but are not limited to, keto-enol; amido-imide; lactamlactimic; enamine-imine; and tautomerization of an enamine to another enamine. A specific example of phenol ketone tautomerization is the interconversion of pyridin-2-ol and pyridin-2 (III) -one, for example

It is understood that certain compounds provided herein may contain one or more centers of asymmetry and therefore can be prepared and isolated in a mixture of isomers such as a racemic mixture or in enantiomerically pure form.

In some embodiments of Formula IX ¹ , X ² , X ^3, and X ^{4 are} independently CH, CF, or CCH3.

In some embodiments, X ¹ , X ² , X ^3, and X ⁴ are each CH.

In some embodiments of Formula IX, ¹ , X ² , X ^3, and X ^{4 are} independently CH, CF, or CCH3 or N, where one of X ¹ , X ² , X ^3, and X ⁴ is N and the rest are independently CH , CF or CCH3.

In some embodiments of Formula IX, ¹ is N, and X ² , X ^3, and X ^{4 are} independently CH or CF.

In some embodiments, X ¹ is N and X ² , X ^3, and X ⁴ are CH. In certain embodiments, X ¹ is N, X ² is CF, and X ³ and X ⁴ are CH.

In some embodiments of Formula IX ¹ , X ² , X ^3, and X ^{4 are} independently CH, CF, or CCH ₃ or N, where two of X ¹ , X ² , X ^3, and X ⁴ are N.

In some embodiments of Formula IX, ¹ and X ³ are N, and X ² and X ^{4 are} independently CH, CF, or CCH ₃ . In one embodiment, X ¹ and X ³ are N and X ² and X ⁴ are CH.

In some embodiments of Formula IX, ¹ and X ² are N, and X ¹ and X ^{4 are} independently CH or CF.

In some embodiments of Formula IX, ¹ and X ² are N, and X ¹ and X ⁴ are CH.

In some embodiments of Formula I, A is H.

In some embodiments of Formula I, A is Cl.

In some embodiments of Formula I, A is CN.

In some embodiments of Formula IA is CH ₃ -.

In some embodiments of Formula I, A is CH3CH2-.

In some embodiments of Formula I, A is cyclopropyl.

In some embodiments of Formula I, A is —CH2CN.

In some embodiments of Formula IA is —CH (CN) CH ₃ .

In some embodiments of Formula I, B is hydrogen.

In some embodiments of Formula IB, is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. Non-limiting examples include methyl, ethyl, propyl, isopropyl, isobutyl, 2-methylbutyl, 2-ethylbutyl, 2,2-dimethylpropyl, difluoromethyl, 2,2-difluoroethyl, and 2,2,2

- 7 035568 trifluoroethyl.

In some embodiments of Formula I, B is hydroxy-C ₂ -C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms or a C ₃ -C ₆ cycloalkylidene ring. In some embodiments of Formula I, B is hydroxy-C ₂ -C ₆ -alkyl - wherein the alkyl moiety is unsubstituted. Non-limiting examples include structures:

In some embodiments of Formula IB, is dihydroxy-C ₃ -C ₆ -alkyl-, wherein the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring. In some embodiments, Formula IB is dihydroxy-C ₃ -C ₆ alkyl. A non-limiting example includes 2,3-dihydroxypropyl.

In some embodiments of Formula IB is (^ - ^^^^^^ - ^ alkyl optionally substituted with 1 to 3 fluorine atoms. In some embodiments of Formula IB is (C ₁ -C ₆ alkoxy) C ₂ -C ₆ -alkyl- optionally substituted with 1 to 3 fluorine atoms Non-limiting examples include structures: \ _r > e.

about.

.about

O '* fH

F

In some embodiments of Formula I, B is (R ¹ R ² N) C1-C6 alkyl-, wherein said alkyl moiety is optionally substituted OH, and R ¹ and R ^{2 are} independently H or C1-C ₆ alkyl ( optionally substituted with 1-3 fluorine atoms). In some embodiments of Formula IB, is (R ¹ R ² N) C1-C6 alkyl, wherein said alkyl moiety is optionally substituted OH, and R ¹ and R ^{2 are} independently H or C2-C ₆ alkyl (optionally substituted 1-3 fluorine atoms). In some embodiments of Formula IB, is (R ¹ R ² N) C1-C6 alkyl, wherein said alkyl moiety is optionally substituted with OH, and R ¹ and R ^{2 are} independently selected from C1-C ₆ alkyl substituents. Non-limiting examples in which B is (R ¹ R ² N) C ₁ -C ₆ alkyl include structures:

In some embodiments of Formula I, B is het-Ar ¹ C1-C3 alkyl, where het-Ar ¹ is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, and optionally substituted with one or more independently selected C1-C ₆ alkyl substituents. In some embodiments, het-Ar ¹ is a 5-6 membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from N and O and optionally substituted with one or more C1-C6 alkyl substituents. Non-limiting examples of het-Ar ¹ C1-C ₃ -alkyl include structures:

In some embodiments of Formula IB is (C ₃ -C ₆ -cycloalkyl) C ₁ -C ₃ alkyl-, wherein said cycloalkyl is optionally substituted with OH. Non-limiting examples include structures:

- 8 035568

In some embodiments of Formula I, B is (het-Cyc ^a ) C ₁ -C ₃ -alkyl-, where het-Cyca is a 4-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O, and is optionally substituted with one or more substituents independently selected from OH, C-C-alkyl (optionally substituted with 1-3 fluorine atoms), hydroxy-C-C-alkyl-, C-C-alkoxy, (C ₁ -C _6- salkyl) C (= O) -, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl - and fluoro, or where het-Cyca is substituted with oxo. Non-limiting examples include structures:

In some embodiments of Formula I, B is het-Cyca, wherein het-Cyca is a 4-6 membered heterocyclic ring containing 1 to 2 ring heteroatoms independently selected from N and O, and is optionally substituted with one or more substituents, independently selected from OH, C-C-alkyl (optionally substituted with 1-3 fluorine atoms), hydroxy-C ₁ -C ₆ alkyl-, C-C-alkoxy, (C1-C ₆ -OKUH) C (= O) -, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl- and fluoro or where het-Cyca is substituted with oxo. In some embodiments, het-Cyca is optionally substituted OH or C-C-alkyl (optionally substituted with 1-3 fluorine atoms). Non-limiting examples include structures:

In some embodiments, Formula IB is C ₃ -C ₆ cycloalkyl, wherein

- 9,035568 said cycloalkyl is optionally substituted with OH. A non-limiting example is the structure

In some embodiments, Formula IB is (C ₁ -C 4 alkyl) C (= O) O — C ₁ C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. A non-limiting example is the structure

In some embodiments of Formula I, B is ^^^ C ^ O ^ -C ^ alkyl-, where R ¹ and R ^{2 are} independently H or C 1 -C ₆ alkyl (optionally substituted with 1 to 3 fluorine atoms). Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is (i) a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third a ring heteroatom that is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, each of said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or C1-C3 alkoxy which is optionally substituted with 1-3 fluorine atoms, ( b) a C3-C6 cycloalkylidene ring; or (c) an oxo group.

The phrase having two ring nitrogen atoms, as used herein, when applied to ring D means that the two ring nitrogen atoms of ring D are the two ring nitrogen atoms depicted in formula I, with one of the ring nitrogen atoms bonded to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the other nitrogen atom of the ring is bonded to the E group.

In one embodiment, ring D is (i) a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, each of said rings not replaced.

In one embodiment, the ring D is a 4-7-membered saturated heterocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group. The phrase containing two ring nitrogen atoms, in the context of this document, when ring D is a saturated monocyclic 4-7 membered heterocyclic ring means that said ring nitrogen atoms are two nitrogen atoms depicted in ring D of formula I, i.e. ... ring D can be represented by structures:

where the wavy line indicates the point of attachment to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to the E group, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1 -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or Cd-C ^ -alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group. In one embodiment, Ring D is an unsubstituted saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms, said ring being substituted with oxo. In one embodiment, ring D is a saturated 6 membered heterocyclic ring containing two ring nitrogen atoms, said ring being a substituted C ₃ -C ₆ cycloalkylidene ring. In one embodiment, ring D

- 10 035568 is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms, said ring being a substituted C ₃ -C ₆ cyclopropylidene ring. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms, said ring being substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1 -3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted by 1-3 fluorine atoms. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms, said ring being substituted ^ - ^ -alkyl optionally substituted with 1 to 3 fluorine atoms. In one embodiment, ring D is a saturated 7-membered heterocyclic ring containing two ring nitrogen atoms, said ring being unsubstituted. In one embodiment, when ring D is a saturated 6-7 membered heterocyclic ring containing two ring nitrogen atoms, the ring D and E moieties of formula I

can be represented by structures:

where the wavy line indicates the point of attachment to the ring containing X ¹ , X ² , X ³ and X ⁴ , and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is substituted with oxo. In one embodiment, Ring D is a substituted C ₃ -C ₆ cyclopropylidene ring. In one embodiment, ring D is substituted with oxo. In one embodiment, ring D is substituted with one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms ... In one embodiment, Ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms, said ring being substituted with one to four ^ - ^ - alkyl groups optionally substituted with 1-3 fluorine atoms. In one embodiment, ring D is unsubstituted, or ring D is substituted with one to four independently selected C ₁ -C ₃ alkyl groups (each of which is optionally substituted with 1 fluorine atom), or ring D is a substituted C ₃ -C ₆ cyclopropylidine ring, or ring D is substituted with oxo. In one embodiment, ring D is a saturated 7-membered heterocyclic ring containing two ring nitrogen atoms, said ring being unsubstituted. Examples of saturated 6- and 7-membered heterocyclic D rings include structures:

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo, and E is as defined for formula I. In one embodiment, Ring D is a saturated 6-7 membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is substituted with oxo. In one embodiment, Ring D is a substituted cyclopropylidene ring. In one embodiment, ring D is substituted with one or two ^ - ^ - alkyl groups, for example, one or two methyl groups.

- 11 035568

In one embodiment, the ring D is a 4-7-membered saturated heterocyclic ring containing two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents (a) hydrogen, (c) _(C1-C6 alkoxy) _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms, (d) (C1-C6 alkyl) C (= O) - optionally substituted with 1-3 fluorine atoms, (e) _{(hydroxy-C2-C6} alkyl) C (= O) - optionally substituted with 1-3 fluorine atoms, (f) (C1-C ₆ -alkoxy) C (= O) -, (g) (C ₃ -C ₆ -cycloalkyl) C (= O) -, wherein said cycloalkyl is optionally substituted with (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl or 5-6 membered heteroaryl ring containing 1-3 ring heteroatom independently selected from N and O, (h) Ar1C1C ₆ -alkyl-, (i) Ar ¹ (C ₁ -C ₆ -alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy-C 1 -C ₆ -alkyl- or C 1 -C ₆ -alkoxy, (j) het-Ar2C1 -C ₆ -alkyl-, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, (k) het-Ar2 _(C1-C6 alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy C1- -C ₆ -alkyl- or C1-C ₆ -alkoxy, (l) het-Ar2C (= O) -, (m) het-Cy (CCO) -, (n) het-Cy (CgC-alkylDo) R ³ R ⁴ NC (= O) - or (cc) het-Ar ² , where Ar ¹ , het-Ar ² , hetCyc ¹ , R ³ and R ⁴ are as defined for formula I. In one embodiment, ring D is a saturated 6-7 membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, Ring D is a saturated 7-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is a saturated 6-7 membered heterocyclic ring, wherein ring D is unsubstituted. In one embodiment, ring D is a saturated 6-membered ring. In one embodiment, ring D is substituted with oxo. In one embodiment, Ring D is a substituted cyclopropylidene ring. In one embodiment, ring D is substituted with one or two C1-C3 alkyl groups, eg, one or two methyl groups.

In one embodiment, the ring D is a 4-7-membered saturated heterocyclic ring containing two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1 to 3 fluorine atoms, or C ₁ -C ₃ alkoxy, which is optionally substituted by 1 to 3 fluorine atoms, (b) a C ₃ -C 6 cycloalkylidene ring, or (c) an oxo group, and E is hydrogen. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. A non-limiting example is the structure:

In one embodiment, the ring D is a 4-7-membered saturated heterocyclic ring containing two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents a (C1 -C6alkoksi) _C1-C6 alkyl, optionally substituted with 1-3 fluorine atoms. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted.

A non-limiting example is the structure:

In one embodiment, the ring D is a 4-7-membered saturated heterocyclic ring containing two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -tsikloαlkilidenovym ring, or (c) an oxo group, and E represents (C1 -C6alkyl) C (= O) - optionally substituted with 1-3 fluorine atoms. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. A non-limiting example is the structure

- 12 035568

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, Q ^ -alkyl, which is optionally substituted with 1-3 fluorine atoms, or Q ^ -alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C ₃ -C ₆ -cycloalkylidene ring or (c) an oxo group and E is (hydroxy C ₂ -C ₆ -alkyl ) C (= O) - optionally substituted with 1-3 fluorine atoms. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. A non-limiting example is the structure

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) ^ - ^ - cycloalkylidene ring, or (c) oxo and E is (C1-C6 alkoxy) C (= O) -. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. A non-limiting example is the structure

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo and E is (C ₃ -C ₆ cycloalkyl) C (= O) -, wherein said cycloalkyl is optionally substituted with (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl or a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N and O, for example pyridinyl. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) ^ - ^ - cycloalkylidene ring or (c) oxo group, and E is Ar ¹ C ₁ -C ₆ alkyl-, where Ar ¹ is as defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is substituted with oxo. In one embodiment, Ar ¹ is unsubstituted. Non-limiting examples include structures:

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which neobyaza- 13 035568 Tel'nykh substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents Ar1 (C1-C ₆ alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy _C1-C6 alkyl, C1-C ₆ -alkoxy, R ^m R ⁿ N- or R ^m R ^{n N-CH2-,} where each R ^m and R ⁿ independently represents H or _C1-C6 alkyl, and Ar ¹ is as defined for formula I. In one embodiment, the ring D represents a saturated 6-membered a heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, Ar ¹ is unsubstituted or substituted with one or more halogen atoms. Non-limiting examples include structures:

In one embodiment, the ring D is a 4-7-membered saturated heterocyclic ring containing two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms 2, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents get- Ar C1C ₆ -alkyl-, wherein the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms and wherein het-Ar ² is as defined for Formula I. In one embodiment, ring D is a saturated 6-7 membered a heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, Ring D is a substituted cyclopropylidene ring. In one embodiment, getAr ² is a 5-6 membered heterocyclic ring containing 1 to 2 ring nitrogen atoms. In one embodiment, het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), and C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, het-Ar ² is a 6-membered heteroaryl ring having 1 to 2 ring nitrogen atoms and is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1- 3 fluorine atoms) and _C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms). Non-limiting examples include structures:

- 14 035568

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 2 2 / ^ fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) oxo, and E is het -Ar (C1

- 15 035568 ^ -alkyl ^^ O) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy-C ₁ -C ₆ -alkyl or ^ - ^ - alkoxy, and het-Ar ² is the same as defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, the alkyl moiety of het-Ar ² (C ₁ -C ₆ -alkyl) C (= O) - is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heterocyclic ring containing 1-2 ring nitrogen atoms. In one embodiment, het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, ^ - ^ - alkyl (optionally substituted with 1-3 fluorine atoms), and ^ - ^ - alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, het-Ar ² is a 6-membered ring containing 1 to 2 ring nitrogen atoms and is optionally substituted with one or more halogens. A non-limiting example includes a structure:

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo, and E is het Ar2C (= O ) -, wherein ιότ-γ ^ (= Ο) - is as defined for formula I. In one embodiment, ring D is a saturated 6-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is unsubstituted. In one embodiment, ring D is a saturated 7-membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heterocyclic ring containing 1-2 ring nitrogen atoms. In one embodiment, het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ₁ -C ₆ -alkyl (optionally substituted with 1-3 fluorine atoms), and ^ - ^ - alkoxy (optionally substituted with 1 -3 fluorine atoms). In one embodiment, het-Ar ² is a 6-membered ring containing 1 to 2 ring nitrogen atoms and is optionally substituted with ^ - ^ - alkoxy. Non-limiting examples include structures:

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group, and E is hetCyc1C (= O) -, where het-Cyc ¹ is as defined for formula I. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, het-Cyc ¹ is a 4-6 membered saturated heterocyclic ring containing a ring nitrogen atom, said heterocyclic ring optionally substituted with one or more independently selected ^ - ^ - alkoxy substituents. A non-limiting example includes a structure

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, Q ^ -alkyl, which is optionally substituted with 1-3 fluorine atoms, or Q ^ -alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group, and E is reT-Cy ^ Cr C ₆ -alkyl, wherein het-Cyc ¹ is as defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one brew

16 035568 ante realization of het-Cyc ¹ is a 4-6 membered saturated heterocyclic ring containing a ring oxygen atom. In one embodiment, het-Cyc ¹ is unsubstituted. A non-limiting example includes a structure

Wo

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring, or (c) oxo, and E is R ³ R ⁴ NC (= O) -, wherein R ³ and R ⁴ are as defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms. In one embodiment, said ring D is unsubstituted. A non-limiting example includes a structure

A'U I

II n <, _Y W o.

In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group, and E is het-Ar ² , with het-Ar ² as defined for Formula I. In one embodiment, ring D is a saturated 6-membered heterocyclic ring containing two ring nitrogen atoms, ring D being unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heterocyclic ring containing 1-2 ring nitrogen atoms. In one embodiment, het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, ^ - ^ - alkyl (optionally substituted with 1-3 fluorine atoms) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms ). In one embodiment, het-Ar ² is a 6-membered ring containing 1 to 2 ring nitrogen atoms, and is optionally substituted with C1 ^ alkoxy. A non-limiting example includes a structure

In one embodiment of Formula I, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or ( c) an oxo group. The phrase having two ring nitrogen atoms, in the context of this document, when ring D is a saturated 7-8 membered bridged heterocyclic ring means that said ring nitrogen atoms are two ring nitrogen atoms depicted in ring D of formula I, with one of the ring atoms nitrogen is bonded to a ring containing X ¹ , X ² , X ³ and X ⁴ , and another nitrogen atom of the ring is bonded to group E as depicted in Formula I. Non-limiting examples, when ring D is a saturated 7-9 membered bridged heterocyclic ring, having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen include the following structures:

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, with the ring D optionally substituted with (a) one

17 035568 by four groups independently selected from halogen, OH, C1-C ₃ -alkyl which is optionally substituted by 1-3 fluorine atoms, or C1-C ₃ -alkoxy which is optionally substituted by 1-3 fluorine atoms, (b) C _{A 3} -C ₆ -cycloalkylidene ring; or (c) an oxo group. In one embodiment, ring D is unsubstituted.

In one embodiment, when ring D is a saturated 7-9 membered bridged heterocyclic ring containing 2-3 ring heteroatoms independently selected from N and O, fragments of rings D and E of formula I, i.e.

can be represented by non-limiting structures:

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -tsikloαlkilidenovym ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted.

In one embodiment, ring D is a saturated 7-membered bridged heterocyclic ring containing two ring nitrogen atoms, represented by the structure

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -tsikloalkilidenovym ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted.

In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ ring or -tsikloalkilidenovym ( c) oxo, and E is as defined for Formula I. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted.

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring of C ₃ -C ₆ or ( c) an oxo group, and E is selected from the group consisting of (a) hydrogen, (b) C1-C ₆ -alkyl, (c) (C ₁ -C ₆ alkoxy) C ₁ -C ₆ -alkyl, (d) (C ₁ -C ₆ -alkyl) C (= O) -, (e) (hydroxy-C ₂ -C ₆ -alkyl) C (= O) -, (f) (QC. ^ Kokc ^ C ^ O) -, (g) (C ₃ -C ₆ -cycloalkyl) C (= O) -, (h) Ar1C1-C ₆ alkyl-, (i) Ar ¹ (C1-C6-alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6-alkoxy, (j) het-Ar ² C1-C ₆ -alkilom-, wherein alkyl Fr. the agent is optionally substituted with 1-3 fluorine atoms, (k) het-Ar ² (C1-C6-alkyl) C (= O) -, wherein said alkyl fragment is optionally substituted with OH, hydroxy-C1-C6-αalkul- or C | -C6-alkoxy, (l) rem-A / C ^ O) -, (m) het-Cy ^ C ^ O) -, (o) R ³ R ⁴ NC (= O) -, (p) Ar1R ³ NC (= O) -, (q) reT-Ar ² N (R ³ ) C (= O) -, (r) (C ^ -alkyl ^, (t) het-Ar ^ O2-, (u) ChC1 -C6-alkyl) pyridinonyl, (v) Ar1C (= O) -, (w) Ar1OC (= O) -, (x) (C3-C6cycloalkyl) CH ₂ C (= O) -, (y) (C ₃ -C ₆ -cycloalkyl) (C ₁ -C ₆ -alkyl) SO ₂ -, (z) Ar ¹ (C ₁ -C ₆ -alkyl) SO ₂ -, (aa) het / ^ 71 ^ 1 - ^^^ / = ^^ - / ΗΗλ GAT-S \ / S ¹ 2 2ρρλ ΓΑΤ-Λΐ * ² GPA Δ Τ ' ¹ GAT-Δ Τ' ² R3 ΙΛ ΓΑΤ-ίΛ / Ρ ¹ CTR ΤΤΟΊΖΊΤΑ tT TQ ΤΓΤ / ΓΛΛΊ / Γ

V / yc - ^ \ _ χ (\ _ /) -, (υυ) het-Azyc - ^ j / ia-v. ^) -Y and (cc) het ^ n, where ζαχ, rex- / A1. , xx and xt ^ X / yc are such

18 035568 as defined for Formula I. In one embodiment, ring D is selected from the structures:

where the wavy line indicates the point of attachment of ring D to a ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring, containing two ring nitrogen atoms, represented by the structure

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, and E is selected from the group consisting of (a) hydrogen, (b) C1- C6-αalkyl, (c) (C1-C6-alkoxy) C1-C6-alkyl-, (d) (Cr ^ -alkyl ^^) -, (e) (hydroxy-C2-C6 alkyl)) C (= 0) -, (f) (C1- C6- alkoxy) C (= o) -, (g) (C3-C6- tsikloalkil) C (= O) -, (h) Ar ^1, C1-C ₆ -alkila- ( i) Ar ¹ (C1S6 alkyl) C (= 0) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6-alkoxy, (j) het-Ar ² C1-C ₆ -alkila- , wherein the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms, (k) het-Ar ² (C1-C6-alkyl) C (= O) -, the alkyl moiety is optionally substituted with OH, hydroxy-C1-C6-alkyl or C1- C6-alkoxy, (l) rst-Ar ² ^) -, (m) het-Cyc ¹ C (= O) -, (o) R ³ R ⁴ NC (= O) -, (p) Ar1N (R ³ ) C (= 0) -, (q) het-ArXi ³ ) C (= 0) -, (r) (CL-alkyl ^ -, (t) het-Ar ^ -, (u) N- (C1- Cealkyl) pyridinonyl, (v) Ar1C (= 0) -, (w) Ar1oC (= 0) -, (x) (C3-C ₆ -cycloalkyl) CH ₂ C (= O) -, (y) (c ₃ -C ₆ cycle alkyl) (C ₁ -C ₆ -alkyl) 80 ₂ -, (z) Ar ¹ (C ₁ -C ₆ -alkyl) 80 ₂ -, (aa) het-Cus1-0C (= 0) -, (bb) het-Cic1-CH ₂ C (= 0) - and (cc) het-Ar ² , where Ar ¹ , het-Ar ² , R ³ and het-Cyc ¹ are as defined for formula I. In one embodiment said ring D is unsubstituted.

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, 0H, C 1 C ₃ -alkyl which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring or (c) oxo, and E is H. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

Л "0, *

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halo, 0H, C 1 C ₃ -alkyl which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring of C ₃ -C ₆ or (c) oxo, and E is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

- 19 035568 where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, Q ^ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or Q ^ -alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group, and E is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example includes a structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or Q ^ -alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) a cycloalkylidene ring C3-C6 or (c ) an oxo group, and E is (C ₁ -C ₆ -alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted by 1-3 fluorine atoms or R ^g R ^h N-, where R ^g and R ^h independently represent H or ^ - ^ - alkyl. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, Q ^ -alkyl,

- 20 035568 which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring of C ₃ -C ₆ or (c) an oxo group, and E represents ( hydroxy _C2-C6 alkyl) C (= O) - optionally substituted with 1-3 fluorine atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X2, X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example includes structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring of C ₃ -C ₆ or (c) oxo and E is (C ₁ -C ₆ alkoxy) C (= O) -. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structures:

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring or (c) oxo, and E is (C ₃ -C ₆ -cycloalkyl) C (= O) -, said cycloalkyl optionally substituted with one or more substituents independently selected from C1-C ₆ -alkyl, C1-C _6- alkoxy, OH, and (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ alkyl, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N and O. In one embodiment implementation E is (C ₃ -C ₆ -cycloalk yl) C (= O) -, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from _C1-C6 alkyl, _C1-C6 alkoxy, OH and (C ₁ -C ₆ alkoxy) C ₁ - C ₆ alkyl-. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

- 21 035568 o o o

Ltd

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring of C3-C6 or ( c) oxo and E is A ^ CpOralkyl-, where Ar ¹ is as defined in formula I. In one embodiment, E is Ar ¹ C1-C6 alkyl-, Ar ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, SrS6 alkyl (optionally substituted with 1-3 fluorine atoms), _C1-C6 alkoxy (optionally substituted with 1-3 fluorine ^{atoms), (R p R q N} ) C1 -C 6 alkoxy, where R ^p and R ^q are independently H or alkyl SrS6 and (getAg ^a) _C1-C6 alkyl, wherein het-Ara is a 5-6 membered heteroaryl ring containing 1- 2 ring nitrogen atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered

- 22 035568 bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group and E is Ar ¹ (C ₁ -C ₆ -αalkyl) C (= O) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy ^ - ^ - alkyl, ^ - ^ - alkoxy, R ^m R ⁿ N- or R ^m R ⁿ N-CH2-, each R ^m and R ^{n are} independently H or ^ - ^ - alkyl, and Ar1 is as defined in formula I. In one embodiment, Ar1 is phenyl, which is unsubstituted or substituted with one or more halogen atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo and E is het-Ar ² C1-C6-αalkyl-, said alkyl moiety being optionally substituted with 1 to 3 fluorine atoms and het-Ar ² is as defined in Formula I. In one embodiment, hetAr ² is 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, or 9-10 membered bicyclic heteroaryl ring containing 1-3 ring nitrogen atoms, where het- Ar ² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C ₆ -alkila (optionally substituted with 1-3 fluorine atoms), ^ - ^ - alkoxy (optionally substituted with 1-3 fluorine atoms) , OH, C3-C ₆ -cycloalkyl, and R ^e R ^f N-, where R ^e and R ^f independently represent H or ^ - ^ - alkyl. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structures:

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

- 23 035568

- 24 035568

I

II, N

- 25 035568

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo and E is het-Ar ² (C1-C6-αalkyl) C (= O) -, said alkyl moiety being optionally substituted with OH, hydroxy-C ₁ -C ₆ -alkyl- or ^ - ^ - alkoxy and het —Ar ² is as defined in Formula I. In one embodiment, the alkyl moiety is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl containing 1 to 2 ring nitrogen atoms and is optionally substituted with one or more halogens. In one embodiment, ring D is unsubstituted. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example is the structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo and E is

- 26 035568

Ar ² C (= O) -, where het-Ar ² is as defined in formula I. In one embodiment, het-Ar ² is a 6-membered heteroaryl ring containing 1 to 2 ring nitrogen atoms and is optionally substituted one or more substituents independently selected from halogen, C ₁ -C ₆ alkoxy (optionally substituted with 1 to 3 fluorine atoms), and (Q - ^^ kokc ^ Q - ^^ kokcu. In one embodiment, ring D is represented by the structures:

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

- 27 035568

about

In one embodiment of Formula I, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring, or ( c) oxo, and E is het-Cyc ¹ C (= O) -, where het-Cyc ¹ is as defined in formula I. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

- 28 035568

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or C1-C _3- alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo and E is R ³ R ⁴ NC (= O) -, where R ³ is H or C1-C6 alkyl and R ⁴ is C1-C6 alkyl. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example includes a structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, C1-C3 alkyl, which is optionally substituted by 1-3 fluorine atoms, or C1-C _3- alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) a cycloalkylidene ring of C ₃ -C ₆ or (c ) oxo and E is Ar1N (R ³ ) C (= O) -, while Ar ¹ and R ³ are as defined in formula I. In one embodiment, Ar ¹ is unsubstituted or substituted C1-C ₆ alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, ring D is unsubstituted. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, C ₁ -C ₃ alkyl which is optionally substituted with 1-3 fluorine atoms, or C1-C ₃ alkoxy which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or ( c) oxo and E is het-Ar2M ^ ³ ) C (= O) -, where het-Ar ² and R ³ are as defined in formula I. In one embodiment, het-Ar ² is unsubstituted or substituted _C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

- 29 035568

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example is the structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo, and E is (C ₁ -C ₆ - ^ k ^) SO ₂ -, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo and E is het-Ar2SO2-, where het-Ar ² is as defined in Formula I. In one embodiment, het-Ar ² is unsubstituted or substituted ^ - ^ - alkoxy (optionally substituted with 1 to 3 fluorine atoms) ... In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example is the structure:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally

- 30,035,568 a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1 to 3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is ^^ - ^ - alkyl ^ iridinonyl. In one embodiment, Ring D is a saturated 78 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo and E is Ar ¹ C (= O) -, where Ar ¹ is as defined in formula I. In one embodiment, Ar ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of from halogen, ^ - ^ - alkyl (optionally substituted with 1-3 fluorine atoms) and ^ - ^ - alkoxy (optionally substituted with 1-3 fluorine atoms) or Ar ¹ is a phenyl ring fused with 5-6- a member heterocyclic ring containing two ring oxygen atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, C ₁ -C ₃ alkyl, which is optionally substituted by 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c ) an oxo group; and E is - 31 035568 is Ar ¹ OC (= O) -, where Ar ¹ is as defined in formula I. In one embodiment, Ar ¹ is unsubstituted. In one embodiment, ring D is unsubstituted. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the wavy line indicates the point of attachment of the D ring to the ring containing X ¹ , X ² , X ^3, and X ⁴ , and the asterisk indicates the point of attachment to E. A non-limiting example includes the structure:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring C ₃ -C ₆ or ( c) oxo, and E is (C ^ C ^ cyclovyl ^ H ^^ O) -, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example includes a structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, Ci-C ₃ alkyl, which is optionally substituted by 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring, or (c) oxo, and E is (C ₃ -C ₆ -cycloalkyl) (C ₁ -C ₃ -alkyl) SO ₂ -, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example includes a structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, C ₁ -C ₃ alkyl, which is optionally substituted with 1 to 3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally

- 32 035568 is substituted by 1-3 fluorine atoms, (b) a cycloalkylidene ring C ₃ -C ₆ or (c) an oxo group and E is Ar ¹ (C ₁ -C ₆ -alkyl) 8O ₂ -, while Ar ¹ is such as defined in Formula I. In one embodiment, Ar ¹ is unsubstituted. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example includes a structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, C-C-alkyl, which is optionally substituted with 1-3 fluorine atoms, or C-C-alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C-C-cycloalkylidene ring, or (c) oxo, and E is het-Cyc ¹ -OC (= O) -, where het-Cyc ¹ is as defined in formula I. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring, containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally containing a third ring heteroatom which is oxygen, said ring optionally substituted with (a) one to four groups, independently selected from halogen, OH, C-C-alkyl, which is optionally substituted with 1-3 fluorine atoms, or C-C-alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C-C-cycloalkylidene ring, or (c) oxo, and E is het-Cyc ¹ -CH ₂ -C (= O) -, wherein het-Cyc ¹ is as defined in Formula I. In one embodiment, ring D is a saturated 7-8 membered a bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example includes a structure

In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said ring is optionally substituted with (a) one - four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring C3-C6 or (c) oxo and E is het-Ar ² , where het-Ar ² is as defined in Formula I. In one embodiment, hetAr ² is a 6-membered ring containing 1 to 2 ring nitrogen atoms, and optionally substituted with ^ - ^ - alkoxy. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring containing two ring nitrogen atoms. In one embodiment, ring D is represented by the structures:

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group. The phrase having two ring nitrogen atoms, in the context of this document, when ring D is a saturated 7-11 membered heterospirocyclic ring means that said ring nitrogen atoms are two ring nitrogen atoms depicted in ring D of formula I, with one of the ring nitrogen atoms bonded with a ring containing X ¹ , X ² , X ³ and X ⁴ , and another nitrogen atom of the ring is bonded to the group E as depicted in Formula I. Non-limiting examples when ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms include structures:

- 34 035568 where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, each of these rings is optionally substituted with (a) one to four groups, independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloαalkylidene ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted.

In one embodiment, when ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, ring D and E moieties of formula I

can be represented by non-limiting structures:

where the wavy line indicates the point of attachment of ring D to a ring containing X ¹ , X ² , X ³ and X ⁴ , each of these rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -αalkyl, which is optionally substituted with 1 to 3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted by 1 to 3 fluorine atoms, (b) a C ₃ -C ₆ -cycloαalkylidene ring or (c) an oxo group and E is such as defined for Formula I. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is represented by the structure

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and the ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group. In one embodiment, said ring D is unsubstituted.

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms or ^ - ^ - alkoxy, which is optionally substituted with 1-3

35,035,568 fluorine atoms, (b) a C ₃ -C ₆ cycloalkylidene ring or (c) an oxo group, and E is selected from the group consisting of (a) hydrogen, (b) C ^ C ^ alkyl optionally substituted 1-3 fluorine atoms, (d) (C1-C6 alkyl ^^) -, wherein said alkyl moiety is optionally substituted with 1-3 fluorine atoms or R ^g R ^h N-, where R ^g and R ^{h are} independently H or C1-Cb- alkyl, (f) (Q-Qs ^ kokc ^ C ^ O) -, (l) hetAr ² C (= O) -, (o) R ³ R ⁴ NC (= O) -, (m) Ar ² SO2 -, (t) het-Ar ^ -, (v) Ar1C (= O) -, (cc) het-Ar ² , and (dd) C3-Cbcycloalkyl, while het-Ar ² , Ar ¹ , R ³ and R ⁴ are as defined for formula I. In one embodiment, said ring D is unsubstituted.

In one embodiment, Ring D is a saturated 9-membered hetero-spirocyclic ring containing two ring nitrogen atoms, represented by the structure

where the wavy line indicates the point of attachment of the D ring to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, and the specified ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) oxo and E is selected from the group consisting of (a) hydrogen, (d) (Q - ^^ kokc ^ C ^ O) - and (o) R ³ R ⁴ NC (= O) -. In one embodiment, said ring D is unsubstituted.

In one embodiment, the ring D is a saturated 7-11 membered geterospirotsiklicheskoe ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents hydrogen. In one embodiment, the specified ring D is represented by structures:

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the implementation of the specified ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment, the ring D is a saturated 7-11 membered geterospirotsiklicheskoe ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents (b) C ^ C ^ alkyl optionally substituted with 1 to 3 fluorine atoms. In one embodiment, said ring D is represented by the structure

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the implementation of the specified ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment of Formula I, Ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) with one to four groups independently selected from halogen, OH, C ₁ -C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene ring of C3-C6 or (c) an oxo group, and E represents (Cr ^ - alkyl ^^) -, wherein said alkyl moiety is optionally substituted with 1-3 fluorine atoms or R ^g R ^h N-, where R ^g and R ^h independently represent H or C ^ C ^ alkyl. In one wa

- 36 035568 At the same time, the specified ring D is represented by the structures:

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the implementation of the specified ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment, the ring D is a saturated 7-11 membered geterospirotsiklicheskoe ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -tsikloαlkilidenovym ring, or (c) an oxo group, and E represents (SgSz alkoxy ^ C ^ O) -. In one embodiment, the specified ring D is represented by structures:

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the implementation of the specified ring D is unsubstituted. Non-limiting examples include structures:

In one embodiment, the ring D is a saturated 7-11 membered geterospirotsiklicheskoe ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents getAr ² C ( = O) -, wherein het-Ar ² is as defined for Formula I. In one embodiment, het-Ar ² is a 5-6 membered heterocyclic ring containing 1-2 ring nitrogen atoms. In one embodiment, het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 13 fluorine atoms), and C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms ). In one embodiment, het-Ar ² is a 6-membered ring containing 1 to 2 ring nitrogen atoms and is optionally substituted with C 1 -C ₆ alkoxy. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is represented by the structure

where the wavy line indicates the point of attachment of the D ring to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. A non-limiting example includes the structure

In one embodiment, the ring D is a saturated 7-11 membered geterospirotsiklicheskoe ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C ₃ alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E represents R ³ R ⁴ NC (= O) -, wherein R ³ and R ⁴ are as defined for Formula I. In one embodiment, R ³ is H and R ⁴ is C ₁ -C ₆ alkyl. In one implementation

- 37 035568 the indicated ring D is represented by the structure

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the implementation of the specified ring D is unsubstituted. A non-limiting example includes a structure:

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C ₃ -C ₆ -cycloalkylidene ring, or (c) an oxo group, and E is Ar1SO ₂ -, while Ar ¹ is as defined for Formula I. In one embodiment, Ar ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, ^ - ^ - alkyl (optionally substituted with 1-3 fluorine atoms ) and ^ - ^ - alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, said ring D is unsubstituted. In one embodiment, said ring D is represented by the structure

where the wavy line indicates the point of attachment of the D ring to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. Non-limiting examples include structures:

4zP

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring, or (c) oxo and E is hetAr ² SO ₂ -, het-Ar ² is as defined for formula I. In one embodiment, 2 het-Ar is a 5-6 membered heterocyclic ring containing 1-2 ring nitrogen atoms. In one embodiment, het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, ^ - ^ - alkyl (optionally substituted with 13 fluorine atoms), and ^ - ^ - alkoxy (optionally substituted with 1-3 fluorine atoms ). In one embodiment, het-Ar ² is a 6-membered ring containing 1 to 2 ring nitrogen atoms and is optionally substituted with ^ - ^ - alkoxy. In one embodiment, said ring D is unsubstituted. In one embodiment, said ring D is represented by the structure where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. A non-limiting example includes the structure:

^L Λχΐ

In one embodiment, ring D is a saturated 7-11 membered heterospiro

38 035568 a cyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ alkyl, which is optionally substituted with 1 to 3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1 to 3 fluorine atoms, (b) a C ₃ -C ₆ -cycloalkylidene ring or (c) an oxo group and E is Ar1C (= O) -, while Ar ¹ is as defined for Formula I. In one embodiment, Ar ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl (optionally substituted with 1 to 3 fluorine atoms), and ^ - N-alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, said ring D is unsubstituted. In one embodiment, said ring D is represented by the structure

where the wavy line indicates the point of attachment of the D ring to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. Non-limiting examples include structures:

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C ₃ -C ₆ -cycloalkylidene ring, or (c) an oxo group, and E is hetAr ² -, wherein het-Ar ² is as defined for formula I. In one embodiment, hetAr ² is a 5-6 membered heterocyclic ring containing 1-2 ring nitrogen atoms. In one embodiment, het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, ^ - ^ - alkyl (optionally substituted with 1-3 fluorine atoms), and ^ - ^ - alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, het-Ar ² is a 6-membered ring containing 1 to 2 ring nitrogen atoms and is optionally substituted with ^ - ^ - alkoxy. In one embodiment, said ring D is unsubstituted. In one embodiment, said ring D is represented by the structure

where the wavy line indicates the point of attachment of the D ring to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. A non-limiting example includes the structure

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C ₃ -C ₆ cycloalkylidene ring, or (c) an oxo group, and E is C ₃ ^ cycloalkyl. In one embodiment, said ring D is unsubstituted. In one embodiment, said ring D is represented by the structure

where the squiggly line indicates the attachment point of the D ring to the ring containing X ¹ , X ² , X ^3, and X ⁴ , and the asterisk indicates the attachment point to E. A non-limiting example includes the structure

In one embodiment, ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halo

- 39 035568 gene, OH, C1-C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or C1-C ₃ -alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo. The phrase having two ring nitrogen atoms, in the context of this document, when ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring means that said ring nitrogen atoms are two ring nitrogen atoms depicted in ring D of formula I, with one of ring nitrogen atoms are bonded to a ring containing X ¹ , X ² , X ^3, and X ⁴ , and another ring nitrogen atom is bonded to group E as depicted in Formula I. Fused rings include 5.5, 5.6, 6.5 and 6.6 condensed ring systems. In one embodiment, said ring D is represented by the structure

where the wavy line indicates the point of attachment of the D ring to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, and the specified ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted by 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloαalkylidene ring or (c) oxo group. In one embodiment, said ring D is unsubstituted.

In one embodiment, ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo and E is as defined for formula I.

In one embodiment, ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C ₃ -C ₆ cycloalkylidene ring or (c) an oxo group and E is hydrogen or (C ₁ -C ₆ -alkoxy) C (= O) -. In one embodiment, ring D is represented by the structure

where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted.

In one embodiment, ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C ₃ -C ₆ cycloalkylidene ring, or (c) oxo and E is hydrogen. In one embodiment, ring D is represented by the structure </ * where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. A non-limiting example is the structure of n

L '

In one embodiment, ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, said ring optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C ₃ -C ₆ -cycloalkylidene ring or (c) an oxo group and E is (C ₁ - C ₆ -alkoxy) C (= O) -. In one embodiment, ring D is

- 40 035568 structure

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E. In one embodiment, the implementation of the specified ring D is unsubstituted. A non-limiting example is the structure:

In one embodiment, Formula I includes compounds of Formula I-A, wherein

X ¹ , X ² , X ³ and X ^{4 are} independently CH, CF, or N, where zero, one, or two of X ¹ , X ² , X ³ and X ⁴ are N;

A is H, CN, Cl, CH ₃ -, CH ₃ CH ₂ -, cyclopropyl, —CH2 CN, or —CH (CN) CH ₃ ;

B represents:

(a) hydrogen, (b) C ₁ -C ₆ -alkyl optionally substituted with 1 to 3 fluorine atoms, (c) hydroxy-C ₂ -C ₆ -alkyl-, where the alkyl moiety is optionally substituted by 1 to 3 fluorine atoms or C ₃ -C ₆ -cycloalkylidene ring, (d) dihydroxy-C ₃ -C ₆ -alkyl, where the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring, (e) (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl optionally substituted with 1 to 3 fluorine atoms, (f) (R ¹ R ² N) C1-C6 -alkyl-, wherein said alkyl moiety is optionally substituted with OH and wherein R ¹ and R ^{2 are} independently H or C1- C ₆ -alkyl (optionally substituted with 1 to 3 fluorine atoms);

(g) het-Ar ¹ C ₁ -C ₃ -alkyl, where het-Ar ¹ is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, and is optionally substituted with one or more independently selected ^ - ^ - alkyl substituents;

(h) (C ₃ -C ₆ -cycloalkyl) C ₁ -C ₃ -alkyl, where said cycloalkyl is optionally substituted with OH, (i) (het-Cyc ^a ) C ₁ -C ₃ -alkyl-, (j) het- Cyca-;

(k) C ₃ -C ₆ -cycloαalkyl-, wherein said cycloalkyl is optionally substituted with OH, (l) (C ₁ -C ₄ -alkyl) C (= O) OC ₁ -C ₆ -alkyl-, where each of ^ - ^ -alkyl and ^ - ^ - alkyl fragments are optionally and independently substituted by 1-3 fluorine atoms, or (m) (R ¹ R ² N) C (= O) C ₁ -C ₆ -alkyl-, where R ¹ and R ^{2 are} independently H or ^ - ^ - alkyl (optionally substituted with 1 to 3 fluorine atoms);

het-Cyca- is a 4-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, ^ - ^ - alkyl (optionally substituted with 1 -3 fluorine atoms), hydroxy-C ₁ -C ₆ -alkyl-, ^ - ^ - alkoxy, (^ - ^ - alkyl ^^ O) -, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ - alkyl and fluoro or where het-Cyca is substituted with oxo;

Ring D represents

where the wavy line indicates the point of attachment to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to the group E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, ^ - ^ - alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group;

E represents:

(a) hydrogen, (c) (QQ ^ kokc ^ Q - ^^ km-, optionally substituted with 1-3 fluorine atoms, (d) (C ₁ -C ₆ -alkyl) C (= O) -, where said alkyl the fragment is optionally substituted by 1-3 fluorine atoms or a substituent R ^g R ^h N-, where R ^g and R ^h independently represent H or Og ^ -alkyl, (e) (hydroxy-C ₂ -C ₆ -alkyl) C (= O) -, optionally substituted with 1-3 fluorine atoms, (f) (C ₁ -C ₆ -alkoxy) C (= O) -, (g) (C ₃ -C ₆ -cycloalkyl) C (= O) -, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from ^ - ^ - alkyl, ^ - ^ - alkoxy, OH and (Q-cs ^ kokc ^ QQ

- 41,035,568 alkyl, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from N and O, (h) Ar ^ -C ^ alkyl-, (i) Ar ^ C-C ^ CO ^ alkyl) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy-C SD-alkyl, C1-C ₆ -alkoxy, R ^m R ⁿ N- or R ^m R ^{n N-CH2-,} wherein each R ^m and R ⁿ independently represents H or C1-C ₆ -alkyl, (j) het-Ag2S1-C ₆ -alkyl-, wherein said alkyl moiety is optionally substituted with 1-3 fluorine atoms, (k) het-Ar2 (C ₁ - C ₆ -alkyl) C (= O) -, where said alkyl moiety is optionally substituted with OH, hydroxy-C 1 -C ₆ -alkyl or C 1 -C ₆ -alkoxy, (l) het-Ar 2 C (= O) -, (m ) het-Cic1C (= O) -, (n) het-Cus ¹ C ₁ -C ₆ -alkyl-, (o) R ³ R ⁴ NC (= O) -, or (cc) het-Ar ² ;

Ag ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms), R ^e RfN-, where R ^e and Rf independently represent H or C1-C6-alkyl, (KK ^ CgCb-alkoxy-, where Rp and R ^q independently represent H or C1-C6-alkyl, and (het-Ar ^a ) C1-C6-alkyl-, where het-Ar ^a is a 5-6 membered heteroaryl ring containing 1-2 ring nitrogen atoms, or Ar ¹ is a phenyl ring fused with 5-6- a membered heterocyclic ring containing 1 to 2 ring heteroatoms independently selected from N and O;

het-Ar ² is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl ring containing 1-3 ring nitrogen atoms, where het -Ag ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, CK, C1-C6-alkyl (optionally substituted with 1-3 fluorine atoms), C1-C6-alkoxy (optionally substituted with 1-3 fluorine atoms) , (C1-C6 alkoxy) C1-C6-alkyl- (optionally substituted with 1-3 fluorine atoms), R ^e RfN-, where R ^e and Rf independently represent H or C | -C6-alkyl, OH, (C ₁ - C ₆ alkoxy) C ₁ -C ₆ alkoxy and C ₃ -C ₆ cycloalkyl;

het-Cuss ¹ is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C ₆ - alkoxy and halogen; and

R ⁴ represents a _C1-C6 alkyl.

In one embodiment of Formula I-A, Ring D is unsubstituted.

In one embodiment of Formula I-A, X ¹ is N; X ² , X ³ and X ⁴ represents CH.

In one embodiment of Formula I-A, A is CK.

In one embodiment of Formula I-A, ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ represents CH; and A represents SK.

In certain embodiments of formula I-A B represents a _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms.

In one embodiment of Formula I-AB, B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms, or hydroxy C ₂ -C ₆ alkyl, wherein the alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring.

In one embodiment of Formula I-AB, B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. In some embodiments of Formula I-AB, B is (C ₁ -C ₆ alkoxy) C ₂ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms.

In one embodiment of Formula I-AB, B is hydroxy-C ₂ -C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring. In one embodiment, the alkyl moiety is unsubstituted.

In one embodiment of Formula I-A, ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is SK; and B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1-3 fluorine or hydroxy-C ₂ -C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with C ₃ -C ₆ cycloalkylidene ring.

In one embodiment of Formula I-A, ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is GN; and B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. In some embodiments, B is (C ₁ -C ₆ alkoxy) C ₂ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms.

In one embodiment of Formula I-A, ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A represents GN; and B is hydroxy C ₂ -C ₆ -alkyl, the alkyl moiety being optionally substituted with a C ₃ -C ₆ cycloalkylidene ring.

- 42 035568

In one embodiment, the alkyl moiety of Group B is unsubstituted.

In one embodiment of Formula IA, E is A ^ Q-Ce ^ HM-, het-Ar ² C1-C6 alkyl-, where the alkyl moiety is optionally substituted with 1-3 fluorine atoms, or Ar ¹ (C1-C ₆ alkyl) C ( = O)) -, while Ar ¹ and het-Ar ² are as defined for formula IA.

In one embodiment of formula IA E Ar ¹ represents a C1-C6-alkul-, het-Ar ² C1-C ₆ alkyl, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, or Ar ₁ (C ₁ -C ₆ alkyl ) C (= O)) -, where Ar1 is unsubstituted phenyl and het-Ar ² is a 5-6 membered heterocyclic ring containing 1-2 ring nitrogen atoms and is optionally substituted with one or more substituents independently selected from the group consisting of from halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment of Formula IA, het-Ar ² is a 6-membered heterocyclic ring containing 1 to 2 ring nitrogen atoms and is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted 1-3 fluorine atoms) and _C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms).

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is (C1-C6 alkoxy) C! -C6 alkyl optionally substituted with 1-3 fluoro or hydroxy C2-C6 alkyl, where the alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring; and E is Ar ¹ C | -C6 -alkyl-. het-Ar ² C1-C6-alkyl, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, ¹ or Ar (C1-C ₆ alkyl) C (= O) -, where Ar ¹ and het-Ar ² have the meanings defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is (C1-C6-alkoxy) C1-C6 alkyl optionally substituted with 1 to 3 fluorine atoms; and E is Ar ¹ C1-C ₆ -alkyl-, het-Ar ² C1-C6-alkyl-, where the alkyl moiety is optionally substituted with 1-3 fluorine, or Ar ¹ (C1-C ₆ -alkyl) C (= O ) -, where Ar ¹ and het-Ar ² are as defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is (^ - ^^^^^) ^ - ^ alkyl optionally substituted with 1-3 fluorine atoms; and E is ArE-Cs ^ nM-, where Ar ¹ is as defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is (^ - ^^^^^) ^ - ^ alkyl optionally substituted with 1-3 fluorine atoms; and E is het-Ar ² C ₁ -C ₆ -alkyl-, where the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms and het-Ar ² is as defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is (^ - ^^^^^) ^ - ^ alkyl optionally substituted with 1-3 fluorine atoms; or E is Ar ¹ (^ - ^ - alkyl ^^ O) wherein said alkyl moiety is optionally substituted with OH, hydroxy-C ₁ -C ₆ -alkyl or C1-C6 alkoxy and Ar ¹ is as defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl, the alkyl moiety being optionally substituted with a C3-C6 cycloalkylidene ring; and E represents Ar ¹ C1-C ₆ -alkyl-, het-Ar ² C1-C6 -alkyl-, the alkyl moiety being optionally substituted by 1-3 fluorine atoms, or Ar ¹ (C1-C ₆ -alkyl) C (= O) -, while Ar ¹ and het-Ar ² are as defined for formula IA. In one embodiment, the alkyl moiety of Group B is unsubstituted.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is hydroxyC ₂ -C ₆ -alkyl, the alkyl moiety being optionally substituted with a C ₃ -C ₆ cycloalkylidene ring; and E is Ar ¹ C1 -O3-alkyl-, where Ar ¹ is as defined for formula IA. In one embodiment, the alkyl moiety of Group B is unsubstituted.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl, the alkyl moiety being optionally substituted with a C3-C6 cycloalkylidene ring; and E is het-Ar ² C1-C ₆ -alkyl-, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms, and het-Ar ² is as defined for formula IA. In one embodiment, the alkyl moiety of Group B is unsubstituted.

In one embodiment of Formula IA, Ring D is unsubstituted; X ¹ represents N; X ² , X ³ and X ⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl, the alkyl moiety being optionally substituted with a C3-C6 cycloalkylidene ring; and E is Ar ¹ (C1-C ₆ -alkyl) C (= O) -, wherein said alkyl moiety is optionally

- 43 035568 substituted by OH, _{hydroxy-C1-C6-alkyl-} or _C1-C6 alkoxy and Ar ¹ is as defined for formula IA. In one embodiment, Ar ¹ is unsubstituted phenyl. In one embodiment, B is hydroxy-C ₂ -C ₆ -alkyl-, wherein the alkyl moiety is unsubstituted.

In one embodiment of Formula IA, Ring D is unsubstituted; X ² represents N; X ¹ , X ³ and X4 are CH; A is CN; B is C1-Cb-alkyl optionally substituted with 1-3 fluoro, (CgC ^ alkoxy ^ -C ^ alkyl optionally substituted with 1-3 fluorine, or (het-Cyc ^a ) C1-C3-αalkyl-; and E is is Ar ¹ C1-C ₆ -alkyl- or Ar ¹ (C ₁ -C ₆ -alkyl) C (= O) -, where the alkyl fragment is optionally substituted with OH, hydroxy-C ₁ -C ₆ -alkyl- or C1-C _6- alkoxy and het-Cyca and Ar ¹ are as defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ² represents N; X ¹ , X ³ and X4 are CH; A is CN; B is C1-Cb-alkyl optionally substituted with 1 to 3 fluorine atoms; and E is Ar ^ Q - ^^ Ku (C ^ O) -, said alkyl moiety being optionally substituted with OH, hydroxy C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and Ar ¹ is such as defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ² represents N; X ¹ , X ³ and X4 are CH; A is CN; B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; and E is Ar ^ -C ^ lkyl- and Ar ¹ is as defined for formula IA.

In one embodiment of Formula IA, Ring D is unsubstituted; X ² represents N; X ¹ , X ³ and X4 are CH; A is CN; B represents (het-Cyc ^a ) C ₁ -C ₃ -alkyl-; and E is ApC ^ C ^ alkyl and het-Cyca and Ar ¹ are as defined for formula IA.

In one embodiment, Formula I includes compounds of Formula I-B, wherein

X ¹ , X ² , X ³ and X4 are independently CH, CF or N, where zero, one or two of X ¹ , X ² , X ³ and X ⁴ are N;

A is H, CN, Cl, CH ₃ -, CH3CH2-, cyclopropyl, —CH2CN, or —CH (CN) CH ₃ ;

B represents:

(a) hydrogen, (b) _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms, (c) hydroxy-C ₂ -C ₆ -alkyl-, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, or C ₃ -C ₆ -cycloalkylidene ring, (d) dihydroxy-C ₃ -C ₆ -alkyl, where the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring, (e) (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl, optionally substituted with 1-3 fluorine atoms, (f) ^^ 2№) _C1-C6 alkyl, wherein said alkyl moiety is optionally substituted by OH and wherein R ¹ and R ² independently represent H or _C1-C6 alkyl ( optionally substituted with 1 to 3 fluorine atoms);

(g) het-ArC ^ C ^ alkyl, where het-Ar ¹ is a 5-6 membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from N, O and S, and optionally substituted with one or more independently selected C1-C ₆ alkyl substituents;

(h) (C ₃ -C ₆ cycloalkyl) _C1-C3 alkyl, wherein said cycloalkyl is optionally substituted with OH, (i) (het-Cyc ^a) C ₁ -C ₃ -alkyl, (j) het-Cyca -;

(k) C ₃ -C ₆ -cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH, (l) (C ₁ -C ₄ -alkyl) C (= O) OC ₁ -C ₆ -alkyl-, where each of C 1- C ₄ -alkyl and C 1 -C ₆ -alkyl moieties are optionally and independently substituted by 1-3 fluorine atoms, or (m) (R ¹ R ² N) C (= O) C1-C6-alkyl-, where R ¹ and R ^{2 are} independently H or C1-C6 alkyl (optionally substituted with 1 to 3 fluorine atoms);

het-Cyca- represents a 4-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O, and optionally substituted with one or more substituents independently selected from OH, _C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), hydroxy-C1-C ₆ -alkyl-, C1-C _6- alkoxy, (C1-C ₆ ^ K ^) C (= O) -, (C ₁ -C _6- alkoxy) C ₁ -C ₆ -alkyl - and fluoro or where het-Cyca is substituted with oxo;

Ring D represents

44 035568 where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen , OH, C'i-C'3-alkyl. which is optionally substituted with 1 to 3 fluorine atoms, or C ₁ -C ₃ alkoxy, which is optionally substituted by 1 to 3 fluorine atoms, (b) a C ₃ -C ₆ cycloalkylidene ring or (c) an oxo group;

E represents:

(a) hydrogen, (b) C ₁ -C ₆ -alkyl, (c) (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl-, (d) (C ₁ -C ₆ -alkyl) C (= O) -, (e) (hydroxy-C ₂ -C ₆ -alkyl) C (= O) -, (f) (C ₁ -C ₆ -alkoxy) C (= O) -, (g) ( C ₃ -C ₆ -cycloalkyl) C (= O) -, (h) Ar ¹ C ₁ -C ₆ -alkyl-, (i) Ar ¹ (C1-C6-alkyl) C (= O) -, where the specified the alkyl moiety is optionally substituted with OH, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, R ^m R ⁿ N- or R ^m R ⁿ N-CH2-, where each R ^m and R ^{n is} independently H or C ₁ -C ₆ -alkyl, (j) het-Ar2C1 -C ₆ -alkyl-, where said alkyl fragment is optionally substituted by 1-3 fluorine atoms, (k) het-Ar ² (C ₁ -C ₆ -alkyl) C (= O) -, where said alkyl moiety is optionally substituted with OH, hydroxy-C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy, (l) het-Ar ² C (= O) -, (m) het-Cus ¹ C (= O) -, (o) R ³ R ⁴ NC (= O) -, (p) Ar ¹ R ³ NC (= O) -, (q) het-Ar ^ W ^ C ^ O) - , (r) (SgSb Og- ^ alkyl, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, (t) het-A1Ao ₂ -, (u) NCHS.AS.-alkilSchiridinonil, (v) Ar ¹ C (= O) -, (w) Ar ¹ OC (= O) -, (x) (C ₃ -C ₆ -cycloalkyl) CH ₂ C (= O) -, (y) (C ₃ -C ₆ -cycloalkyl) (C ₁ -C ₆ -alkyl ^ O ₂ -, (z) AAC ^ Cb-alkyl ^ Og-, ( aa) het-Cus ¹ -OC (= O) -, (bb) het-Cus ¹ -CH ₂ -C (= O) - or (cc) het-Ar ² ;

Ar ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CK, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms), R ^e R ^f N-, where R ^e and R ^f independently represent H or C1-C ₆ -alkyl, (K ^^ C ^ C ^ alkoxy-, where R ^p and R ^q independently represent H or C1-C6-alkyl, and (het-Ar ^a) C1-C ₆ alkyl, wherein het-Ar ³ represents a 5-6 membered heteroaryl ring containing 1-2 nitrogen ring atoms, or Ar ¹ represents a phenyl ring fused to a 5-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O;

het-Ar ² is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl ring containing 1-3 ring nitrogen atoms, where het -Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, CK, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms) , (C1-C6 alkoxy) C1-C6-alkyl- (optionally substituted with 1-3 fluorine atoms), R ^e R ^f N-, where R ^e and R ^f independently represent H or C1-C ₆ -alkyl, OH, ( C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkoxy and C ₃ -C ₆ cycloalkyl;

het-Cy ^ is a 4-6 membered saturated heterocyclic ring containing 1-2 ring heteroatoms independently selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C ₁ -C ₆ -alkoxy and halogen;

R ³ is H or C ₁ -C ₆ -alkyl and

R ⁴ is C ₁ -C ₆ alkyl.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ represents CH.

In one embodiment of Formula IB, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula I-B, A is CK.

- 45 035568

In one embodiment of Formula I-B, Ring D is

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C.'iC.'3-alkyl. which is optionally substituted by 1-3 fluorine atoms, or C ₁ -C ₃ -alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group.

In one embodiment of Formula I-B, Ring D is

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, and the ring D is unsubstituted.

In one embodiment of Formula IB, B is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; (C ₁ -Cb-alkoxy) C ₁ -C ₆ -alkyl optionally substituted with 1 to 3 fluorine atoms; hydroxy-C ₂ -C ₆ -alkyl, where the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring; het-Ar ¹ C ₁ -C ₃ -alkyl-; or (het Sus ^a) C ₁ -C ₃ -alkyl-; where het-Ar ¹ and het-Cus ^a are as defined for formula IB.

In some embodiments of Formula IB, B is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. In some embodiments of Formula IB, B is C ₁ -C ₆ alkyl.

In one embodiment of Formula IB, B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms, or hydroxy C ₂ -C ₆ alkyl, wherein the alkyl moiety is optionally substituted C ₃ -C ₆ -cycloalkylidene ring.

In one embodiment of Formula IB, B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. In some embodiments of Formula IB, B is (C ₁ -C ₆ alkoxy) C ₂ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms.

In one embodiment of Formula IB, B is hydroxy-C ₂ -C ₆ -alkyl-, the alkyl moiety optionally substituted with a C ₃ -C ₆ cycloalkylidene ring. In one embodiment, the alkyl moiety of Group B is unsubstituted.

In one embodiment of Formula IB, B is het-Ar ¹ C ₁ -C ₃ -alkyl-, where hetAr ¹ is as defined for Formula IB

In one embodiment of formula IB B is (het Sus ^a) C ₁ -C ₃ -alkyl-; where getCyc ^a is as defined for formula IB.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; and B is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms. In some embodiments of Formula IB, B is C ₁ -C ₆ alkyl.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; and B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ -alkyl optionally substituted with 1 to 3 fluorine atoms or hydroxy-C ₂ -C ₆ -alkyl-, where the alkyl moiety is optionally substituted with C ₃ -C ₆ -cycloalkylidene ring. In one implementation,

X ¹ represents N; X ² , X ³ and X ⁴ is CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; and B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl, optionally substituted with 1 to 3 fluorine atoms. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ is CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; and B is hydroxy C ₃ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring. In one embodiment, the alkyl moiety of Group B is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; and B is het-Ar ¹ C ₁ -C ₃ -alkyl-, het-Ar ¹ being as defined for formula IB. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. IN

46,035568 in one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; and B represents (het-Cyc ^a ) C ₁ -C ₃ -alkyl-; where het-Cyc ' ¹ is as defined for formula IB. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is Q ^ -alkyl optionally substituted with 1 to 3 fluorine atoms; and ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C-C-alkyl, which is optionally substituted with 1-3 fluorine atoms, or C-C-alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group. In one embodiment of Formula IB, said ring D is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms or hydroxy C ₂ -C ₆ ^ km-, where the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring ; and ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C-C-alkyl, which is optionally substituted with 1-3 fluorine atoms, or C-C-alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C6-cycloalkylidene ring or (c) oxo group. In one embodiment of Formula IB, said ring D is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is hydroxy-C ₃ -C ₆ -alkyl optionally substituted with a C ₃ -C ₆ cycloalkylidene ring; and ring D is *

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, and the ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B is het-Ar ¹ C ₁ -C ₃ -alkyl-, where he-Ar ¹ is as defined for formula IB; and ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C-C-alkyl, which is optionally substituted with 1-3 fluorine atoms, or C-C-alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b)

- 47 035568

With ₃ -Cb-cycloalkyldene ring or (c) oxo group. In one embodiment of Formula IB, Ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B represents (het-Cyc ^a ) C ₁ -C ₃ -alkyl-; moreover, het-Cyc ³ is as defined for formula IB; and ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or C ₁ -C _3- alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group. In one embodiment of Formula IB, Ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, E is het-Ar ² C1-C6-alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms, het-Ar2C (= O) -, Ar ¹ R ³ NC (= O) - or (C1-C ^ ₆ alkyl, O ₂ -, wherein het-Ar ^2, Ar ¹ and R ³ are as defined for formula IB In one embodiment, the het-Ar ² represents a 5-6 membered heteroaryl ring. containing 1-2 ring heteroatoms independently selected from N and O is optionally substituted with one or more substituents independently selected from the group consisting of halogen, ^ - ^ - alkyl (optionally substituted with 1-3 fluorine atoms) and ^ - ^ - alkoxy (optionally substituted with 1 to 3 fluorine atoms).

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is ^ - ^ - alkyl optionally substituted with 1 to 3 fluorine atoms; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl which is optionally substituted with 1 to 3 fluorine atoms, or C.'iC.'3-alkoxy. which is optionally substituted with 1 to 3 fluorine atoms, (b) a C ₃ -C ₆ cycloalkylidene ring or (c) an oxo group; and E is het-Ar ^ -Cs-alkyl, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, het-Ar ² C (= O) -, Ar ¹ R ³ NC (= O) or (^ - ^ -alkyl ^ O ^, where het-Ar ² , Ar ¹ and R ³ are as defined for Formula IB. In one embodiment of Formula IB, said ring D is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; ring D is

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C3-C6 cycloalkylidene ring or (c) oxo; and E is het-Ar ² C ₁ -C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms. In one embodiment of Formula IB, said ring D is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH. In one embodiment of Formula IB, X ¹ is

- 48 035568 itself N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B represents a _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or C | -C ₃ -alkoxy. which is optionally substituted with 1 to 3 fluorine atoms, (b) a C ₃ -C 6 cycloalkylidene ring or (c) an oxo group; and E is het-ArC (= O) -. whereby het-Ar ² is as defined for formula IB. In one embodiment of Formula IB, said ring D is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or C1-C _3- alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group ; and E is Ar1R ³ NC (= O) -, where Ar ¹ is as defined for formula IB. In one embodiment of Formula IB, said ring D is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; ring D is

A ^ where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group; and E is (C1-Cb-alkyl) 8O2-. In one embodiment of Formula IB, said ring D is unsubstituted. In one embodiment, X ¹ is N; X ² , X ³ and X ⁴ represent CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH. In one embodiment of Formula IB, X ¹ is N and X ² , X ³ and X ⁴ are CH, or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B represents (C1-C ₆ alkoxy) C ₁ to C ₆ alkyl optionally substituted with 1-3 fluorine atoms or hydroxy-C ₃ -C ₆ -alkyl, optionally substituted C ₃ -C ₆ cycloalkylidene ring; ring D is

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C3-C6 cycloalkylidene ring or (c) oxo; and E is het-Ar ² C1-C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, het-Ar2C (= O) -, Ar1R ³ NC (= O)

- 49 035568 or (C1-C ₆ -alkyl ^ O ₂ - where het-Ar ² , Ar ¹ and R ³ are represented as defined for formula IB. In one embodiment, ring D is unsubstituted. X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is (C-C ^ alkoxyH-Cs-alkyl, optionally substituted with 1 to 3 fluorine atoms; ring D is ^ ^νΧ 2> ι where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alknl, which is optionally substituted with 1-3 fluorine atoms, or C1-C3 -alkoxy which is optionally substituted with 1-3 fluorine atoms, (b) C3-C6-cycloalkylidene ring, or (c) an oxo group; and E represents a het-Ar ² C1-C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with 1- 3 fluorine atoms, het-Ar ² C (= O) -, Ar1R ³ NC (= O) or (C1-C ₆ -alknl ^ O ₂ -, while het-Ar ² , Ar ¹ and R ³ are such as defined for formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ^3, and X ⁴ are CH. In one embodiment Iante realizations X ¹ and X ³ represent N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alknla, which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group; and E is het-Ar ² C1-C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms, het-Ar ² C (= O) -, Ar1R ³ NC (= O) or (C1-C ₆ -alknl ^ O ₂ -, wherein het-Ar ² , Ar ¹ and R ³ are as defined for formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ^3, and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B is het-Ar ¹ C ₁ -C ₃ -alkyl-, where het-Ar ¹ is as defined for formula IB; ring D is where the squiggly line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alknla, which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C3-C6 cycloalknlidene ring or (c) oxo; and E is het-Ar ² C1-C ₆ -alknl, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, het-Ar ² C (= O) -, Ar1R ³ NC (= O) or (C1-C ₆ -alknl ^ O ₂ -, where het-Ar ² , Ar ¹ and R ³ are as defined for Formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, X ¹ is N ; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B represents a (het Sus ^a) _C1-C3 -alknl-, prnchem het Sus ^and is as defined for Formula I-V; ring D is

- 50 035568

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 -alkyl, which is optionally substituted by 1 to 3 fluorine atoms, or C.'iC.'3-alkoxy. which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylugene ring, or (c) an oxo group; and E is het-Ar ² C1-C ₆ -alkyl, the alkyl moiety being optionally substituted with 1-3 fluorine atoms, het-Ar ² C (= O) -, Ar ¹ R ³ NC (= O) or (C -Cb-alkyl ^ O ^, wherein het-Ar ² , Ar ¹ and R ³ are as defined for formula I-B. In one embodiment, said ring D is unsubstituted. In one embodiment, X ¹ is N ; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula I-B, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C3-C6 cycloalkylidene ring or (c) oxo; and E is het-Ar ² C1-C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms and het-Ar ² is as defined for formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl ring containing 1 to 2 ring heteroatoms independently selected from N and O, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl (optionally substituted with 1 to 3 fluorine atoms); and C ₁ -C ₆ alkoxy (optionally substituted with 1 to 3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; the ring D is \ [χ · ^Ν · χ.

* where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH , C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group; and E represents het-Ag2S (= O) -, wherein het-Ar ² is as defined for formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl ring containing 1-2 ring heteroatoms independently selected from N and O is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1 —C ₆ -alkyl (optionally substituted with 1 to 3 fluorine atoms); and C ₁ -C ₆ alkoxy (optionally substituted with 1 to 3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D is

- 51 035568

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C.'iC.'3-alkyl. which is optionally substituted with 1 to 3 fluorine atoms, or C ₁ -C ₃ alkoxy, which is optionally substituted by 1 to 3 fluorine atoms, (b) a C ₃ -C ₆ cycloalkylidene ring or (c) an oxo group; and E is Ar ¹ R ³ NC (= O) - where Ar ¹ and R ³ are as defined by formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D represents' ⁵ % ^{, X} E> 1 *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or C ₁ -C _3- alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group; and E is (CsCb-alkyl ^ Og-. In one embodiment, said ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ^3, and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; ring D is where the squiggly line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted by 1-3 fluorine atoms, or C1-C3 alkoxy which is optionally substituted by 1-3 fluorine atoms, (b) C3-C6 cycloalkylidene ring or (c) oxo; and E is het-Lu ² C1-C ₆ -alkyl, wherein the alkyl moiety is optionally substituted by 1-3 fluorine atoms, het-Lu ² C (= O) -, Ar ^ ³ KC (= O) or (CsCb- alkyl ^ Og-, where het-Ar ² , Ar ¹ and R ³ are as defined for formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ represent CH.

In one embodiment, X ¹ and X ³ are N and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; L is SK; B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; the ring D is '^ N' ^X Q> | *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group; and E is het-Lu ² C1-C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms and het-Lu ² is as defined for formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, het-Lg ² is a 5-6 membered heteroaryl ring containing 1 to 2 ring heteroatoms independently selected from N and O, is optionally substituted with one or more substituents independently selected from the group consisting of from halogen, C ₁ -C ₆ alkyl (optionally substituted with 1-3 fluorine atoms) and _C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; ring D is

Am '' 'y>

* where the squiggly line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH , C ₁ -Cz-alkyl, which is optionally substituted by 1-3 fluorine atoms, or ^^ 3 ^^^ ¾ which is optionally substituted by 1-3 fluorine atoms, (b) C3-C ₆ -cycloalkylidene ring or (c) an oxo group; and E is het-Ar ² C (= O) -, wherein het-Ar ² is as defined for formula IB. In one embodiment, said ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl ring containing 1-2 ring heteroatoms independently selected from N and O is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Cj -C'6-alkyl (optionally substituted with 1-3 fluorine atoms); and Cj-C'6-alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; ring D is \ L ' ^N ' x.

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C 3 -alkyl which is optionally substituted with 1-3 fluorine atoms, or G-Cs ^ ro ^^ which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) an oxo group; and E is Ar ¹ R ³ NC (= O) - where Ar ¹ and R ³ are as defined by formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1 to 3 fluorine atoms; the ring D is ^ ^ν Ά> Ι *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C 3 -alkyl which is optionally substituted with 1-3 fluorine atoms, or G-Cs ^ ro ^^ which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) an oxo group; and E is (C ₁ -C ₆ -alkyl) SO ₂ -. In one embodiment, ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is hydroxy-C ₂ -C ₆ -alkyl; ring D is

- 53 035568

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is het-Ar ² C ₁ -C ₆ -alkyl, where the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms, or rem-Ai (CpO), where het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from a group consisting of halogen and C ₁ -C ₆ alkoxy (optionally substituted with 1 to 3 fluorine atoms) and het-Ar ² is as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B is hygroxy-C ₂ -C ₆ alkyl; ring D is

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is het-Ar ² C1-C6 alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms, where het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1 Cg-alkoxy ( optionally substituted with 1 to 3 fluorine atoms) and het-Ar ² is as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N; and X ² , X ³ and X ⁴ are CH or X ¹ and X ³ are N; and X ² and X ⁴ are CH; A is CN; B represents hydroxy - ^^ - alkyl; ring D is

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is γ € τ-γ0 '(= Ο), where het-Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen and C.'rC.'6-alkoxy (optionally substituted 1- 3 fluorine atoms) and het-Ar ² is as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hygroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D is

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is Ar ¹ N (R ³ ) C (= O) and Ar ¹ and R ³ are as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy - ^^ - alkyl optionally substituted with a C ₃ -C ₆ cycloalkylidene ring; ring D is

- 54 035568 where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is het-Ar ² C ₁ -C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms, or het-Ar ² C (= O), and het-Ar ² is as defined for formula I-B. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D is where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is het-Ar ² C ₁ -C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms, and het-Ar ² is as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D is where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is het-Ar ² C (= O) - and het-Ar ² is as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy - ^^ - alkyl optionally substituted with a C ₃ -C ₆ cycloalkylidene ring; ring D is *

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is het-Ar ² C ₁ -C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms, and het-Ar ² is as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; B is hydroxy C ₂ -C ₆ alkyl optionally substituted with C ₃ -C ₆ cycloalkylidene ring; ring D is *

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E; and E is het-Ar ² C ₁ -C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 to 3 fluorine atoms, and het-Ar ² is as defined for formula IB. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A represents

- 55 035568

CN; and B is het-Ar ¹ C ₁ -C ₃ -alkyl-, where he-Ar ¹ is as defined for formula IB; ring D is

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms, or C ^ C ^ alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) C3-C6 cycloalkylidene ring or (c) oxo; and E is het-Ar ² C1-C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms and het-Ar ² is as defined for formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl ring containing 1-2 ring heteroatoms independently selected from N and O is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ₁ -C ₆ -alkyl (optionally substituted with 1-3 fluorine atoms); and C.'iC.'6-alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B is het-Ar ¹ C ₁ -C ₃ -alkyl-, where he-Ar ¹ is as defined for formula IB; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, CrC.'3-alkyl. which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy, which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group; and E is het-Ar ² C (= O) -, wherein het-Ar ² is as defined for formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl ring containing 1 to 2 ring heteroatoms independently selected from N and O, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1 -S6 alkyl (optionally substituted with 1-3 fluorine atoms) and _C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CK; and B is het-Ar ¹ C ₁ -C ₃ -alkyl-, where he-Ar ¹ is as defined for formula IB; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl, which is optionally substituted by 1-3 fluorine atoms, or C ₁ -C _3- alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo group; and E is Ar ¹ R ³ NC (= O) - where Ar ¹ and R ³ are as defined by formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CK; and B is het-Ar ¹ C ₁ -C ₃ -alkyl-, where he-Ar ¹ is as defined for formula IB; ring D is

- 56 035568

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C ₁ -C ₃ -alkyl which is optionally substituted with 1 to 3 fluorine atoms, or C.'iC.'3-alkoxy. which is optionally substituted with 1-3 fluorine atoms, (b)

A C ₃ -C ₆ cycloalkyligenic ring or (c) an oxo group; and E is (C ^ Cs-alkyl ^ O ^. In one embodiment, ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ^3, and X ⁴ are CH. In one embodiment X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B represents a (het Sus ^a) C ₁ -C ₃ -alkyl-, wherein het Sus ^and is as defined for formula IB; ring D is * where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted by 1-3 fluorine atoms, or C1-C3 alkoxy which is optionally substituted by 1-3 fluorine atoms, (b) C3-C6 cycloalkylidene ring or (c) oxo group ; and E is het-Ar ² C1-C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with 1 to 3 fluorine atoms and het-Ar ² is as defined for formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl ring containing 1 to 2 ring heteroatoms independently selected from N and O is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ₁ -C ₆ -alkyl (optionally substituted with 1 to 3 fluorine atoms); and C ₁ -C ₆ -alkoxy (optionally substituted with 1 to 3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B represents a (het Sus ^a) C ₁ -C ₃ -alkyl-, wherein het-Cyca is as defined for formula IB; ring D is *

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluorine atoms, or C1-C3 alkoxy which is optionally substituted with 1-3 fluorine atoms, (b) a C3-C6 cycloalkylidene ring or (c) an oxo group; and E is het-Ar ² C (= O) -, wherein het-Ar ² is as defined for formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, het-Ar ² is a 5-6 membered heteroaryl ring containing 1 to 2 ring heteroatoms independently selected from N and O is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1 —C ₆ -alkyl (optionally substituted with 1 to 3 fluorine atoms); and C ₁ -C ₆ alkoxy (optionally substituted with 1 to 3 fluorine atoms). In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B represents a (het Sus ^a) C ₁ -C ₃ -alkyl-, wherein het-Cyca is as defined for formula IB; ring D is

- 57 035568 where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen , OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -tsikloαlkilidenovym ring or a (c ) an oxo group; and E is Ar1R ³ NC (= O) -, while Ar ¹ and R ³ are as defined by formula IB. In one embodiment, ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment of Formula IB, X ¹ is N and X ² , X ^3, and X ⁴ are CH; or X ¹ and X ³ are N and X ² and X ⁴ are CH; A is CN; and B is (het-Cyc ^a ) C ₁ -C ₃ -alkyl-, where het-Cyca is as defined for formula IB; ring D is

where the wavy line indicates the point of attachment of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and an asterisk indicates the point of attachment to E, and ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) C ₃ -C ₆ -tsikloalkilidenovym ring, or (c) oxo; and E is (C ₁ -C ₆ ^ kuh) SO ₂ -. In one embodiment, ring D is unsubstituted. In one embodiment, X ¹ is N; and X ² , X ³ and X ⁴ are CH. In one embodiment, X ¹ and X ³ are N; and X ² and X ⁴ are CH.

In one embodiment, Formula I includes compounds of Formula I-C, wherein

X ¹ , X ² , X ³ and X ^{4 are} independently CH, CF, or N, where zero, one, or two of X ¹ , X ² , X ³ and X ⁴ are N;

A is H, CN, Cl, CH ₃ -, CH ₃ CH ₂ -, cyclopropyl, —CH2 CN, or —CH (CN) CH ₃ ;

B represents:

(a) hydrogen, (b) _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms, (c) hydroxy-C ₂ -C ₆ -alkyl, wherein the alkyl moiety is optionally substituted C ₃ -C ₆ - cycloalkylidene ring, (d) dihydroxy-C ₃ -C ₆ -alkyl, wherein the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring, (e) (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl optionally substituted with 1- 3 fluorine atoms, (f) ^^ ² K) C1-C6-alkyl-, where R ¹ and R ² independently represent H or C1-C6-alkyl (optionally substituted with 1-3 fluorine atoms);

(g) het-Ar ¹ C1-C3 -alkyl, where het-Ar ¹ is a 5-6 membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from N, O and S, and optionally substituted with one or more independently selected C1-C6 alkyl substituents;

(h) (C ₃ -C ₆ -cycloalkyl) C 1 -C ₃ -alkyl-, (i) (het-Cyc ^a ) C ₁ -C ₃ -alkyl-, or (j) het-Cyca;

het-Cyca represents a 4-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O, and optionally substituted by OH, _C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), hydroxy C ₁ -C ₆ -alkyl-;

Ring D represents

where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to E;

E represents:

(a) hydrogen, (b) _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms, (d) (C ^ C ^ alkyl ^^ O) -, wherein said alkyl moiety is optionally substituted with 1-3 fluorine atoms or substituent R ^g R ^h N-, wherein R ^g and R ^h independently represent H or C1-C ₆ -alkyl, (f) (C1-C ₆ -alkoxy) C (= O) -,

- 58 035568 (l) het-Ar2C (= O) -, (o) R ³ R ⁴ NC (= O) -, (s) Ar1SO ₂ -, (t) reT-Ar2SO ₂ -, (v) Ar ¹ C (= O) -, (cc) het-Ar ² or (dd) C ₃ -C ₆ -cycloalkyl;

R ³ represents H or C-C-alkyl; and

R ⁴ is C-C alkyl.

In one embodiment of Formula IC, X ¹ is N; X ² , X ³ and X ⁴ represent CH.

In one embodiment of Formula I-C, A is CN.

In one embodiment of Formula IC, X ¹ is N; X ² , X ³ and X ⁴ are CH; and A is CN.

In one embodiment of Formula I-C B is (C-C-alkoxy-C-C-alkyl optionally substituted with 1 to 3 fluorine atoms, or hydroxy-C-C-alkyl, wherein the alkyl moiety is optionally substituted with a C-C-cycloalkylidene ring.

In some embodiments of Formula IC, B is (C-C-alkoxy ^ -Calkyl, optionally substituted with 1 to 3 fluorine atoms. In some embodiments of Formula IC, B is (C-C-alkoxy ^ -C-alkyl, optionally substituted with 1-3 fluorine atoms.

In one embodiment of Formula I-C B is hydroxy - ^ - C-alkyl-, wherein the alkyl moiety is optionally substituted with a C-C cycloalkylidene ring. In one embodiment, the alkyl moiety of Group B is unsubstituted.

In one embodiment of Formula IC, X ¹ is N; X ² , X ³ and X ⁴ are CH; A is CN; and B is (C-C-alkoxy-C-C-alkyl optionally substituted with 1 to 3 fluorine atoms.

In one embodiment of Formula IC, X ² is N; X ¹ , X ³ and X ⁴ are CH; A is CN; and B is hydroxy-C-C-alkyl-, the alkyl moiety being optionally substituted with a C-C-cycloalkylidene ring; and E is (C ₁ -C ₆ alkoxy) C (= O) -.

In one embodiment of Formula IC, X ¹ is N; X ² , X ³ and X ⁴ are CH; A is CN; and B is hydroxy-C-C-alkyl-, the alkyl moiety being optionally substituted with a C-C cycloalkylidene ring. In one embodiment, the alkyl moiety of Group B is unsubstituted.

Compounds of formula I include pharmaceutically acceptable salts thereof.

In addition, compounds of Formula I also include other salts of such compounds, which are optionally pharmaceutically acceptable salts and which may be useful as intermediates for the preparation and / or purification of compounds of Formula I and / or for separation of enantiomers of compounds of Formula I. Non-Limiting Examples Pharmaceutically acceptable salts of the compounds of Formula I include monohydrochloride, dihydrochloride, trifluoroacetate and ditrifluoroacetate. In one embodiment, compounds of Formula I include trifluoroacetic acid salts and dihydrochlorides.

In addition, it should be understood that the compounds of formula I or their salts can be isolated in the form of solvates and, accordingly, that any such solvate is included in the scope of the present invention. For example, compounds of Formula I and their salts can exist in unsolvated as well as solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. In one embodiment, compounds of Formula I include the compounds of Examples 1-561 and stereoisomers and pharmaceutically acceptable salts and solvates thereof. In one embodiment, the compounds of Examples 1-561 are in free base form. In one embodiment, the compounds of Examples 1-561 are dihydrochlorides and trifluoroacetates.

The term “pharmaceutically acceptable” indicates that a compound or a salt or composition thereof is chemically and / or toxicologically compatible with the other ingredients contained in the formulation and / or the patient being treated.

Compounds provided herein may also contain unnatural atomic isotope ratios for one or more of the atoms that make up such compounds. That is, an atom, in particular when referred to in relation to a compound of formula I, includes all isotopes and isotopic mixtures of a given atom, both naturally occurring and synthetically produced, either naturally or enriched in isotopic composition. For example, when hydrogen is mentioned, it is meant to refer to ¹ H, ² H, ³ H, or mixtures thereof; when carbon is mentioned, ¹¹ C, ¹² C, ¹³ C, ¹⁴ C or mixtures thereof are meant; when nitrogen is mentioned, it is meant that it refers to ¹³ N, ¹⁴ N, ¹⁵ N or mixtures thereof; when oxygen is mentioned, it is meant to refer to ¹⁴ O, ¹⁵ O, ¹⁶ O, ¹⁷ O, ¹⁸ O, or mixtures thereof; and when fluorine is mentioned, it is understood that it refers to ¹⁸ F, ¹⁹ F or their

- 59 035568 mixtures. The compounds provided herein therefore also include compounds with one or more isotopes of one or more types of atoms and mixtures thereof, including radioactive compounds, where one or more non-radioactive atoms have been replaced by one of its radioactively enriched isotopes. The radiolabeled compounds are useful as drugs, eg, anti-cancer drugs, research agents, eg, testing agents, and diagnostics, eg, in vivo imaging agents. It is intended that all isotopic variants of the compounds provided herein, whether radioactive or not, are included within the scope of the present invention. For illustrative purposes, Schemes 1-6 illustrate general methods for preparing the compounds provided herein, as well as basic intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are depicted in the diagrams and discussed below, other starting materials and reagents can be readily used to prepare a variety of derivatives and / or other reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using chemical methods well known to those of skill in the art.

Scheme 1

Scheme 1 illustrates a general synthesis scheme for compound 12 where A is CN and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I.

Compound 2 is prepared by treating 3-bromo-5-methoxypyridine (compound 1), which is commercially available, with O- (mesitylsulfonyl) hydroxylamine. O-mesitylsulfonylhydroxylamine can be prepared according to the procedure described in Mendiola, I, et al., Org. Process Res. Dev. 2009, 13 (2), 263267. Compound 2 can be contacted with ethyl propiolate to provide a mixture of compounds 3A and 3B, which are typically prepared in a ratio of about 2: 1 to about 9: 1, respectively. A mixture of compounds 3A and 3B can be treated with 48% HBr at elevated temperatures, followed by purification by recrystallization or chromatography to isolate compound 4A as

- 60 035568 minor isomer and compound 4B as the major isomer. After isolating compound 4A, it can be treated with POCl ₃ to give compound 5. The formyl group can be converted to an oxime group using NH2OH to give compound 6. The oxime group can be converted to a nitrile group using acetic anhydride to give compound 7. Methoxy group of compound 7 can be converted to hydroxy by treating compound 7 with aluminum trichloride to give compound 8.

To prepare compound 12 in which B is hydrogen, compound 12 can be prepared by coupling compound 8 with the corresponding boronic acid ester 10 (wherein ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I; P ¹ is an amino protecting group, Z is -B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (1-6C) alkyl or R ^x and R ^y together with the atoms to which they are bonded form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C - ^ - alkyl)) to prepare compound 11a using appropriate palladium-catalyzed cross-coupling reaction conditions, for example Suzuki cross-coupling reactions (eg, using a palladium catalyst and an optional ligand in the presence of an inorganic base, eg Pd (PPh ₃ ) ₄ and Na ₂ CO ₃ in dioxane at elevated temperatures). The protecting group P ¹ on the D ring of 11a can be removed under standard conditions (for example, the Boc group can be removed by treating 11a with an acid, such as HCl) to give compound 12 where B is hydrogen and E is hydrogen. Alternatively, the deprotected ring D can be functionalized (i.e., contacted with or treated with an appropriate reagent) to introduce group E under standard conditions, such as described below, to provide compound 12, wherein B is hydrogen and E is as defined for formula I, except where E is not hydrogen.

Alternatively, to prepare compound 12 where B is as defined for formula I is not hydrogen, compound 11a can be contacted with a reagent such as C1-C _g ^ Kra-OH, optionally substituted 1-3 fluorine atoms, hygroxy-C ₂ -C ₆ -alkyl-OH, dihydroxy-C ₃ -C ₆ -alkyl-OH, (C ₁ -Cg-alkoxy) C ₁ -Cg-alkyl-X, optionally substituted by 1-3 atoms fluorine, (R1R ² N) C1-Cg ^ Kra-OH, where R1 and R ² are as defined for formula I, het-Ar1C1C3-alkyl-OH, (C ₃ -C _g -cycloalkyl) C ₁ -C ₃ -alkyl-OH, (het-Cyc ^a ) C1-C3-alkyl-OH or het-Cyca-OH, where het-Ar ¹ and het-Cyca is as defined for formula I, and each of said optionally substituted with a protecting group under Mitsunobu reaction conditions (eg PPh3 and diisopropyl azodicarboxylate) to provide compound 11. Compound 12 can then be prepared from compound 11 as described above followed by removal of the protecting group from B if present.

As an alternative method for the preparation of compound 12, in which B is as defined for formula I and is not hydrogen, compound 9 can be prepared by contacting compound 8 with a reagent such as C1-C _g ^ Kra-X, optionally substituted with 1-3 fluorine atoms, hydroxy-C ₂ -C _g -alkyl-X, dihydroxy-C ₃ -C _g -alkyl-X, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ alkyl-X, optionally substituted by 1-3 fluorine atoms, (R1R ² N) C1-Cg ^ Kra-X, where R1 and R ² are as defined for formula I, het-Ar ¹ C1-C ₃ -alkyl-X, (C ₃ -C _g -cycloalkyl) C ₁ -C ₃ -alkyl-X, (hetCyc ^a ) C1-C3 ^ KM-X or het-Cyca-X, where het-Ar ¹ and het-Cyca are as defined for formula I, and X is a leaving atom or group (halide or triflate), in the presence of a suitable base (for example, an alkali metal carbonate such as potassium carbonate), each of these reagents being optionally substituted with a protecting group (for example, tert-butyldimethylsilyl g group if group B contains one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1 to 3 fluorine atoms, compound 9 can be prepared by contacting compound 8 with C ₁ -C _g -alkyl-X, said alkyl optionally substituted with 1-3 fluorine atoms, and X is halogen, such as Br or Cl, or a leaving group such as triflate. Compound 11 can then be prepared by cross-coupling 9 with the corresponding boronic acid ester 10 using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki cross-coupling reaction conditions (e.g., using a palladium catalyst and an optional ligand in presence of an inorganic base, for example, Pd (PPh ₃ ) ₄ and Na ₂ CO ₃ in dioxane at elevated temperatures). Compound 12 can then be prepared from compound 11 as described above, followed by removal of the protecting group from B, if present.

- 61 035568

Scheme 2

'x ¹ ^ l ^{2 8} 14

Scheme 2 illustrates another general synthetic scheme for compound 12 where A is CN and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I.

Compound 9 (prepared, for example, as described in Scheme 1), in which B is as defined for Formula I, may be contacted under cross-coupling conditions with the corresponding boronic acid ester 13 (where X ¹ , X ² , X ³ and X ⁴ is as defined for formula I; L ² is a leaving group such as triflate or halide; Z is —B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (LbOalkyl, or R ^x and R ^y, together with the atoms to which they are bonded, form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C - ^ - alkyl)) using appropriate reaction conditions palladium-catalyzed cross-couplings, such as Suzuki cross-coupling reaction conditions (for example, using a palladium catalyst and an optional ligand in the presence of an inorganic base such as Pd (PPh3) 4 and Na2CO3 in dioxane at elevated temperatures) to provide compound 14. Compound 1 6 can be obtained by contacting under coupling conditions of compound 14 with compound 15, wherein ring D is as defined for formula I, and P ¹ is an amino protecting group under appropriate SNAr conditions (e.g., optionally in the presence of a base, such as K2CO ₃ and at elevated temperatures). The protecting group P ¹ on the D ring of compound 16 can be removed under standard conditions (eg, the Boc group can be removed by treating compound 1 with an acid, eg, HCl) to provide compound 12 where E is hydrogen. Alternatively, the deprotected ring D may be functionalized (i.e., contacted with or treated with an appropriate reagent) to introduce group E under standard conditions such as described below to provide compound 12, wherein E is as defined for formula I, except when E is not hydrogen.

- 62 035568

Scheme 3

Scheme 3 illustrates a general synthetic scheme for compound 21 where A is CN and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I.

Compound 18 can be prepared by coupling compound 4A (prepared, for example, as described in Scheme 1) with the corresponding boronic acid ester 10 (wherein ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for Formula I; P ¹ is an amino protecting group, Z is —B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (1-6C) alkyl or R ^x and R ^y together with atoms to which they are attached form a 5-6 membered ring optionally substituted with 1-4 substituents selected from _(C1-C3 alkyl)), using the appropriate conditions for cross-coupling reactions catalyzed by palladium, e.g., cross reaction conditions Suzuki couplings (eg using a palladium catalyst and an optional ligand in the presence of an inorganic base, eg Pd (PPh ₃ ) ₄ and Na ₂ CO ₃ in dioxane at elevated temperatures). Compound 19 can be prepared by treating compound 18 with aluminum trichloride.

For compound 21 in which B is as defined for formula I, is not hydrogen, the compound 20 may be prepared by contacting compound 19 with a reagent such as _C1-C6 alkyl-X, optionally substituted 1 -3 fluorine atoms, hydroxy-C ₂ -C ₆ -alkyl-X, dihydroxy-C ₃ -C ₆ -alkyl-X, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl-X, optionally substituted 1-3 fluorine atoms, ^^^ C-C ^ alkyl-X, where R ¹ and R ² are as defined for formula I, het-Ar ¹ C1-C3-alkyl-X, (C3-C6-cycloalkyl ) C1-C3-alkyl-X, (het-Cyc ^a) C1-C ₃ alkyl or het-X-X-Cyca, wherein het-Ar ¹ and het-Cyca are as defined for formula I, and X represents a leaving atom or group (halide or triflate), in the presence of a suitable base (for example, an alkali metal carbonate such as potassium carbonate), each of these reagents being optionally substituted with a protecting group (for example, a tert-butyldimethylsilyl group if group B contains one y or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1 to 3 fluorine atoms, the compound can be prepared by contacting compound 19 with C | -C ₆ - <1alkyl-X. wherein said alkyl is optionally substituted with 1 to 3 fluorine atoms, and X is halogen, such as Br or Cl, or a leaving group such as triflate. The protecting group P ^{1 of} ring D of compound 20 can be removed under standard conditions (for example, the Boc group can be removed by treating compound 20 with an acid, for example, HCl), to obtain compound 21, where E is H. Alternatively, ring D with removed the protecting group of compound 21 can be functionalized (i.e., contacted with or treated with an appropriate reagent) to introduce group E under standard conditions such as described below to produce compound 21, wherein E is as defined for formula I, except when E is not hydrogen.

Alternatively, to obtain compound 21, where B is as defined for

- 63 035568 of the formula I, is not hydrogen, the compound 19 may be brought into contact with a reagent, such as _C1-C6 alkyl-OH optionally substituted with 1-3 fluorine atoms, hydroxy-C ₂ -C ₆ -alkyl-OH , dihydroxy-C ₃ -C ₆ -alkyl-OH, (C1-C ₆ -alkoxy) Cj-Cb-alkyl-X, optionally substituted with 1 to 3 fluorine atoms, ^^ ² X) C1-C6-alkyl-OH, where R1 and R ² are as defined for formula I, het-Ar ¹ C1C ₃ -alkyl-OH, (C ₃ -C ₆ -cycloalkyl) C1-C ₃ -alkyl-OH, (het-Cus ^a ) C1 -C3-alkyl-OH or het-Cus ^a -OH, where het-Ar ¹ and het-Cus ^a are as defined for formula I, and each of these reagents is optionally substituted with a protecting group, under Mitsunobu reaction conditions ( e.g. PPh3 and diisopropyl azodicarboxylate) to give compound 20. Compound 21 can then be prepared from compound 20 as described above, followed by removal of the protecting group from B, if present.

When group B is hydrogen, compound 21 can be prepared from compound 19 following the deprotection and optional functionalization steps described herein.

Scheme 4

Scheme 4 illustrates a general synthesis scheme for compound 21 where A is CN and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I.

Compound 22 can be prepared by treating compound 4A (prepared, for example, as described in Scheme 1) with aluminum trichloride.

To obtain compound 21 in which B is hydrogen, compound 19 can be prepared by coupling compound 22 with the corresponding boronic acid ester 10 (wherein ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I; P ¹ is an amino protecting group, Z is -B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (1-6C) alkyl or R ^x and R ^y together with atoms to which they are attached form 5-6chlennoe ring optionally substituted with 1-4 substituents selected from _(C1-C3 alkyl)), using the appropriate conditions for cross-coupling reactions catalyzed by palladium, e.g., cross-reaction conditions Suzuki couplings (eg, using a palladium catalyst and an optional ligand in the presence of an inorganic base, eg Pd (PPh ₃ ) ₄ and Na ₂ CO ₃ in dioxane at elevated temperatures). Compound 21 can be prepared from compound 19 according to the method described for Scheme 3.

Alternatively, to prepare compound 21, wherein B is as defined for formula I, is not hydrogen, the compound 23 may be prepared by contacting compound 22 with a reagent such as _C1-C6 alkyl-X, optionally substituted by 1-3 fluorine atoms, hydroxy-C ₂ -C ₆ -alkyl-X, dihydroxy-C ₃ -C ₆ -alkyl-X, (C1-C ₆ -alkoxy) C1-C ₆ -alkyl-X, optionally substituted 1-3 fluorine atoms, ^^ ² X) C1-C6-alkyl-X, where R ¹ and R ² are as defined for formula I, het-Ar1C1-C3-alkyl-X, (C ₃ -C ₆ cycloalkyl) _C1-C3 alkyl-X, (het Sus ^a) _C1-C3 alkyl or X-het Sus ^and -X-Ar wherein het ¹ and het Sus ^and are as defined for Formula I, and X is

- 64 035568 represents a leaving atom or group (halide or triflate), in the presence of a suitable base (for example, an alkali metal carbonate such as potassium carbonate), each of these reagents being optionally substituted with a protecting group (for example, a tert-butyldimethylsilyl group if group B contains one or two additional hydroxy groups). For example, when B is ^ - ^ - alkyl optionally substituted with 1 to 3 fluorine atoms, compound 23 can be prepared by contacting compound 22 with C ₁ -C ₆ -alkyl-X, said alkyl optionally substituted with 1-3 fluorine atoms, and X is halogen such as Br or Cl, or a leaving group such as triflate. Compound 20 can be prepared by coupling compound 23 with compound 10 as described in Scheme 3. Compound 21 can be prepared from compound 20 according to the method described for Scheme 3.

Alternatively, to prepare compound 21, wherein B is as defined for formula I, is not hydrogen, the compound 19 may be brought into contact with a reagent, such as _C1-C6 alkyl-OH optionally substituted with 1-3 fluorine atoms, hydroxy-C ₂ -C ₆ -alkyl-OH, dihydroxy-C ₃ -C ₆ -alkyl-OH, (C1-C ₆ -alkoxy) C1-C ₆ -alkyl-X, optionally substituted by 1-3 atoms fluorine ^^ 2N) _C1-C6 alkyl-OH, where R ¹ and R ² are as defined for formula I, het-Ar'CjS3-alkyl-OH, (C3 -C6 cycloalkyl) C1 -C3 -alkyl-OH, (het Sus ^a) _C1-C3 alkyl-OH or het Sus ^and -OH, wherein het-Ar ¹ and het-Cyca are as defined for formula I, and wherein each of of these reagents is optionally substituted with a protecting group under Mitsunobu reaction conditions (e.g. PPh ₃ and diisopropyl azodicarboxylate) to give compound 20. Compound 21 can then be prepared from compound 20 as described in Scheme 3, followed by removal of the protecting group from B if she is present.

Scheme 5

1. Removal of Y ¹ \ protective group: if γ ___________________g ХЗ 2 2, Optional ⁰ π ί functionalizations Λ ²¹

Scheme 5 illustrates a general synthetic scheme for compound 21 wherein A is CN and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I.

Compound 22 can be prepared by treating compound 4A (prepared, for example, as described in Scheme 1) with aluminum trichloride.

To prepare compound 21 in which B is as defined for formula I is not hydrogen, compound 23 can be prepared by contacting compound 22 with a reagent such as Cl-C ₆ -alkyl-X, optionally substituted with 1 -3 fluorine atoms, hydroxy-C ₂ -C ₆ -alkyl-X, dihydroxy-C ₃ -C ₆ -alkyl-X, (Cl-C ₆ -alkoxy) Cl-C ₆ -alkyl-X, optionally substituted 1- 3 fluorine atoms, (R ¹ R ² N) Cl-C6-alkyl-X, where R ¹ and R ² are as defined for formula I, het-Ar ¹ Cl-C3-alkyl-X, (C ₃ - C ₆ -cycloαalkyl) Cl-C ₃ -alkyl-X, (het-Cyc ^a ) Cl-C3-alkyl-X or het-Cyca-X, where het-Ar ¹ and het-Cyca are as defined for formula I, and X is a leaving atom or group (halide or triflate), in the presence of a suitable base (for example, an alkali metal carbonate such as potassium carbonate), each of these reagents being optionally substituted with a protecting group (for example, tert-butyldimethylsilyl group if group B with holds one or two additional hydroxy groups). For example, when B is a C1-C ₆ alkyl optionally substituted with 1-3 fluorine atoms, the compound may be prepared by contacting compound 22 with Q - ^^ u ^ -X, wherein said alkyl is optionally substituted with 1-3 fluorine atoms, and X is halogen such as Br or Cl or a leaving group such as triflate.

Connection 24 can be obtained by contacting connection 23 with a complex

- 65 035568 boronic acid ester 13 (where X ¹ , X ² , X ³ and X ⁴ is as defined for formula I; L ² is a leaving group such as triflate or halide); Z is B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (1-6C) alkyl, or R ^x and R ^y together with the atoms to which they are attached form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (GG-alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g. Suzuki cross-coupling reaction conditions (e.g., using a palladium catalyst and an optional ligand in the presence of an inorganic bases, for example, Pd (PPh ₃ ) ₄ and Na ₂ CO ₃ in dioxane at elevated temperatures).

To prepare compound 21 where B is hydrogen, compound 24 can be prepared by contacting compound 22 directly with compound 13, as described above.

Compound 20 can be prepared by contacting under coupling conditions of compound 24 with compound 15, wherein P ¹ is an amino protecting group under appropriate SNAr conditions (e.g., optionally in the presence of a base such as K ₂ CO ₃ and at elevated temperature) ... Compound 21 can be prepared from compound 20 according to the method described for Scheme 3.

Scheme 6

Scheme 6 illustrates a general synthesis scheme for compound 31 where A is Cl and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I.

Compound 25 can be prepared by treating compound 4A (prepared, for example, as described in Scheme 1) with aluminum trichloride.

Compound 26 can be prepared by treating compound 25 with aluminum trichloride.

To prepare compound 31 in which B is as defined for formula I is not hydrogen, compound 27 can be prepared by contacting compound 26 with a reagent such as QG ^ km-X, optionally substituted with 1 to 3 atoms fluorine, hydrokcu-C ₂ -C ₆ ^ k ^ -X, dihydroxy-C ₃ -C ₆ -alkyl-X, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl-X, optionally substituted 1- 3 fluorine atoms, (R ^ NIG-G ^ km-X, where R ¹ and R ² are as defined for formula I, het-Ar ¹ C1-C3-alkyl-X, (C3-C6-cycloalkyl) C1 -C3-alkyl-X, (het-Cyc ^a) C1-C ₃ alkyl or het-X-X-Cyca, wherein het-Ar ¹ and het-Cyca are as defined for formula I, and X represents leaving atom or group (halide or triflate), in the presence of a suitable base (for example, an alkali metal carbonate such as potassium carbonate), each of these reagents being optionally substituted with a protecting group (for example, a tert-butyldimethylsilyl group if group B contains one or two before additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluorine atoms, the compound can be prepared by contacting compound 26 with GG-ONKHn-X, said alkyl optionally substituted with 1-3 fluorine atoms, and X is halogen such as Br or Cl; or a leaving group such as triflate.

- 66 035568

Compounds 28 (where group B is methyl), 29 (where group B is hydrogen) and 30 (where group B is not hydrogen) can be prepared by cross-coupling of compounds 25, 26 and 27, respectively, with the corresponding ester boronic acid 10 (where ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I; P ¹ is an amino protecting group, Z is -B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (1-6C) alkyl, or R ^x and R ^y together with the atoms to which they are attached form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C ₃ -alkyl)), using appropriate palladium-catalyzed cross-coupling reaction conditions, for example, Suzuki cross-coupling reaction conditions (for example, using a palladium catalyst and an optional ligand in the presence of an inorganic base, for example, Pd (PPh ₃ ) ₄ and Na ₂ CO ₃ in dioxane at elevated temperatures).

The protecting group P ¹ on ring D of compound 29 or 30 can be removed under standard conditions (eg, the Boc group can be removed by treating compound 29 or 30 with an acid, eg HCl) to obtain compound 31 where E is hydrogen. Alternatively, the deprotected ring D may be functionalized (i.e., contacted with or treated with an appropriate reagent) to introduce group E under standard conditions such as described below to provide compound 31, wherein E is as defined for formula I, except when E is not hydrogen.

Ring D of compounds 12, 21, and 31 illustrated in Schemes 1-6 can be functionalized (i.e., contacted with or treated with an appropriate reagent) to introduce a group E, wherein E is as defined for Formula I, for except where E is not hydrogen using standard chemical transformations well known to those skilled in the art. The term functionalized, as used herein, refers to the step in which a compound of Formula 12, 21 or 31 wherein E is hydrogen is contacted with or treated with a reagent to produce a compound of Formula 12, 21 or 31, wherein E is as defined for Formula I, except when E is not hydrogen.

For example, a compound of formula I, wherein E represents a _(C1-C6 alkyl) C (= O) -, optionally substituted with one to three fluorines; (hydroxy-C ₂ -C ₆ -alkyl) C (= O) - optionally substituted with one to three fluorine atoms; (C1-C ₆ -alkoxy) C (= O) -; (C ₃ -C ₆ -cycloalkyl) C (= O) - (wherein said cycloalkyl is optionally substituted with (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ alkyl or a 5-6 membered heteroaryl ring containing 1-3 ring heteroatom independently selected from N and O); Ag ¹ (C1-C6 alkyl) C (= O) - (where the alkyl moiety is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6 alkoxy); het-Ar ² (C1C ₆ alkyl) C (= O) - (wherein alkyl moiety is optionally substituted with OH, hydroxy _C1C-6 alkyl or C1C ₆ alkoxy); or het-Cus ¹ (C ₁ -C ₆ -alkyl) C (= O) -, can be obtained by treating a compound 12 containing a deprotected ring D (i.e., compound 12 where E is hydrogen), the corresponding carboxylic acid using conventional amide bond formation conditions, for example, treatment of the corresponding carboxylic acid with an activating agent (e.g. HATU) followed by the addition of a compound 12 containing the deprotected ring D (i.e. where E is H) in the presence of a base (e.g., amine base, such as DIEA) in a suitable solvent (such as DMA), to obtain a functionalized compound 12 (i.e., in this case, the compound 12 where E represents _(C1-C6 alkyl) C (= O) - optionally substituted with one to three fluorine atoms; (hydroxy-C ₂ -C ₆ -alkyl) C (= O) - optionally substituted with one to three fluorine atoms; (C1-C ₆ -alkoxy) C (= O) -; ( C ₃ -C ₆ -cycloalkyl) C (= O) - (wherein said cycloalkyl is optionally substituted with (C1-C ₆ -alkoxy) C1-C ₆ -a lkyl or 5-6 membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from N and O); Lr ¹ (C1-C6 alkyl) C (= O) - (where the alkyl moiety is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6 alkoxy); het-Ar ² _(C1-C6 alkyl) C (= O) (wherein the alkyl moiety is optionally substituted with OH, _{hydroxy-C1-C6-alkyl-} or _C1-C6 alkoxy); or het-Cus ¹ (C ₁ -C ₆ -alkyl) C (= O) -). The same chemical transformations can be used in the cases of compounds 21 and 31 to obtain functionalized compounds 21 and 31 (i.e. in this case compounds 21 and 31, respectively, where E is (C ₁ -C ₆ -alkyl) C (= O) - optionally substituted with one to three fluorine atoms; (hydroxy-C ₂ -C ₆ -alkyl) C (= O) - optionally substituted with one to three fluorine atoms; (C1-C ₆ -alkoxy) C (= O) - ; (C ₃ -C ₆ -cycloalkyl) C (= O) - (wherein said cycloalkyl is optionally substituted with (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl or a 5-6 membered heteroaryl ring containing 1- 3 ring heteroatoms independently selected from N and O); Ar ¹ (C1-C6 alkyl) C (= O) - (wherein alkyl moiety is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6 alkoxy); het-Ar ² _(C1-C6 alkyl) C (= O) - (wherein alkyl moiety is optionally substituted with OH, _{hydroxy-C1-C6-alkyl-} or C1-C6 alkoxy); Sus or het ¹ (C ₁ -C ₆ -alkyl) C (= O) -). As another example, a compound of Formula I wherein E is het-Cic1C (= O) - or R ^ KC ^ O) - can be prepared by first activating the nitrogen atom in ring D with the deprotected group of compound 12 (i.e. where E is H) triphosgene in the presence of DIEL and in a solvent such as DCM, followed by the addition of an amine reagent having the formula het-Cuc1-H or R3R4NH (where het-Cuc1-H is saturated 4-6

67 035568 membered heterocycle containing 1 to 2 ring heteroatoms independently selected from N, O and S, where the ring contains at least one ring N atom, and -H indicates that hydrogen is bonded to a ring nitrogen atom, wherein said heterocycle optionally substituted with one or more independently selected C1-C ₆ alkoxy substituents), to obtain a functionalized compound 12 (i.e., in this case, the compound 12 where E represents GGT-Sus'S O) -or R ³ R ⁴ NC (= O) -). The same chemical transformations can be used in the cases of compounds 21 and 31 to obtain functionalized compounds 21 and 31 (i.e. in this case compounds 21 and 31, respectively, where E is het-Cic1C (= O) - or R ³ R ⁴ NC (= O) -).

As another example, the compound of formula I, wherein E represents a _C1-C6 alkyl optionally substituted with one to three fluorine atoms, (C ₁ -C ₆ alkoxy) C ₁ -C ₆ -alkyl, optionally substituted 1-3 fluorine atoms, Ar ¹ C1-C6-alkyl-het-Ar ² C1-C6-alkyl-, and the alkyl fragment is optionally substituted by 1-3 fluorine atoms, or het-Cus ¹ C1-C6-alkyl-, can be obtained by treatment deprotected compounds 12 (i.e., where E is H) with an appropriate reagent having the formula C1-C6-alkyl-X, optionally substituted with one to three fluorine atoms, (C1-C6 alkoxy) C1-C6-alkyl-X, optionally substituted with 1-3 fluorine atoms, Ar ¹ C1-C ₆ -alkyl-X, het-Ar ² C1-C6 alkyl-X, or het-Cus ¹ C1-C ₆ -alkyl-X, where X is Br or Cl in the presence of a base such as DIEA in a solvent at ambient or elevated temperature) to obtain a functionalized compound 12 (i.e., in this example, compound 12 where E is _C1-C6 alkyl, optionally optionally substituted with one to three fluorine atoms, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl, optionally substituted by 1-3 fluorine atoms, Ar ¹ C1-C6-alkyl-, het-Ar ² C1-C6- alkyl, wherein the alkyl moiety is optionally substituted by 1 to 3 fluorine atoms or het-Cus ¹ C1-C6 alkyl-). The same chemical transformations can be used in the cases of compounds 21 and 31 to obtain functionalized compounds 21 and 31 (i.e. in this case compounds 21 and 31, respectively, where E is C1-C6-alkyl, optionally substituted with one to three atoms fluorine, (C1-C6-alkoxy) C1-C6-alkyl optionally substituted with 1-3 fluorine atoms, Ar ¹ C1-C ₆ -alkyl, het-Ar ² C1-C6-alkyl, the alkyl moiety being optionally substituted by 1-3 fluorine atoms or het-Cus ¹ C1-C ₆ -alkyl-).

As another example, the compound of formula I, wherein E represents a _C1-C6 alkyl optionally substituted with one to three fluorines; (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl, optionally substituted by 1 to 3 fluorine atoms, Ar ¹ C ₁ -C ₆ -alkyl-het-Ar ² C ₁ -C ₆ -alkyl, the alkyl moiety being optionally substituted with 1 -3 fluorine atoms, or het-Cus ¹ C1-C6-alkyl) can be obtained by treating compound 12 with a removed protecting group (i.e., the compound where E is H) with an appropriate aldehyde, for example (C1-C5- alkyl (C = O) H, optionally substituted by one to three fluorine atoms, (C1 -C6 alkoxy) (C1-C5 alkyl) C (= O) H, optionally substituted by one to three fluorines; Ar ¹ (C 1 C ₆ -alkyl) C (= O) H; het-Ar ² (C1-C5-alkyl) C (= O) H; or het-Cus ¹ (C1-C ₆ -alkyl) -C (= O) H, c presence of a reducing agent, e.g., NaBH (AcO) ₃ to give functionalized compound 12 (i.e., in this example, compound 12 where E is _C1-C6 alkyl optionally substituted with one to three fluorine atoms, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl optionally substituted by 1-3 fluorine atoms, Ar ¹ C1-C6-alkyl-, het-Ar ² C1-C6-alk yl, where the alkyl moiety is optionally substituted with 1-3 fluorine atoms or het-Cus ¹ C1-C6-alkyl-). The same chemical transformations can be used in the cases of compounds 21 and 31 to obtain functionalized compounds 21 and 31 (i.e. in this case compounds 21 and 31, respectively, where E is C1-C6-alkyl, optionally substituted with one to three atoms fluorine; (C1-C6-alkoxy) C1-C6-alkyl, optionally substituted by 1-3 fluorine atoms; Ar ¹ C1-C ₆ -alkyl, het-Ar ² C1-C6-alkyl, the alkyl moiety being optionally substituted by 1-3 fluorine atoms or het-Cus ¹ C1-C ₆ -alkyl-).

Accordingly, also provided herein is a method for preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined herein, which comprises:

(a) for a compound of formula I wherein E is H, A is CN, —CH2CN, or —CH (CN) CH ₃ and B, X ¹ , X ² , X ³ , X ⁴ and ring D are such as defined for formula I, a combination of the corresponding compound 9, formula

N = \

where B is as defined for formula I with the corresponding boronic acid ester of formula 10

where P ¹ is a protecting group for the amino group, Z is -B (OK ^x ) (OK ^y ),

- 68 035568 where R ^x and R ^y are H or C1-C ₆ -alkyl, or R ^x and R ^y together with the atoms to which they are attached form a 5-6 membered ring optionally substituted with 1-4 substituents, selected from C1-C3 alkyl, and X ¹ , X ² , X3 and X ⁴ are as defined for formula I, in the presence of a palladium catalyst and optionally a ligand, and in the presence of a base followed by deprotection; or (b) for a compound of formula I, wherein A, B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I except that E is not hydrogen, functionalization the corresponding compound of formula

where A, ring D, B, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I, and E ¹ is hydrogen; or (c) for a compound of formula I wherein A is CN and ring D, B, X ¹ , X ² , X ³ , X ⁴ and E are as defined for formula I, contacting a corresponding compound of formula 14

as defined for formula I, and L ² represents wherein B, X ^1, X ^2, X ³ and X ⁴ are the same leaving group or atom, with a compound of formula 15, n _h Lr A D P ¹ where P ¹ represents a protecting a group for an amino group, followed by removal of the protecting group P ¹ and optionally functionalizing ring D; or (d) for a compound of formula I where E is H, A is CN and B, X ¹ , X ² , X ³ , X ⁴ and ring D are as defined for formula I, a combination of a compound of formula 14

where L ² represents a leaving group or atom, and B, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I, with a compound of formula 15

where P ¹ represents a protecting group for an amino group, followed by removal of the protecting group P ¹ ; or (e) for a compound of formula I wherein A is H, B is H, and X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I, treating a compound of formula 18

where P ¹ is an amino protecting group and X ¹ , X ² , X ³ , X ⁴ , ring D are as defined for formula I, with aluminum chloride to give compound 19

- 69 035568

where ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I, and P ¹ is a protecting group for an amino group; followed by removal of the protecting group P ¹ and optional functionalization of ring D; or (f) for a compound of formula I wherein A is H, B is C ^ C ^ alkyl optionally substituted with 1 to 3 fluorine atoms, hydroxy-C ₂ -C ₆ -alkyl, dihydroxy-C ₃ -C ₆ - α-alkyl, (C ₁ -C ₆ alkoxy ^ -C ^ alkyl, optionally substituted by 1-3 fluorine atoms, ^^ K ^ -C ^ alkyl, (het-Ar ^ CgCr alkyl, (C ₃ -C ₆ -cycloalkyl) C ₁ -C ₃ -alkyl, (het-Cyc ^a ) C ₁ -C ₃ -alkyl or het-Cyca, where R ¹ , R ² , het-Ar ¹ , het-Cyca, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I, (i) treating a compound of formula 18

where P ¹ represents a protecting group for an amino group and X ¹ , X ² , X ³ , X ⁴ ; and ring D are as defined for formula I with aluminum chloride to give compound 19

where ring D is as defined for formula I, P ¹ is an amino protecting group, and X ¹ , X ² , X ³ and X ⁴ are as defined for formula I;

(ii) contacting compound 19 with a C ^ C ^ alkyl-X optionally substituted with 1 to 3 fluorine atoms, hydroxy-C ₂ -C ₆ -alkyl-X, where the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring, dihydroxy-C ₃ -C ₆ -alkyl-X, (C ₁ -C ₆ -alkoxy) C ₁ -C ₆ -alkyl-X, optionally substituted with 1-3 fluorine atoms, ^^ ² ^ C1-C6-alkyl-X, (het -Ar ¹ ) C1-C ₃ -alkyl-X, (C ₃ -C ₆ -cycloalkyl) C ₁ C ₃ -alkyl-X, (het-Cyc ^a ) C ₁ -C ₃ -alkyl-X or het-Cyca -X, where R ¹ , R ² , het-Ar ¹ and het-Cyca are as defined for formula I, and X is a leaving atom or group, for example, a halide or triflate, in the presence of a base, to give compound 20

where ring D is as defined for formula I, P ¹ is an amino protecting group, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I, and B is C1-C6 alkyl optionally substituted with 1 to 3 fluorine atoms, hydroxy-C2-C6 alkyl, dihydroxy-C3-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl optionally substituted with 1 to 3 fluorine atoms, (R1R ² N ) C1C6-alkyl, (het-Ar ¹ ) C ₁ -C ₃ -alkyl, (C ₃ -C ₆ -cycloalkyl) C ₁ -C ₃ -alkyl, (het-Cyca) C ₁ -C ₃ -alkyl or het -Cyca, where R ¹ , R ² , het-Ar ¹ , het-Cyca are as defined for formula I, followed by removal of the protecting group P ¹ and, optionally, functionalization of ring D; or (g) for a compound of formula I wherein A is H, B is H, and X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I, treating the compound of formula

N = \ _X N ^ -A

Ji T

NSU ^^ Bg, where A represents H or Cl, the corresponding boronic acid ester of the form 70 035568 ly 10

where ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I;

P1 represents a protecting group for an amino group; Z is -B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (1-6C) alkyl, or R ^x and R ^y together with the atoms to which they are attached form 5-6 -membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl to provide a compound of formula 19 but

P ¹ where ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I, P1 is an amino protecting group and A is H or Cl, followed by removal of the protecting group P ¹ and optional functionalization of ring D; or (h) for a compound of formula I wherein A is H or Cl and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I, a combination of a compound of formula

where A is H or Cl and B is as defined for Formula I with the corresponding boronic acid ester of Formula 10

where ring D, X ¹ , X ² , X ³ and X ⁴ are as defined for formula I;

P1 is an amino protecting group and Z is -B (OR ^x ) (OR ^y ) and R ^z and R ^y are H or (1-6C) alkyl, or R ^x and R ^y together with atoms to which they are linked form a 5-6 membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl in the presence of a palladium catalyst and optionally a ligand and in the presence of a base to give a compound of formula%

R ¹ where ring D, X ¹ , X ² , X ³ , X ⁴ and B are as defined for formula I; A represents H or Cl; and P1 is an amino protecting group, followed by removal of the P1 protecting group and optionally functionalizing the D ring;

(i) for a compound of formula I wherein A is H and B, X ¹ , X ² , X ³ , X ⁴ , ring D and E are as defined for formula I, a combination of a compound of formula 24

where L ² represents a leaving group, and B, X ¹ , X ² , X ³ and X ⁴ are as defined

- 71 035568 for formula I, with a compound of formula 15

where P ¹ is an amino protecting group and ring D is as defined for formula I to give a compound of formula 20

where P ¹ represents an amino protecting group and ring D, X ¹ , X ² , X ³ , X ⁴ and B are as defined for formula I, followed by removal of the protecting group P ¹ and optionally functionalizing ring D; and removing any additional protecting groups, if present, and optionally forming a pharmaceutically acceptable salt thereof.

The term "protecting group for an amino group" in the context of this invention refers to a derivative from groups commonly used to block or protect an amino group when reacting with other functional groups of the compound. Examples of suitable protecting groups for use in any of the methods described herein include carbamates, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives that can be removed to regenerate the desired amino group. Non-limiting examples of amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Additional examples of these groups and other protecting groups can be found in T. W. Greene, et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

Hydroxy groups can be protected by any suitable hydroxy protecting group, for example, as described by T. W. Greene, et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. Examples include benzyl, trityl, silyl ethers, and the like.

The nitrogen atoms in the compounds described in any of the above methods, may be protected by any suitable protecting group for the nitrogen atom, for example as described in Greene & Wuts, eds., Protecting Groups in Organic Synthesis, 2 ^nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of nitrogen protecting groups include acyl and alkoxycarbonyl groups such as tert-butoxycarbonyl (BOC), phenoxycarbonyl, and [2- (trimethylsilyl) ethoxy] methyl (SEM).

The ability of test compounds to act as RET inhibitors can be demonstrated using the assay described in Example A.

IC50 values are presented in table. five.

In some embodiments, compounds provided herein exhibit effective and selective inhibition of RET. For example, compounds provided herein exhibit nanomolar activity against wild-type RET and selected RET mutants, including the KIF5B-RET fusion and the V804M gatekeeper gene mutation, with minimal activity against related kinases.

In some embodiments, compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof, selectively target RET kinase.

For example, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, can selectively target RET kinase over other kinase or non-kinase targets.

In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits at least 30-fold selectivity for RET kinase over another kinase. For example, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits at least 40-fold selectivity; at least 50 times selectivity; at least 60-fold selectivity; at least 70-fold selectivity; at least 80-fold selectivity; at least 90-fold selectivity; at least 100-fold selectivity; at least 200-fold selectivity; at least 300-fold selectivity; at least 400-fold selectivity; at least 500-fold selectivity; at least 600-fold selectivity; at least 700-fold selectivity; at least 800-fold selectivity; at least 900-fold selectivity; or at least 1000-72,035,568 fold selectivity for RET kinase over another kinase. In some embodiments, the selectivity for a RET kinase over another kinase is determined in a cellular assay (eg, a cellular assay as provided herein).

In some embodiments, compounds provided herein may exhibit selectivity for RET kinase over KDR kinase (eg, VEGFR2). In some embodiments, selectivity for RET kinase over KDR kinase is observed without loss of effectiveness of the gatekeeper mutant. In some embodiments, the selectivity over KDR kinase is at least 10-fold (e.g., at least 40-fold selectivity; at least 50-fold selectivity; at least 60-fold selectivity; at least 70-fold selectivity; at least 80-fold selectivity; at least 90-fold selectivity; at least 100-fold selectivity;

multiple selectivity; at least 200-fold selectivity;

multiple selectivity; at least 300-fold selectivity;

multiple selectivity; or at least 400-fold selectivity) by KIF5B-RET (i.e., compounds were more effective against KIF5B-RET than against KDR). In some embodiments, the selectivity for RET kinase over KDR kinase is about 30-fold. In some embodiments, at least 150, at least 250, and at least 350 are selected for inhibition of RET kinase over KDR kinase is at least 100-fold. In some embodiments, the selectivity for RET kinase over KDR kinase is at least 150-fold. In some embodiments, the selectivity for RET kinase over KDR kinase is at least 400-fold. Without wishing to be bound by theory, it is believed that effective inhibition of KDR kinase is a common feature among multikinase inhibitors (MCIs) that target RET and may be the source of the dose-limiting toxicity observed with such compounds.

In some embodiments, the inhibition of V804M was similar to that observed for wild-type RET. For example, the inhibition of V804M exceeded the inhibition of wild-type RET by about 2-fold (eg, about 5-fold, about 7-fold, about 10-fold) (ie, the compounds were equally effective against wild-type RET and V804M). In some embodiments, the selectivity for wild type RET kinase or V804M over another kinase is determined in a cellular assay (eg, a cellular assay as provided herein). In some embodiments, compounds provided herein exhibit selective cytotoxicity against RET mutant cells. In some embodiments, compounds provided herein exhibit penetration into the brain and / or central nervous system (CNS). Such compounds are able to cross the blood-brain barrier and inhibit RET kinase in the brain and / or other structures of the central nervous system. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (eg, RET-associated cancer, such as RET-associated brain or CNS cancer) may include administering (eg, oral administration) of the compound to the patient. In some such embodiments, the compounds provided herein are useful in the treatment of primary brain tumor or brain metastases.

In some such embodiments, the compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof, exhibit one or more of high gastrointestinal absorption, low elimination, and low potential for drug interactions.

The compounds of formula I are useful for the treatment of diseases and disorders that can be treated with a RET kinase inhibitor, such as RET-associated diseases and disorders, for example, proliferative disorders such as cancers, including hematological cancers and solid tumors, as well as gastrointestinal disorders, such as IBS.

In the context of this document, the terms treat or treat refers to therapeutic or palliative measures. Advantageous or desirable clinical results include, but are not limited to, amelioration, in whole or in part, of symptoms associated with a disease or disorder or condition, a decrease in the severity of a disease, stabilization (i.e., no worsening) of a disease state, inhibition or slowdown disease progression, a decrease in the intensity or temporary relief of a disease condition (eg, one or more symptoms of a disease) and remission (both partial and complete), both detectable and undetectable. Treatment also means extending the survival time compared to the expected life without treatment.

In the context of this document, the interchangeably used terms subject, individual

- 73 035568 or patient refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates and humans. In some such embodiments, the patient is a human. In some such embodiments, the subject has experienced and / or demonstrated at least one symptom of a disease or disorder to be treated and / or prevented. In some such embodiments, the subject has been identified or diagnosed as having cancer with dysregulation of the RET gene, RET protein, or their expression or activity, or the level of any of them (RET-associated cancer) (for example, as defined by an approved regulatory authority, such as an FDA-approved assay or kit). In some such embodiments, the subject has a tumor that is positive for dysregulation of the RET gene, RET protein, or their expression, or their activity, or the level of any of them (eg, as determined by a regulatory body approved assay or kit). The subject can be a subject with tumor (s) that are positive for dysregulation of the RET gene, RET protein, or their expression, or their activity, or the level of any of them (for example, determined as positive with using an approved regulatory body, such as an FDA-approved assay or kit). A subject can be a subject whose tumors are characterized by dysregulation of the RET gene, RET protein, or their expression, or their activity, or the level of any of them (for example, when determining such a characteristic of a tumor using an approved regulatory body, for example, an FDA-approved assay or kit ). In some such embodiments, the subject is suspected of having a RET-associated cancer. In some such embodiments, the subject has a medical history indicating that the subject has a tumor that is characterized by dysregulation of the RET gene, RET protein, or their expression, or their activity, or the level of any of them (and, optionally, history disease indicates that the subject should be treated with any of the compositions provided herein). In some such embodiments, the patient is a pediatric patient.

In the context of this document, the term pediatric patient refers to a patient less than 21 years of age at the time of diagnosis or treatment. The term pediatric can be further subdivided into different subpopulations, including: newborns (from birth and during the first month of life); young children (from 1 month to two years); children (from two years old to 12 years old); and adolescents (12 to 21 years of age (up to, but not including, twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams &Wilkins; 1994. In some such embodiments, the age of the pediatric patient is from birth through the first 28 days of life, from 29 days to less than two years, from two years to less than 12 years, or from 12 years to 21 years (up to but not including twenty-second birthday). In some such embodiments, the age of the pediatric patient is from birth through the first 28 days of life, from 29 days to less than 1 year, from one month to less than four months, from three months to less than seven months, from six months to less than 1 year, from 1 year to less than 2 years, from 2 years to less than 3 years, from 2 years to less than 7 years, from 3 years to less than 5 years, from 5 years to less than 10 years old, 6 years old to less than 13 years old, 10 years old to less than 15 years old, or 15 years old to less than 22 years old.

In certain embodiments of the invention, the compounds of Formula I are useful in preventing diseases and disorders as defined herein (eg, autoimmune diseases, inflammatory diseases, and cancer). In the context of this document, the term prevention means the prevention of the appearance, reappearance or spread, in whole or in part, of the disease or pathological condition described in this document or its symptom. In the context of this document, the term RET-associated disease or disorder refers to diseases or disorders associated with or characterized by dysregulation of the RET gene, RET kinase (also referred to herein as the RET kinase protein), or their expression, or their activity, or level of any (eg, one or more) of them (eg, any types of dysregulation of the RET gene, RET kinase, RET kinase domain, or their expression, or their activity, or the level of any of them). Non-limiting examples of RET-associated diseases or disorders include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).

In the context of this document, the term RET-associated cancer refers to cancers associated with or characterized by dysregulation of the RET gene, RET kinase (also referred to herein as the RET kinase protein), or their expression, or their activity, or the level of any of them. Non-limiting examples of RET-associated cancers are described in this document.

Expression of dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them refers to a genetic mutation (for example, a translocation of the RET gene, which leads to the expression of a fusion protein, a deletion in the RET gene that leads to the expression of RET- squirrel who

- 74 035568 contains a deletion of at least one amino acid from the wild-type RET protein, a mutation in the RET gene that results in the expression of a RET protein with one or more point mutations, or an alternative spliced version of RET mRNA that results in RET protein having a deletion of at least one amino acid in the RET protein compared to the wild-type RET protein) or RET gene amplification, which leads to overexpression of the RET protein, or autocrine activity as a result of overexpression of the RET gene in the cell, which leads to to a pathogenic increase in the activity of the kinase domain of the RET protein (for example, the constitutively active kinase domain of the RET protein) in the cell. As another example, dysregulation of the RET gene, RET protein or their expression or activity, or the level of any of them, may be a mutation in the RET gene, which encodes a RET protein that is constitutively active or has increased activity compared to the protein , encoded by the RET gene, which does not contain the mutation. For example, dysregulation of a RET gene, a RET protein, or their expression, or their activity, or the level of any of them may result from gene or chromosome translocation, resulting in the expression of a fusion protein that contains the first portion of RET that contains a functional kinase domain, and the second part of the partner protein (i.e., non-RET). In some examples, dysregulation of a RET gene, a RET protein, or their expression or activity, or the level of any of them, may result from gene translocation of one RET gene to another non-RET gene. Non-limiting examples of fusion proteins are described in table. 1. Non-limiting examples of point mutations / insertions / deletions in the RET kinase protein are described in table. 2. Additional examples of mutations in the RET kinase protein (eg, point mutations) are RET inhibitor resistance mutations. Non-limiting examples of mutations in resistance to RET inhibitors are described in table. 3 and 4.

The term wild-type or wild-type describes a nucleic acid (e.g., a RET gene or RET mRNA) or protein (e.g., a RET protein) that can be found in a subject who does not have a RET-associated disease, such as a RET-associated cancer (and optionally also not at increased risk of developing a RET-associated disease and / or having no suspected RET-associated disease), or can be found in a cell or tissue from a subject without a RET-associated disease, such as RET-associated cancer (and, optionally, also not at increased risk of developing a RET-associated disease and / or having no suspected RET-associated disease).

The term regulator refers to a government agency that approves the medical use of pharmaceutical agents in a country. For example, the United States Food and Drug Administration (FDA) is a non-limiting example of a regulatory body.

Provided herein is a method of treating cancer (eg, RET-associated cancer) in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. For example, provided herein are methods of treating RET-associated cancer in a patient in need of such treatment, the method comprising a) detecting dysregulation of a RET gene, RET kinase or their expression, or their activity, or the level of any of them in a sample from the patient; and b) administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more fusion proteins. Non-limiting examples of RET gene fusion proteins are described in table. 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more point mutations / insertions in the RET kinase protein. Non-limiting examples of point mutations / insertions / deletions in the RET kinase protein are described in table. 2. In some embodiments, point mutations / insertions / deletions in the RET kinase protein are selected from the group consisting of M918T, M918V, C634W, V804L, and V804M. In some embodiments, the compound of Formula I is selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-associated cancer) is hematologic cancer. In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-associated cancer) is a solid tumor. In some variants

- 75 035568 implementation of any of the methods or uses described herein, cancer (e.g., RET-associated cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer or refractory differentiated thyroid cancer), adenoma of the thyroid gland, neoplasms of the endocrine glands, adenocarcinoma of the lung, carcinoma from lung bronchiole cells, multiple endocrine neoplasias of type 2A or 2B (MEN2A or MEN2B, respectively ), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, breast carcinoma, breast neoplasms, colorectal cancer (e.g. metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, inflammatory myofibroids a regional tumor or cancer of the cervix. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-associated cancer) is selected from the following group: acute lymphoblastic leukemia (ALL), acute myelocytic leukemia (AML), adolescent cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid-rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor carcinoma of unknown primary site, cardiac tumors, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, local neoplasms, neoplasms, colon cancer, colorectal cancer, craniopharynx cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ, embryo ionic tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial embryonic cell tumor, extrahepatic embryonic cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma, gastric cancer , gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GST), embryonic cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, central nervous system tumor heart, hepatocellular cancer, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, neuroendocrine pancreatic tumors, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal and oral cancer, liver cancer lung cancer, lymphoma, macroglobulus inemia, malignant fibrous bone histiocytoma, osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck, carcinoma of the midline, oral cavity cancer, multiple endocrine neoplasia syndrome, myeloma, myeloid mycosis, myeloid mycosis local neoplasms, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung neoplasms, lung cancer, neoplasms , bronchogenic carcinoma, neoplasms of the bronchi, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, cancer of the paranasal sinuses and nasal cavity, parasite cancer toid gland, penile cancer, pharyngeal cancer, pheochromositoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary abdominal cancer, prostate cancer, rectal cancer, colon cancer , colon neoplasms, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sesari syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell neck cancer, stomach cancer, T- cell lymphoma, testicular cancer, throat cancer, thymoma and carcinoma of the thymus, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, carcinoma of unknown primary site, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms' tumor.

In some embodiments, hematologic cancers (e.g., hematologic cancers that are RET-associated cancers) are selected from the group consisting of leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, e.g., acute lymphocytic leukemia ( ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (acute) leukemia (CNL) ), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilinear myelodysplasia (mixed myelodysplasia AML (mixed line AML / TMD) LDSL (MLS) syndrome of mixed origin ), mie

- 76,035,568 loproliferative disorders (MPN) and multiple myeloma (MM). Additional examples of hematologic cancers include myeloproliferative disorders (MPNs) such as polycythemia vera (PT), essential thrombocytopenia (ET), and primary idiopathic myelofibrosis (IMF / IPF / PMF). In one embodiment, the hematologic cancer (eg, hematologic cancer that is a RET-associated cancer) is AML or CML.

In some embodiments, the cancer (eg, RET-associated cancer) is a solid tumor. Examples of solid tumors (eg, solid tumors that are RET-associated cancers) include, for example, thyroid cancer (eg, papillary thyroid cancer, medullary thyroid cancer), lung cancer (eg, adenocarcinoma of the lung, small cell lung cancer), cancer pancreas, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck tumors, neuroblastoma and melanoma. See, for example, Nature Reviews Cancer, 2014, 14, 173-186. In some embodiments, the cancer is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuromatosis, and cervical cancer.

In some embodiments, the patient is a human.

The compounds of formula I and their pharmaceutically acceptable salts and solvates are also useful in the treatment of RET-associated cancer.

Accordingly, this document also provides a method of treating a patient who is diagnosed with or who is determined to have a RET-associated cancer, for example, any of the typical RET-associated cancers described herein, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate, or a pharmaceutical composition thereof as defined herein. Dysregulation of the RET kinase, the RET gene or their expression, or their activity, or the level of any (eg, one or more) of them, can contribute to oncogenesis. For example, dysregulation of the RET kinase, the RET gene or their expression, or their activity, or the level of any of them, may be a translocation, overexpression, activation, amplification, or mutation of the RET kinase, the RET gene or the RET kinase domain. The translocation may involve translocations involving the RET kinase domain, mutations may involve mutations involving the RET ligand binding site, and amplification may occur with the RET gene. Other variants of dysregulation may include RET mRNA splice variants and RET autocrine / paracrine signaling, which may also contribute to tumorigenesis.

In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises overexpression of wild-type RET kinase (eg, resulting in autocrine activation). In some embodiments of the invention, dysregulation of the RET gene, RET kinase protein or their expression, or their activity, or the level of any of them, comprises overexpression, activation, amplification, or mutation in a chromosomal segment containing the RET gene or a portion thereof including, for example, a portion of a kinase domain or part capable of exhibiting kinase activity.

In some embodiments, dysregulation of the RET gene, RET kinase protein or their expression, or their activity, or the level of any of them, comprises one or more chromosomal translocations or inversions resulting in the fusion of the RET gene. In some embodiments, the dysregulation of the RET gene, RET kinase protein or their expression or activity, or the level of any of them is the result of genetic translocations in which the expressed protein is a fusion protein containing residues of a non-RET partner protein, and contains a minimum of the functional domain of RET kinase.

Non-limiting examples of RET fusion proteins are shown in table. 1.

- 77 035568

Table 1

Typical RET Fusion Partners and Cancers

Merger partner Non-limiting typical RET-associated cancers BCR Chronic myelomonocytic leukemia (CML) CLIP1 Adenocarcinoma KIF5B NSCLC, ovarian cancer, spitzoid neoplasms; adenocarcinoma of the lung ^3, 4, 14.28. adenosquamous cell carcinoma ¹⁵ CCDC6 (also called PTCl, D10S170 or H4) NSCLC, colon cancer, papillary thyroid cancer; adenocarcinomas; adenocarcinoma of the lung; metastatic colorectal cancer ⁵ ; adenosquamous cell carcinomas ¹⁵ , breast cancer ³⁰ PTC1ex9 (new rebuilding of CCDC6) Metastatic papillary thyroid cancer ² NCOA4 (also called RTSZ, ELE1 and RFG) Papillary thyroid cancer ²¹ , NSCLC, colon cancer, salivary gland cancer, metastatic colorectal cancer ⁵ ; lung adenocarcinoma ¹⁵ ; adenosquamous cell carcinoma ¹⁵ diffuse sclerosing variant

- 78 035568

papillary cancer 16 thyroid gland, breast cancer ³⁰ , acinar cell carcinoma, mammary analogue of secretory carcinoma ³³ TRIM33 (also called RTS7 and RFG7) NSCLC, papillary thyroid cancer ERC1 (also called ELKS) Papillary thyroid cancer, breast cancer FGFR1OP CML, primary myelofibrosis with secondary acute myeloid leukemia MB D I (also known as PCM1) Papillary thyroid cancer RAB61P2 Papillary thyroid cancer PRKAR1A (also called PTS2) Papillary thyroid cancer TRIM24 (also called RTS6) Papillary thyroid cancer KTN1 (also called RTS8) Papillary thyroid cancer GOLGA5 (also called RTS5) Papillary thyroid cancer, spitzoid neoplasms NOOKZ Papillary thyroid cancer KIAA1468 (also called RTS9 and RFG9) Papillary thyroid cancer, lung adenocarcinoma ^8, 12 TRIM27 (also called RFP) Papillary thyroid cancer AKAR 13 Papillary cancer

- 79 035568

thyroid gland FKBP15 Papillary thyroid cancer SPECC1L Papillary thyroid cancer; thyroid carcinoma TBL1XR1 Papillary thyroid cancer; thyroid carcinoma CEP55 Diffuse gastric cancer ⁷ CUXI Lung adenocarcinoma ACBD5 Papillary thyroid carcinoma MYH13 Medullary thyroid carcinoma ¹ Undescribed Inflammatory myofibroblastic tumor ⁶ PIBF1 Carcinoma from lung bronchioles ⁹ KIAA1217 (also called SKT) Papillary thyroid cancer is ^{1 and '13} lung adenocarcinoma NSCLC ^{14 14} MPRIP NMCRL ¹¹ HRH4-RET Thyroid cancer and / or papillary thyroid carcinoma ¹⁷ Ria-RET Thyroid cancer and / or papillary thyroid carcinoma ¹⁷ RFG8 Papillary thyroid carcinoma ¹⁰ FOXP4 Adenocarcinoma 19 lung MYH10 Infantile myofibromatosis ²⁰ HTIF1 Various ²² TIF1G Various ²²

- 80 035568

H4L Various ²² PTC4 (new rebuild NCO4 / ELE1) Papillary thyroid cancer ^ ³ FRMD4A NMCRL ²⁴ SQSTM1 Papillary thyroid carcinoma ²⁵ AFAP1L2 Papillary carcinoma ~ 95 thyroid gland AFAP1 NMCRL ³¹ PPFIBP2 Papillary carcinoma ~ 95 thyroid gland EML4 Papillary thyroid cancer ^ho PARD3 NMCRL ²⁷ UVELD Papillary thyroid cancer ^xy RASGEF1A Breast cancer ³⁰ TEL In vitrei ⁴ RUFY1 Colorectal cancer ³⁵ OLFM4 Small intestine cancer ³⁶ UEVLD Papillary carcinoma of the thyroid gland ⁷ DLG5 Non-anaplastic thyroid cancer (NTH) ³⁸ RRBP1 Colon cancer ³⁹

¹ Grubbs et al., J. Clin. Endocrinol. Metab. 100: 788-793, 2015.

² Halkova et al., Human Pathology 46: 1962-1969, 2015.

³ US patent No. 9297011.

⁴ US Patent No. 9216172.

⁵ Le Rolle et al., Oncotarget. 6 (30): 28929-37, 2015.

⁶ Antonescu et al., Am J Surg Pathol. 39 (7): 957-67, 2015.

⁷ US Patent Application Publication No. 2015/0177246.

⁸ US Patent Application Publication No. 2015/0057335.

⁹ Japanese Patent Application Publication No. 2015 / 109806A.

¹⁰ Chinese Patent Application Publication No. 105255927A.

¹¹ Fang, et al. Journal of Thoracic Oncology 11.2 (2016): S21-S22.

¹² European Patent Application Publication No. EP3037547A1.

¹³ Lee et al., Oncotarget. DOI: 10.18632 / oncotarget.9137, published electronically ahead of print, 2016.

¹⁴ Saito et al., Cancer Science 107: 713-720, 2016.

¹⁵ Pirker et al., Transl. Lung Cancer Res. 4 (6): 797-800, 2015.

¹⁶ Joung et al., Histopathology 69 (1): 45-53, 2016.

¹⁷ PCT Patent Application Publication No. WO 2016/141169.

¹⁸ Klugbauer et al. Cancer Res. 60 (24): 7028-32, 2000.

¹⁹ Bastien et al., Journal of Molecular Diagnostics, 18 (6): 1027, Abstract Number: S120, 2016 Annual Meeting of the Association for Molecular Pathology, Charlotte, NC, 2016.

²⁰ Rosenzweig et al., Pediatr Blood Cancer, doi: 10.1002 / pbc. 26377,2016.

²¹ Su et al., PLoS One, 11 (111): e0165596, 2016.

²² US Patent No. 9487491.

²³ Fugazzola et al., Oncogene, 13 (5): 1093-7, 1996.

²⁴ Velcheti et al., J Thorac Oncol., 12 (2): e15-e16. doi: 10.1016 / j.jtho.2016.11.274, 2017.

²⁵ Iyama et al., Thyroid, doi: 10.1089 / thy.2016.0673, 2017.

²⁶ Demeure et al., World J Surg. 38 (6): 1296-305. doi: 10.1007 / s00268-014-2485-3, 2014.

²⁷ Sabari et al., Oncoscience, Advance Publications, www.impactjournals.com/oncoscience/files/papers/1/345/345.pdf, 2017.

²⁸ US Patent Application Publication No. 2017/0014413.

²⁹ Lu et al., Oncotarget, doi: 10.18632 / oncotarget. 17412, [pre-print electronic publication], 2017.

³⁰ Hirshfield et al., Cancer Research, (February 2017), vol. 77, No. 4, Supp. 1. Abstract Number: P3-07-02. Meeting Info: 39th Annual CTRC-AACR San Antonio Breast Cancer Symposium. San Antonio, TX, United States. 06 Dec 2016 - 10 Dec 2016.

³¹ Morgensztern et al., Journal of Thoracic Oncology, (January 2017), vol. 12, No. 1, Supp. 1, p. S717S718, Abstract Number: P1.07-035, Meeting Info: 17th World Conference of the International Association for

- 81 035568 the Study of Lung Cancer, IASLC 2016. Vienna, Austria. 04 Dec 2016.

³² Dogan et al., Laboratory Investigation, (February 2017), vol. 97, Supp. 1, p. 323A. Abstract Number: 1298, Meeting Info: 106th Annual Meeting of the United States and Canadian Academy of Pathology, USCAP 2017. San Antonio, TX, United States.

³³ Dogan et al., MODERN PATHOLOGY, Vol. 30, Supp. [2], p. 323A-323A. MA 1298, 2017.

³⁴ Publication of PCT Patent Application No. WO 2017/146116.

³⁵ Publication of PCT Patent Application No. WO 2017/122815.

³⁶ Reeser et al., J. Mol. Diagn., 19 (5): 682-696, doi: 10.1016 / j.jmoldx.2017.05.006, 2017.

³⁷ Lu et al., Oncotarget, 8 (28): 45784-45792, doi: 10.18632 / oncotarget.17412, 2017.

³⁸ Ibrahimpasic et al. Clin. Cancer Res., Doi: 10.1158 / 1078-0432. CCR-17-1183, 2017.

³⁹ Kloosterman et al. Cancer Res. 77 (14): 3814-3822. doi: 10.1158 / 0008-5472.CAN-16-3563, 2017.

In some embodiments, dysregulation of a RET gene, RET kinase, or expression or activity thereof, or the level of any of them comprises the presence of one or more deletions (e.g., an amino acid deletion at position 4), insertions, or point mutations in the RET kinase. In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises deletion of one or more RET kinase residues resulting in constitutive activity of the RET kinase domain.

In some embodiments, the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises at least one point mutation in the RET gene that results in a RET kinase that has one or more amino acids substitutions, insertions or deletions compared to wild-type RET kinase (see, eg, point mutations listed in Table 2).

table 2

Protein activating RET kinase point mutations / insertions / deletions

Typical RET_____________ point mutations

Amino acid position 2_____________________ ίAmino acid position 3______________________

Amino acid position 4_____________________

Amino acid position 5______________________

Amino acid position 6_____________________

Amino acid position 7_____________________

Amino acid position 8_____________________

Amino acid position 11_____________________

Amino acid position 12_____________________

Amino acid position 13

- 82 035568

Amino acid position 20___________________

Amino acid position 32 (e.g. S32L)

Amino acid position 34 (e.g. D34S) ____

Amino acid position 40 (e.g. L40P) ____

Amino acid position 56 (e.g. L56M) ³⁰

Amino acid position 64 (e.g. P64L) ____

Amino acid position 67 (e.g. R67H) Amino acid position 114 (e.g. R114H) Amino acid position 136 (e.g. glutamic acid per stop codon) _____________

Amino acid position 145 (e.g. V145G) Amino acid position 180 (e.g. arginine per stop codon) ___________________________________

Amino acid position 200

Amino acid position 292 (e.g. V292M)

Amino acid position 294__________________

Amino acid position 321 (eg G321R) Amino acid position 330 (eg R330Q) Amino acid position 338 (eg T338I) Amino acid position 360 (eg R360W) Amino acid position 373 (eg alanine frame shift) ___________________________________

Amino acid position 393 (e.g. F393L) Amino acid position 423 (e.g. G423R) ²⁷

Amino acid position 432__________________

Amino acid position 446 (e.g. G446R) ²⁸ A of amino acid residues 505-506 (in-frame deletion of 6 germline base pairs in exon 7) ³ __________________

Amino acid position 510 (eg A510V) Amino acid position 511 (eg E511K) Amino acid position 513 (eg G513D ⁷ * Amino acid position 515 (eg C515S, C515W ⁴ ) ___________________________________

Amino acid position 525 (e.g. R525W) ⁷ *

Amino acid position 531 (e.g. C531R or 9 base pair ² duplication) ______________

Amino acid position 532 (e.g. duplication) ² _________________________________

Amino acid position 533 (e.g. G533C, G533S) ______________________________________

Amino acid position 550 (e.g. G550E) Amino acid position 591 (e.g. V591I) Amino acid position 593 (e.g. G593E) Amino acid position 595 (e.g. E595D and

- 83 035568

E595A) ¹⁸ ______________________________________

Amino acid position 600 (for example, R600Q) Amino acid position 602 (for example, 1602V) ⁶ Amino acid position 603 (for example, K603Q, K603E ² ) _____________________________________

Amino acid position 606 (eg Y606C) Amino acid position 609 (eg C609Y, C609S, C609G, C609R, C609F, C609W, C609C ³² ) Amino acid position 611 (eg C611R, C611S, C611G, CF611Y, CW611)

Amino acid position 616 (eg E616Q) ²³ Amino acid position 618 (eg C618S, C618Y, C618R, C618Y, C618G, C618F, C618W) Amino acid position 619 (eg F619F) Amino acid position 620 (eg C20, C620S, C206 , C620L, C620Y, C620F) Amino acid position 623 (eg E623K) Amino acid position 624 (eg D624N) Amino acid position 630 (eg C630A, C630R, C630S, C630Y, C630F, C630W) __________

Amino acid position 631 (e.g. D631N, D631Y, D631A, D631G, D631V, D631E) _________

Amino acid position 632 (for example, E632K, E632G ^{5 n} ) ___________ __________________

A amino acid residues 632-633 (in-frame deletion of 6 germline base pairs in exon 11) ⁹ ________________

Amino acid position 633 (for example, duplication of 9 base pairs ² ) _________________

Amino acid position 634 (for example, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A or C634T, or ELCR insert ² , or 12 bp duplication ² ) (for example, causing thyroid gland) ___________________

Amino acid position 635 (for example, R635G) Amino acid position 636 (for example, T636P ² , T636M ⁴ ) ___________________________________

Amino acid position 640 (for example, A640G) Amino acid position 641 (for example, A641S, A641T ⁸ ) _____________________________________

Amino acid position 648 (e.g. V648I) Amino acid position 649 (e.g. S649L) ²⁸ Amino acid position 664 (e.g. A664D) Amino acid position 665 (e.g. H665Q)

Amino acid position 666 (for example, K666E, K666M, K666N, K666R)

- 84 035568

Amino acid position 675 (T675T, silent nucleotide substitution) ¹⁸ __________________________

Amino acid position 686 (e.g. S686N)

Amino acid position 689 (e.g. S689T) ¹⁸

Amino acid position 691 (e.g. G691S)

Amino acid position 694 (e.g. R694Q)

Amino acid position 700 (e.g. M700L)

Amino acid position 706 (e.g. V706M,

V706A) __________________________________

Amino acid position 713, splice variant (for example, E713K) ⁶ ____________________________

Amino acid position 732 (for example, E732K) ²⁰

Amino acid position 736 (e.g. G736R) ⁶

Amino acid position 748 (e.g. G748C)

Amino acid position 750 (for example, A750P)

Amino acid position 765 (e.g. S765P)

Amino acid position 766 (e.g. P766S,

Р766М ⁶ ) ____________ ________________

Amino acid position 768 (e.g. E768Q,

E768D) _____________ ________________

Amino acid position 769 (e.g. L769L)

Amino acid position 770 (e.g. R770Q)

Amino acid position 771 (e.g. D771N)

Amino acid position 777 (e.g. N777S)

Amino acid position 778 (e.g. V778I)

Amino acid position 781 (e.g. Q781R)

Amino acid position 788 (e.g. I788I ³² )

Amino acid position 790 (e.g. L790F)

Amino acid position 791 (e.g. Y791F,

Y791N ²⁴ ) ____________ _________________

Amino acid position 802__________________

Amino acid position 804 (for example, V804L ^{15 16} , V804M ^{15 16} , V804E ¹² ) (for example, causing

MCG) ________________________

Amino acid position 805 (for example, E805K)

Amino acid position 804/805 (e.g.

V804M / E805K) ¹⁷ ____________________________

Amino acid position 806 (e.g. Y806F, Y806S ¹² , Y806G, Y806C ^{2 12 14} , Y806E ¹⁴ , Y806H ¹² , Y806N ¹² , Y806Y ³² ) _____________________________

Amino acid position 810 (e.g. G81 OR ¹² , G810S ¹² , G810A ¹³ ) __________________

Amino acid position 818 (for example, E818K)

Amino acid position 819 (e.g. S819I)

Amino acid position 823 (e.g. G823E)

- 85 035568

Amino acid position 826 (e.g. Y826M,

Y826S) ¹⁰ _______________________________________

Amino acid position 833 (e.g. R833C) Amino acid position 836 (e.g. S836S) ¹⁹

Amino acid position 841 (e.g. P841L,

Р841Р) _______________________________________

Amino acid position 843 (e.g. E843D) Amino acid position 844 (e.g. R844W, R844Q, R844L) ______________________________

Amino acid position 848 (for example, M848T)

Amino acid position 852 (e.g. I852M) Amino acid position 865 (e.g. L865V) ¹² Amino acid position 870 (e.g. L870F) ¹² Amino acid position 873 (e.g. R873W)

Amino acid position 876 (e.g. A876V)

Amino acid position 881 (e.g. L881V)

Amino acid position 882___________________

Amino acid position 883 (e.g. A883F,

A883S, A883T) _______________________________

Amino acid position 884 (for example, E884K)

Amino acid position 886 (e.g. R886W) Amino acid position 891 (e.g. S891A, S891S ³² ) ___________________________________________

Amino acid position 897 (e.g. R897Q)

Amino acid position 898 (e.g. D898V) Amino acid position 900 (e.g. Y900F) ²²

Amino acid position 901 (for example, E901K)

Amino acid position 904 (e.g. S904F, S904S, S904C ² ) ___________________________

Amino acid position 905 (for example, Y905F) ²² Amino acid position 907 (for example, K907E, K907M) __________________________________

Amino acid position 908 (e.g. R908K)

Amino acid position 911 (e.g. G911D) Amino acid position 912 (e.g. R912P, R912Q) ___________________________________

Amino acid position 918 (for example, M918T ² , M918V, M918L ⁶ ) (for example, causing thyroid gland) Amino acid position 919 (for example, A919V)

Amino acid position 921 (for example, E921K) Amino acid position 922 (for example, S922P, S922Y) _______________________________________

Amino acid position 930 (for example, T930M)

Amino acid position 961 (e.g. F961L)

Amino acid position 972 (e.g. R972G)

- 86 035568

Amino acid position 981 (e.g. Y981F) ²²

Amino acid position 982 (e.g. R982C)

Amino acid position 1009 (for example,

M1009V) _________________________________

Amino acid position 1015 (e.g.

IY1015F) ²² _______________________________________

Amino acid position 1017 (e.g. D1017N)

Amino acid position 1041 (e.g. VI041G)

Amino acid position 1064 (for example, Ml 064T)

Amino acid position 1096 (e.g. Y1096F) ²¹ ______________________________________

RET + 3 ¹ ____________________________________ (In-frame deletion in exons 6 and

I) ²⁵ ___________________________________________ (Deletion of 3 i.o. within the reading frame in exon 15) ²⁶ ________________________________________________________

Nucleotide position 2136 + 2 (e.g. 2136 + 2T + G) ²⁹ __________________________________ (de! 632-636 ins6) ³¹ ____________________________________

Amino acid positions 791 and 852 (e.g.

Y791F + I852M) ³¹ _______________________________

Amino acid positions 634 and 852 (e.g., C634R + 1852M) ³¹ _____________________________ ¹ US Patent Application Publication No. 2014/0272951.

² Krampitz et al., Cancer 120: 1920-1931, 2014.

³ Latteyer, et al., J. Clin. Endocrinol. Metab. 101 (3): 1016-22, 2016.

⁴ Silva, et al. Endocrine 49.2: 366-372, 2015.

⁵ Scollo, et al., Endocr. J. 63 (1): 87-91, 2016.

⁶ Jovanovic, et al., Prilozi 36 (1): 93-107, 2015.

⁷ Qi, et al., Oncotarget. 6 (32): 33993-4003, 2015. * R525W and G513D act in combination with S891A to enhance oncogenic activity.

⁸ Kim, et al. ACTA ENDOCRINOLOGICA-BUCHAREST 11.2, 189-194, 2015.

⁹ Cecchirini, et al. Oncogene, 14, 2609-2612, 1997.

¹⁰ Karrasch, et al. Eur. Thyroid J., 5 (1): 73-7, 2016.

¹¹ Scollo et al., Endocr. J. 63: 87-91, 2016.

¹² Publication of PCT Patent Application No. WO 2016/127074.

¹³ Huang et al., Mol. Cancer Ther., 2016 Aug 5.pii: molcanther. 0258.2016. [Electronic publication before printing].

¹⁴ Carlomagno, et al., Endocr. Rel. Cancer 16 (1): 233-41, 2009.

¹⁵ Yoon et al., J. Med. Chem. 59 (1): 358-73, 2016.

¹⁶ US Patent No. 8629135.

¹⁷ Cranston, et al. Cancer Res. 66 (20): 10179-87, 2006.

¹⁸ Kheiroddin et al., Clin. Laboratory 62 (5): 871-6, 2016.

¹⁹ Ceolin et al., PLoS One. 11 (2): e0147840, doi: 10.1371 / journal.pone.0147840, 2016.

²⁰ Nadezda et al., Summer Undergraduate Research Programs (SURP) Student Abstracts, University of Oklahoma Health Sciences Center, 2016.

²¹ Liu et al., J. Biol. Chem., 271 (10): 5309-12,1995.

²² Kato et al. Cancer Res. 62: 2414-22, 2002.

²³ Gray et al., Endocrine Pathology, doi: 10.1007 / s12022-016-9451-6, 2016.

²⁴ De Almeida et al., Endocrine Reviews, 2016, Vol. 37, No. 2, Supp. Supplement 1. Abstract Number: SUN-068; 98 ^th Annual Meeting and Expo of the Endocrine Society, ENDO 2016. Boston, MA, US. 01 Apr 2016 - 04 Apr 2016.

²⁵ Vanden et al., Annals of Oncology, 2016, Vol. 27, Supp. Supplement 6. Abstract Number: 427PD; 41 ^st European Society for Medical Oncology Congress, ESMP 2016. Copenhagen, Denmark. 07 Oct 2016 - 11 Oct 2016.

²⁶ Romei et al., European Thyroid Journal (August 2016), vol. 5, Supp. Supplement 1, p. 75; 39 ^th Annual Meeting of the European Thyroid Association, ETA 2016. Copenhagen, Denmark. 03 Sep 2016 - 06 Sep 2016.

²⁷ Lee et al., Oncotarget, 8 (4): 6579-6588, doi: 10.18632 / oncotarget.14172, 2017.

²⁸ Zhang et al., Laboratory Investigation, (February 2017), vol. 97, Supp. 1, p. 209A. Abstract Number: 840, Meeting Info: 106th Annual Meeting of the United States and Canadian Academy of Pathology, USCAP 2017. San Antonio, TX, United States.

²⁹ Borecka et al., European Journal of Cancer, (July 2016), vol. 61, No. 1, p. S26, Abstract Number: 162, Meeting Info: 24th Biennial Congress of the European Association for Cancer Research, EACR 2016. Manches

- 87 035568 ter, United Kingdom.

³⁰ Corsello et al., Endocrine Reviews, (JUN 2014), Vol. 35, No. 3, Suppl. S, p. SUN-0322, Meeting Info .: 96th Annual Meeting and Expo of the Endocrine-Society, Chicago, IL, USA, June 21-24, 2014.

³¹ Gazizova et al., Endocrine Reviews, (JUN 2014), Vol. 35, No. 3, Suppl. S, p. SAT-0304, Meeting Info .: 96th Annual Meeting and Expo of the Endocrine-Society, Chicago, IL, USA, June 21-24, 2014.

³² Sromek et al., Endocr Pathol, dor 10.1007 / s12022-017-9487-2, 2017.

In some embodiments, the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises at least one point mutation in the RET gene that results in a RET kinase that has one or more amino acid substitutions, insertions, or deletions compared to wild-type RET kinase (see, eg, point mutations listed in Table 2a).

Table 2a

Typical protein activating RET kinase point mutations / insertions / deletions

Typical RET_____________ point mutations

Amino acid position 20____________________

Amino acid position 32 (e.g. S32L) _____

Amino acid position 34 (e.g. D34S) _____

Amino acid position 40 (e.g. L40P) _____

Amino acid position 64 (e.g. P64L) _____

Amino acid position 67 (e.g. R67H) _____

I Amino acid position 114 (e.g. R114H) Amino acid position 145 (e.g. V145G) Amino acid position 200

Amino acid position 292 (e.g. V292M)

Amino acid position 294___________________

Amino acid position 321 (eg G321R) Amino acid position 330 (eg R330Q) Amino acid position 338 (eg T338I) Amino acid position 360 (eg R360W) Amino acid position 393 (eg F393L) Amino acid position 432___________________

Δ amino acid residues 505-506 (in-frame deletion of 6 germline base pairs in exon 7) __________________

Amino acid position 510 (eg A510V) Amino acid position 511 (eg E511K) Amino acid position 513 (eg G513D) Amino acid position 515 (eg C515S, C515W ⁴ ) ___________________________________

Amino acid position 525 (e.g. R525W) Amino acid position 531 (e.g. C531R or 9 bp duplication) _______________

Amino acid position 532 (e.g.

- 88 035568 duplication) ________________________________

Amino acid position 533 (e.g. G533C, G533S) ____________________________________

Amino acid position 550 (e.g. G550E) Amino acid position 591 (e.g. V591I) Amino acid position 593 (e.g. G593E) Amino acid position 595 (e.g. E595D and E595A) ____________________________________

Amino acid position 600 (for example R600Q) Amino acid position 602 (for example 1602V) Amino acid position 603 (for example K603Q, K603E) ____________________________________

Amino acid position 606 (for example, Y606C) Amino acid position 609 (for example, C609Y, C609S, C609G, C609R, C609F, C609W) __________

Amino acid position 611 (for example, C611R, C611S, C611G, C611Y, C611F, C611W) _________

Amino acid position 616 (for example, E616Q) Amino acid position 618 (for example, C618S, C618Y, C618R, C618G, C618F, C618W) _________

Amino acid position 620 (eg C620S, C620W, C620R, C620G, C620L, C620Y, C620F) Amino acid position 623 (eg E623K) Amino acid position 624 (eg D624N) Amino acid position 630 (eg C630A, C630S, C630F, C630W) __________

Amino acid position 631 (e.g. D631N, D631Y, D631A, D631G, D631V, D631E) _________

Amino acid position 632 (for example, E632K, E632G) ____________________________________

Δ amino acid residues 632-633 (in-frame deletion of 6 germline base pairs in exon 11) _______________

Amino acid position 633 (e.g. 9 bp duplication) ________________

Amino acid position 634 (for example, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A or C634T, or insert ELCR2, or duplicate 12 bp) (for example, causing thyroid gland) ___________________

Amino acid position 635 (for example, R635G) Amino acid position 636 (for example, T636P, T636M) __________________________________

Amino acid position 640 (e.g. A640G) Amino acid position 641 (e.g. A641S, A641T)

- 89 035568

Amino acid position 648 (eg V648I) Amino acid position 649 (eg S649L) Amino acid position 664 (eg A664D) Amino acid position 665 (eg H665Q) Amino acid position 666 (eg K666E, K666M, K666N, K666R) ____________

Amino acid position 686 (eg S686N) Amino acid position 689 (eg S689T) Amino acid position 691 (eg G691S) Amino acid position 694 (eg R694Q) Amino acid position 700 (eg M700L) Amino acid position 706 (eg V706A6M, V706M) ____________ _______________

Amino acid position 713, splice variant (for example, E713K) ____________________________

Amino acid position 732 (eg E732K) Amino acid position 736 (eg G736R) Amino acid position 748 (eg G748C) Amino acid position 750 (eg A750P) Amino acid position 765 (eg S765P) Amino acid position 766 (eg P766S), P766M __________________________________

Amino acid position 768 (e.g. E768Q, E768D) _____________ ________________

Amino acid position 769 (eg L769L) Amino acid position 770 (eg R770Q) Amino acid position 771 (eg D771N) Amino acid position 777 (eg N777S) Amino acid position 778 (eg V778I) Amino acid position 781 (eg Q781R) Amino acid position 781 (eg Q781R) 790 (e.g. L790F) Amino acid position 791 (e.g. Y791F, Y791N) __________________________________

Amino acid position 802_________________

Amino acid position 804 (for example, V804L, V804M, V804E) (for example, causing thyroid gland) Amino acid position 805 (for example, E805K) Amino acid position 804/805 (for example, V804M / E805K) ____________________________

Amino acid position 806 (e.g. Y806F, Y806S, Y806G, Y806C, Y806E, Y806H, Y806N)

Amino acid position 810 (e.g. G810R, G810S, G810A) ________________

Amino acid position 818 (eg E818K) Amino acid position 819 (eg S819I)

- 90 035568

Amino acid position 823 (e.g. G823E) Amino acid position 826 (e.g. Y826M, Y826S) ______________________________________

Amino acid position 833 (e.g. R833C) Amino acid position 836 (e.g. S836S) Amino acid position 841 (e.g. P841L, P841P) _________________________________________

Amino acid position 843 (e.g. E843D) Amino acid position 844 (e.g. R844W, R844Q, R844L) _______________________________

Amino acid position 848 (e.g. M848T) Amino acid position 852 (e.g. I852M) Amino acid position 865 (e.g. L865V) Amino acid position 870 (e.g. L870F)

I Amino acid position 873 (e.g. R873W) Amino acid position 876 (e.g. A876V) Amino acid position 881 (e.g. L881V) Amino acid position 882___________________

Amino acid position 883 (for example, A883F, A883S, A883T) _______________________________

Amino acid position 884 (eg E884K) Amino acid position 886 (eg R886W) Amino acid position 891 (eg S891A) Amino acid position 897 (eg R897Q) Amino acid position 898 (eg D898V) Amino acid position 900 (eg Y900F) Amino acid position 900 901 (for example, E901K) Amino acid position 904 (for example, S904F, S904S, S904C) ____________________________________

Amino acid position 907 (for example, K907E, K907M) __________________________________

Amino acid position 908 (e.g. R908K) Amino acid position 911 (e.g. G911D) Amino acid position 912 (e.g. R912P, R912Q) ____________________________________

Amino acid position 918 (for example, M918T, M918V, M918L) (for example, causing MTC) Amino acid position 919 (for example, A919V) Amino acid position 921 (for example, E921K) Amino acid position 922 (for example, S922P, S922Y) ______________________________________

Amino acid position 930 (eg T930M) Amino acid position 961 (eg F961L) Amino acid position 972 (eg R972G) Amino acid position 982 (eg R982C) Amino acid position 1009 (eg M1009V) __________________________________

Amino acid position 1015 (eg Y1015F) Amino acid position 1017 (eg D1017N) Amino acid position 1041 (eg VI041G) Amino acid position 1064 (eg M1064T) Amino acid position 1096 (eg Y1096F) RET + 3 (In-frame deletion in exons 6 and 11) ______________________________________ (Deletion of 3 bp within the reading frame in the exon

eleven_________________________

In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises a splice variation in RET mRNA that results in the expression of a protein that is a variant of alternative RET splicing with at least one deleted residue (compared to wild-type RET kinase), which leads to constitutive activity of the RET kinase domain.

A RET kinase inhibitor as defined herein includes any compound that exhibits RET inhibitory activity. In some embodiments, the inhibitor

- 91 035568

RET kinase is selective for RET kinase. Typical RET kinase inhibitors may exhibit an inhibition activity (IC ₅₀ ) against RET kinase of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less less than about 25 nM, less than about 10 nM, or less than about 1 nM as defined in the assay described herein. In some embodiments, RET kinase inhibitors may exhibit an inhibition activity (IC ₅₀ ) against RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as defined in the analysis suggested in this document.

In the context of this document, the first RET kinase inhibitor or the first RET inhibitor is an RET kinase inhibitor as defined herein, but which does not contain a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. In the context of this document, the second RET kinase inhibitor or the second RET inhibitor is a RET kinase inhibitor as defined herein, but which does not contain a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. When both the first and second RET inhibitors are present in the method provided herein, the first and second RET kinase inhibitors are different.

In some embodiments, the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of at least one point mutation in the RET gene that results in the production of a RET kinase that has one or more amino acid substitutions, or insertions, or deletions in the RET gene that result in the production of RET kinase with the insertion or deletion of one or more amino acids as compared to wild type RET kinase. In some cases, the resulting RET kinase is more resistant to inhibition of its phosphotransferase activity by one or more of the first RET kinase inhibitors compared to wild type RET kinase or RET kinase not containing such a mutation. Such mutations, optionally, do not reduce the sensitivity of a cancer cell or tumor containing RET kinase to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., compared to a cancer cell or tumor that does not contain this particular RET inhibitor resistance mutation) ... In such embodiments, a mutation in resistance to RET inhibitors can result in an RET kinase that has one or more of an increased V _max , a decreased K _M for ATP, and an increased K for a first RET kinase inhibitor in the presence of a first RET kinase inhibitor. compared to wild type RET kinase or RET kinase not having the same mutation in the presence of the same first RET kinase inhibitor.

In other embodiments of the invention, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises at least one point mutation in the RET gene that results in the production of a RET kinase that has one or more amino acid substitutions as compared to wild type RET kinase and which has increased resistance to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as compared to wild type RET kinase or RET kinase not containing such a mutation. In such embodiments, a mutation in resistance to RET inhibitors can result in a RET kinase that is characterized by one or more of an increased V _max , a decreased K _m, and a decreased K d in the presence of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as compared to RET kinase wild type or RET kinase not containing such a mutation in the presence of the same compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

Examples of mutations in resistance to RET inhibitors may, for example, include point mutations, insertions or deletions at and near the ATP binding site in the tertiary structure of RET kinase, including, but not limited to, a gatekeeper residue, P-loop residues, residues in the DFG motif or near it and amino acid residues of the front of the solvent of the ATP pocket. Additional examples of these types of mutations include changes in residues that can affect enzyme activity and / or drug binding, including, but not limited to, residues in the activation loop, residues that are adjacent to or interact with the activation loop, residues that affect conformation active or inactive enzyme, changes, including mutations, deletions and insertions in the loop passing into the C-helix and through the C-helix. Specific residues or regions of residues that can be changed (and are mutations of resistance to RET inhibitors) include, but are not limited to, those listed in table. 3 based on the sequence of the wild-type human RET protein (e.g. SEQ ID NO: 1). Additional examples of positions of mutations of resistance to RET inhibitors are shown in table. 4. Changes in these residues can include changes in one or more amino acids, insertions within or flanking them, and deletions within or flanking them. Model Sequence of Mature Human RET Protein (SEQ ID NO: 1)

- 92 035568

MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKL YVDQAAGTPL LYVHALRDAP EEVPSFRLGQ HLYGTYRTRL HENNWICIQE DTGLLYLNRS LDHSSWEKLS VRNRGFPLLT VYLKVFLSPT SLREGECQWP GCARVYFSFF NTSFPACSSL KPRELCFPET RPSFRIRENR PPGTFHQFRL LPVQFLCPNI SVAYRLLEGE GLPFRCAPDS LEVSTRWALD REQREKYELV AVCTVHAGAR EEWMVPFPV TVYDEDDSAP TFPAGVDTAS IAWEFKRKED TWATLRVFD ADWPASGEL VRRYTSTLLP GDTWAQQTFR VEHWPNETSV QANGSFVRAT VHDYRLVLNR NLSISENRTM QLAVLVNDSD FQGPGAGVLL LHFNVSVLPV SLHLPSTYSL SVSRRARRFA QIGKVCVENC QAFSGINVQY KLHSSGANCS TLGWTSAED TSGILFVNDT KALRRPKCAE LHYMWATDQ QTSRQAQAQL LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CGGLGSPTGR CEWRQGDGKG ITRNFSTCSP STKTCPDGHC DWETQDINI CPQDCLRGSI VGGHEPGEPR GIKAGYGTCN CFPEEEKCFC EPEDIQDPLC DELCRTVIAA AVLFSFIVSV LLSAFCIHCY HKFAHKPPIS SAEMTFRRPA QAFPVSYSSS GARRPSLDSM ENQVSVDAFK ILEDPKWEFP RKNLVLGKTL GEGEFGKWK ATAFHLKGRA GYTTVAVKML KENASPSELR DLLSEFNVLK QVNHPHVIKL YGACSQDGPL LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDH PDERALTMGD LISFAWQISQ GMQYLAEMKL VHRDLAARNI LVAEGRKMKI SDFGLSRDVY EEDSYVKRSQ GRIPVK WMAI ESLFDHIYTT QSDVWSFGVL LWEIVTLGGN PYPGIPPERL FNLLKTGHRM ERPDNCSEEM YRLMLQCWKQ EPDKRPVFAD ISKDLEKMMV KRRDYLDLAA STPSDSLIYD DGLSEEETPL VDCNNAPLPR ALPSTWIENK LYGMSDPNWP GESPVPLTRA DGTNTGFPRY PNDSVYANWM LSPSAAKLMD TFDS

In some embodiments, the compounds of Formula I and pharmaceutically acceptable salts and solvates are useful in the treatment of patients who develop cancers with mutations in resistance to RET inhibitors (e.g., which lead to increased resistance to the first RET inhibitor, e.g., a substitution at the amino acid position 804, eg V804M, V804L, or V804E, and / or one or more of the RET inhibitor resistance mutations listed in Tables 3 and 4), when dosed in combination or as adjunctive therapy to existing drugs (eg other inhibitors RET kinase, for example, the first and / or second RET kinase inhibitors). Examples of the first and second RET kinase inhibitors are described herein. In some embodiments, the first or second RET kinase inhibitors can be selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

In some embodiments, the compounds of Formula I, or pharmaceutically acceptable salts and solvates thereof, are useful in the treatment of cancer that is defined to contain one or more RET inhibitor resistance mutations (which result in increased resistance to a first or second RET inhibitor, such as a substitution at the amino acid position 804, such as V804M, V804L or V804E). Non-limiting examples of mutations in resistance to RET inhibitors are shown in table. 3 and 4.

Table 3

RET inhibitor resistance mutations

Typical RET resistance mutations_____________________________________

Amino acid position 732 (for example, E732K) ⁷ __________________________________

Amino acid position 788 (e.g. I788N) ⁸ __________________________________

Amino acid position 804 (for example, V804M ^{* 1 2} , U804E ¹² , V804E ^{6 7 8} ) ________________

Amino acid position 804/805 (e.g. V804M / E805K) ³ _______________________

Amino acid position 806 (eg Y806C ^{4 6} , Y806E ⁴ , Y806S ⁶ , Y806H ⁶ , Y806N ⁶ ) Amino acid position 810 (eg G810A ⁵ , G810R ⁶ , G810S ⁶ ) ___________________

Amino acid position 865 (e.g. L865V ⁶ )

Amino acid position 870 (eg L870F ⁶ ) ¹ Yoon et al., J. Med. Chem. 59 (1): 358-73, 2016.

² US Patent No. 8629135.

³ Cranston, et al. Cancer Res. 66 (20): 10179-87, 2006.

⁴ Carlomagno, et al., Endocr. Rel. Cancer 16 (1): 233-41, 2009.

⁵ Huang et al. Mol. Cancer Ther., 2016 Aug 5.pii: molcanther. 0258.2016. [Electronic publication prepress].

⁶ Publication of PCT Patent Application No. WO 2016/127074.

⁷ Nadezda et al., Summer Undergraduate Research Programs (SURP) Student Abstracts, University of Oklahoma Health Sciences Center, 2016.

⁸ Plenker et al. Sci. Transl. Med., 9 (394), doi: 10.1126 / scitranslmed.aah6144, 2017.

- 93 035568

Table 4

Additional Typical Amino Acid Positions of RET Inhibitor Resistance Mutations

Amino Acid and RET Position Typical mutation Mechanistic rationale for resistance L730 R Steric hindrance and / or active conformational effect G731 V Steric hindrance and / or active conformational effect E732 TO Steric hindrance and / or active conformational effect G733 V Steric hindrance and / or active conformational effect E734 to Steric hindrance and / or active conformational effect L760 m Active conformational effect K761 E Active conformational effect E762 TO Active conformational effect N763 D Active conformational effect

- 94 035568

A764 V Active conformational effect S765 N Active conformational effect P766 A Active conformational effect S767 C Active conformational effect E768 TO Active conformational effect L779 M Steric hindrance and / or active conformational effect 1788 M Steric hindrance and / or active conformational effect M868 R Steric hindrance and / or active conformational effect K869 E Steric hindrance and / or active conformational effect L870 Q Steric hindrance and / or active conformational effect V871 M Steric hindrance and / or active conformational effect H872 R Steric hindrance and / or active conformational effect R873 P Steric hindrance and / or active conformational effect D874 Y Steric hindrance and / or active conformational effect L881 R Steric hindrance and / or active conformational effect L895 M Active conformational effect S896 N Active conformational effect R897 C Active conformational effect D898 Y Active conformational effect V899 G Active conformational effect Y900 D Active conformational effect E901 TO Active conformational effect E902 TO Active conformational effect D903 Y Active conformational effect S904 FROM Active conformational effect Y905 D Active conformational effect V906 Μ Active conformational effect K907 Ε Active conformational effect R908 Ρ Active conformational effect S909 C Active conformational effect Q910 R Active conformational effect G911 C Active conformational effect R912 Ρ Active conformational effect

The oncogenic role of RET was first described in papillary thyroid carcinoma (PCT) (Grieco et al., Cell, 1990, 60, 557-63), which arises from thyroid follicular cells and is the most common malignant neoplasm of the thyroid gland. Approximately 20-30% of PCTs contain somatic chromosomal rearrangements (translocations or inversions) linking the promoter and 5'-regions of constitutively expressed, unrelated genes to the RET tyrosine kinase domain (Greco et al., QJ Nucl. Med. Mol. Imaging, 2009, 53, 440-54), sti

- 95 035568 thus mutating its ectopic expression in thyroid cells. Fusion proteins resulting from such rearrangements are called RET / PTC proteins (PTC - from the English papillary thyroid carcinoma). For example, RET / PTC 1 is a fusion product between CCDD6 and RET that is commonly found in papillary thyroid carcinomas. Likewise, RET / PTC3 and RET / PTC4 are fusion products of ELE1 and RET that are commonly found in papillary thyroid carcinomas, although the fusion processes resulting in RET / PTC3 and RET / PTC4 result in different proteins with different molecular weights. (see, for example, Fugazzola et al., Oncogene, 13 (5): 1093-7, 1996). Some RET fusion products associated with PCT are not called RET / PTC, but are instead simply referred to as a fusion protein. For example, fusion products between RET and ELKS and PCM1 can be found in the PCT, but these fusion proteins are called ELKS-RET and PCM1-RET (see, for example, Romei and Elisei, Front. Endocrinol. (Lausanne), 3:54, doi : 10.3389 / fendo.2012.00054, 2012). The role of RET-PTC rearrangements in the pathogenesis of PCT has been confirmed in transgenic mice (Santoro et al., Oncogene, 1996, 12, 1821-6). To date, many fusion partners have been identified for PCT and other cancers, all of which have a protein / protein interaction domain that induces ligand-independent RET dimerization and kinase activity (see, eg, Table 1). Recently, about 2% of patients with lung adenocarcinoma had a 10.6 Mb pericentric inversion on chromosome 10, where the RET gene is mapped, generating various variants of the chimeric KIF5B-RET gene (Ju et al., Genome Res., 2012, 22, 436- 45; Kohno et al., 2012, Nature Med, 18, 375-7; Takeuchi et al., Nature Med, 2012, 18, 378-81; Lipson et al., 2012, Nature Med., 18, 382-4 ). The fusion transcripts are highly expressed, and the resulting chimeric proteins contain the N-terminal portion of the KIF5B supercoil region, which mediates homodimerization, and the entire RET kinase domain. None of the RET-positive patients have other known oncogenic changes (such as EGFR or K-Ras mutations, ALK translocation), suggesting the possibility that the KIF5B-RET fusion may be a driver mutation in lung adenocarcinoma. The oncogenic potential of KIF5B-RET was confirmed by transfection of the fusion gene into cultured cell lines: similar to that observed with RET-PTC fusion proteins, KIF5B-RET is constitutively phosphorylated and induces the transformation of NIH-3T3 and IL-3-independent growth of BA- cells F3. However, other RET fusion proteins have been identified in patients with lung adenocarcinoma, such as the CCDC6-RET fusion protein, which has been shown to play a key role in the proliferation of the human lung adenocarcinoma LC-2 / ad cell line (Journal of Thoracic Oncology, 2012, 7 (12): 1872-1876). RET inhibitors have been shown to be useful in the treatment of lung cancer containing RET rearrangements (Drilon, A.E. et al. J Clin Oncol 33, 2015 (suppl; abstr 8007)). Fusion RET proteins have also been identified in patients with colorectal cancer (Song Eun-Kee, et al. International Journal of Cancer, 2015, 136: 1967-1975).

In addition to rearrangements of the RET sequence, point mutations with the acquisition of the function of the RET proto-oncogene also stimulate oncogenic events, as shown in the case of medullary thyroid carcinoma (MTC), which develops from cells that produce parafollicular calcitonin (de Groot, et al., Endocrine Rev., 2006 , 27, 535-60; Wells and Santoro, Clin. Cancer Res., 2009, 15, 7119-7122).

About 25% of thyroid gland cases are associated with multiple endocrine neoplasia type 2 (MEN2 or MEN2), a group of inherited cancer syndromes affecting neuroendocrine organs caused by germline activating RET point mutations. In the MEN2 subtypes (MEN2A, MEN2B and familial MTC / MIT), mutations of the RET gene demonstrate a strong phenotype-genotype correlation, which determines the different aggressiveness of the MTC and the clinical manifestations of the disease. In MEN2A syndrome, mutations involve one of six cysteine residues (mainly C634) located in the cysteine-rich extracellular region, resulting in ligand-independent homodimerization and constitutive activation of RET. The thyroid gland develops in patients at a young age (beginning at 5-25 years), and pheochromocytoma (50%) and hyperparathyroidism can also develop. MEN2B is mainly caused by the M918T mutation, which is located in the kinase domain. This mutation constitutively activates RET in the monomeric state and alters the recognition of the substrate by the kinase. MEN2B syndrome is characterized by early onset (<1 year) and very aggressive MTC, pheochromocytoma (50% of patients), and ganglioneuromas. In the case of thyroid gland, the only manifestation of the disease is thyroid gland, which usually occurs in adulthood. Many different mutations have been found covering the entire RET gene. The remaining 75% of MTC cases are sporadic, and about 50% of them are characterized by somatic RET mutations: the most common mutation is M918T, which, as in the case of MEN2B, is associated with the most aggressive phenotype. RET somatic point mutations have also been described for other tumors such as colorectal cancer (Wood et al., Science, 2007, 318, 110813) and small cell lung cancer (Jpn. J. Cancer Res., 1995, 86, 1127-30) ... RET signaling components have been found to be expressed in primary breast tumors and functionally interact with the estrogen receptor-cc pathway in breast tumor cell lines (Boulay et al., Cancer Res. 2008, 68, 3743-51; Plaza-Menacho et al. ., Oncogene, 2010, 29, 4648-57), while expression and activation of RET by ligands of the GDNF family may play an important role in perineural invasion

- 96,035,568 different types of cancer cells (Ito et al., Surgery, 2005, 138, 788-94; Gil et al., J. Natl. Cancer Inst, 2010, 102, 107-18; Iwahashi et al., Cancer , 2002, 94, 167-74).

RET is also expressed in 30-70% of invasive breast cancers, with expression relatively more common in estrogen receptor positive tumors (PlazaMenacho, I, et al., Oncogene, 2010, 29, 4648-4657; Esseghir, S. , et al., Cancer Res., 2007, 67, 11732-11741; Morandi, A., et al., Cancer Res., 2013, 73, 3783-3795; Gattelli, A., EMBO Mol. Med, 2013, 5, 1335-1350). The identification of RET rearrangements has been reported in the PDX subgroup (patient-derived xenografts) developed in colorectal cancer. Although the frequency of such events in patients with colorectal cancer remains to be determined, these data suggest a role for RET as a target in this indication (Gozgit et al., AACR Annual Meeting 2014). Studies have shown that the RET promoter is frequently methylated in colorectal cancer, and heterozygous missense mutations, which are predicted to reduce RET expression, occur in 5-10% of cases, suggesting that RET may have some features of a tumor suppressor in sporadic cancers. colon (Luo, Y., et al., Oncogene, 2013, 32, 2037-2047; Sjoblom, T., et al., Science, 2006, 268-274; Cancer Genome Atlas Network, Nature, 2012, 487, 330-337).

Data are now emerging for an increasing number of tumor types that they express significant levels of wild-type RET kinase, which may affect tumor progression and spread. RET is expressed in 50-65% of pancreatic duct carcinomas, and expression is more common in metastatic tumors and more poorly differentiated tumors (Ito, Y, et al., Surgery, 2005, 138, 788-794; Zeng, Q., et al ., J. Int. Med. Res. 2008, 36, 656-664). In neoplasms of hematopoietic lines of differentiation, RET is expressed in acute myeloid leukemia (AML) with monocytic differentiation, as well as in CML (Gattei, V. et al., Blood, 1997, 89, 2925-2937; Gattei, V., et al., Ann Hematol 1998, 77, 207-210; Camos, M., Cancer Res. 2006, 66, 6947-6954). Recent studies have identified rare chromosomal rearrangements in which RET is involved in patients with chronic myelomonocytic leukemia (CML). CML is often associated with rearrangements of several tyrosine kinases that result in the expression of chimeric cytosolic oncoproteins that lead to activation of RAS pathways (Kohlmann, A., et al., J. Clin. Oncol. 2010, 28, 28582865). In the case of RET, gene fusions that bind RET to BCR (BCR-RET) or to an oncogenic partner, fibroblast growth factor receptor 1 (FGFR1OP-RET), were transformed in early hematopoietic progenitor cells and could shift the maturation of these cells towards monocytic pathways, probably through the initiation of RET-mediated RAS signaling (Ballerini, P., et al., Leukemia, 2012, 26, 2384-2389).

RET expression has also been shown to occur in several other tumor types, including prostate cancer, small cell lung cancer, melanoma, renal cell carcinoma, and head and neck tumors (Narita, N., et al., Oncogene, 2009, 28, 3058-3068; Mulligan, LM, et al., Genes Chromosomes Cancer, 1998, 21, 326-332; Flavin, R., et al., Urol. Oncol, 2012, 30, 900-905; Dawson, DM, J Natl Cancer Inst, 1998, 90, 519-523). In neuroblastoma, the expression and activation of RET by GFL play a role in the differentiation of tumor cells, potentially interacting with other receptors of the neurotrophic factor, decreasing the regulation of N-Myc, the expression of which is a marker of a poor prognosis (Hofstra, RM, W., et al., Hum. Genet. 1996, 97, 362-364; Petersen, S. and Bogenmann, E., Oncogene, 2004, 23, 213-225; Brodeur, GM, Nature Ref. Cancer, 2003, 3, 203-216).

Multipurpose inhibitors are known that cross-react with RET (Borrello, MG, et al., Expert Opin. Ther. Targets, 2013, 17 (4), 403-419; International Patent Applications Nos. WO 2014/141187, WO 2014/184069 and WO 2015/079251). Accordingly, provided herein are methods of treating a patient diagnosed with (or determined to have) cancer, which comprise administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. Also provided herein are methods of treating a patient who is identified or diagnosed as having RET-associated cancer, which comprises administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, a patient who has been identified or diagnosed as having RET-associated cancer by an approved regulatory body, for example, an FDA-approved test or assay to detect dysregulation of the RET gene, RET kinase, or their expression, or their activity, or level any of them in a patient's body or a biopsy sample from a patient, or by performing any of the non-limiting examples of the analyzes described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer can be a cancer that contains one or more RET inhibitor resistance mutations.

Also provided are methods of treating cancer in a patient in need thereof, comprising (a) determining whether the patient's cancer is RET-associated cancer; and (b) if the cancer is defined as a RET-associated cancer, administering to the patient a therapeutically effective amount of a compound of the form

- 97,035,568 ly I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, the subject has previously received treatment with a first RET inhibitor or has previously received other anti-cancer therapy, such as tumor resection or radiation therapy. In some embodiments of the invention, the presence of RET-associated cancer in a patient is determined using an approved regulatory body, for example, an FDA-approved test or assay to detect dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in the body a patient or in a biopsy sample from a patient, or by performing any of the non-limiting examples of analyzes described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer can be a cancer that contains one or more RET inhibitor resistance mutations.

Also provided are methods of treating a patient, which include analyzing a sample obtained from a patient to determine if the patient is characterized by dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them, and administering (e.g., specific or selective administration ) a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, to a patient who has been found to be dysregulated in the RET gene, RET kinase or their expression, or their activity, or the level of any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments of these methods, the subject has previously received treatment with a first RET inhibitor or has previously received other anti-cancer therapy, such as tumor resection or radiation therapy. In some embodiments, the patient is a patient with suspected RET-associated cancer, a patient with one or more symptoms of RET-associated cancer, or a patient at increased risk of developing an RET-associated cancer. In some embodiments, the assay employs next generation sequencing, pyrosequencing, immunohistochemistry, or FISH separation. In some embodiments, the assay is a regulatory approved assay, such as an FDA approved kit. Additional non-limiting analysis methods that can be used in these methods are described in this document. Additional analysis methods are also known in the art. In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more mutations in resistance to RET inhibitors.

Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of RET-associated cancer in a patient who has been identified or diagnosed as having RET-associated cancer by analysis (e.g., in vitro analysis) a sample obtained from a patient to determine whether the patient is characterized by dysregulation of the RET gene, RET kinase, or their expression, or their activity, or the level of any of them, while the presence of dysregulation of the RET gene, RET kinase, or their expression, or their activity, or the level of any of them, indicates that the patient has RET-associated cancer. Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of RET-associated cancer in a patient who has been identified or diagnosed as having RET-associated cancer by analyzing a sample obtained from the patient, to determine whether the patient is characterized by dysregulation of the RET gene, RET kinase, or their expression, or their activity, or the level of any of them, while the presence of dysregulation of the RET gene, RET kinase, or their expression, or their activity, or the level of any of these indicates that the patient has RET-associated cancer. Some embodiments of any of the methods or uses described herein further include recording the patient's medical history (e.g., on a computer-readable medium) that the patient has been determined to have dysregulation of the RET gene, RET kinase, or their expression, or their activity, or level of any of these, by analysis, and that he should administer a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the assay employs next generation sequencing, pyrosequencing, immunohistochemistry, or FISH separation. In some embodiments, the assay is a regulatory approved assay, such as an FDA approved kit. In some embodiments, the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more RET inhibitor resistance mutations.

Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof

- 98 035568 for use in the treatment of cancer in a patient in need thereof or in a patient who has been identified or diagnosed as having RET-associated cancer. Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of cancer in a patient who has been identified or diagnosed as having RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer, for example, a RET-associated cancer, having one or more RET inhibitor resistance mutations. In some embodiments, a patient is identified or diagnosed as having a RET-associated cancer using an approved regulatory body, such as an FDA-approved kit for determining RET gene dysregulation, RET kinase or their expression, or their activity, or the level of any of them in the patient's body or a biopsy sample from the patient. According to this document, RET-associated cancer includes cancers described herein and known in the art. In some embodiments of any of the methods or uses described herein, the patient has been identified or diagnosed as having cancer with dysregulated RET gene, RET kinase, or their expression, or activity, or level of any of them. In some embodiments of any of the methods or uses described herein, the patient has a tumor that is positive for dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them. In some embodiments of any of the methods or uses described herein, the patient can be a patient with tumor (s) positive for dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them ... In some embodiments of any of the methods or uses described herein, the patient may be a patient having tumors with dysregulated RET gene, RET kinase, or expression, or activity, or level of any of them. In some embodiments of any of the methods or uses described herein, the patient is suspected of having a RET-associated cancer (eg, cancer having one or more RET inhibitor resistance mutations). In some embodiments, provided herein are methods of treating RET-associated cancer in a patient in need of such treatment, comprising a) determining the presence of dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in the sample from the patient; and b) administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more fusion proteins. Non-limiting examples of RET gene fusion proteins are described in table. 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more point mutations / insertions / deletions in the RET kinase protein. Non-limiting examples of point mutations / insertions / deletions in the RET kinase protein are described in table. 2. In some embodiments, point mutations / insertions / deletions in the RET kinase protein are selected from the group consisting of M918T, M918V, C634W, V804L, and V804M. In some embodiments, the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more RET inhibitor resistance mutations. Non-limiting examples of mutations in resistance to RET inhibitors are described in table. 3 and 4. In some embodiments, the RET inhibitor resistance mutation is V804M. In some embodiments, the presence of cancer with dysregulated RET gene, RET kinase or their expression or activity, or the level of any of them, is determined using an approved regulatory body, for example, an FDA-approved assay or kit. In some embodiments, a tumor that is positive for dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them, is a tumor that is positive for one or more RET inhibitor resistance mutations. In some embodiments, the presence of a tumor dysregulated in the RET gene, RET kinase or their expression or activity, or the level of any of them, is determined using an approved regulatory body, for example, an FDA-approved assay or kit. In some embodiments of any of the methods or uses described herein, the patient has a history record indicating that the patient has a tumor with dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them (for example, a tumor having one or more RET inhibitor resistance mutations). In some embodiments, a history record indicates that the patient should be treated with one or more compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof, or compositions provided herein. In some embodiments, the cancer with dysregulated RET gene, RET kinase or their expression or activity, or the level of any of them, is a cancer having one or more RET inhibitor resistance mutations. In some embodiments of the invention, the presence of cancer with dysregulated RET gene, RET kinase or their expression, or their activity, or the level of any of them is

- 99 035568 redistributed using an approved regulatory body such as an FDA approved assay or kit. In some embodiments, a tumor that is positive for dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them, is a tumor that is positive for one or more RET inhibitor resistance mutations. In some embodiments, the presence of a tumor dysregulated in the RET gene, RET kinase or their expression or activity, or the level of any of them, is determined using an approved regulatory body, for example, an FDA-approved assay or kit. Also provided are methods of treating a patient that include administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a patient who has a medical history that indicates that the patient has dysregulation of the RET, RET kinase, or expression thereof , or their activity, or the level of any of them. Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of RET-associated cancer in a patient having a medical history record that indicates that the patient has a dysregulation of the RET, RET kinase gene, or their expression, or their activity, or the level of any of them. Some embodiments of these methods and uses may further include: the step of analyzing a sample from the patient to determine if the patient has dysregulation of the RET, RET kinase gene or their expression, or their activity, or level of any of them, and recording the information in the clinical a patient file (for example, on a machine-readable medium) that the patient has been found to have dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them. In some embodiments, the assay is an in vitro assay. For example, this is an assay that uses next generation sequencing, immunohistochemistry, or FISH separation. In some embodiments, the assay is approved by a regulatory authority, such as an FDA-approved kit. In some embodiments, the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more RET inhibitor resistance mutations.

Also provided herein is a method for treating a subject. The method includes analyzing a sample obtained from a subject to determine if the subject has a dysregulation of a RET gene, a RET protein or their expression, or a level of any of them. The method also includes administering to a subject identified as having dysregulation of the RET gene, RET protein or expression or activity thereof, or the level of any of them, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the dysregulation in the RET gene, RET kinase protein, or expression thereof, or their activity is a gene or chromosomal translocation that results in the expression of a RET fusion protein (e.g., any of the RET fusion proteins described herein). In some embodiments, the RET fusion product may be selected from a KIF5B-RET fusion and a CCDC6RET fusion. In some embodiments, the dysregulation in the RET gene, RET kinase protein or their expression, or their activity, or the level of any of them is one or more point mutations in the RET gene (for example, any of one or more point mutations described herein RET mutations). One or more point mutations in the RET gene can result, for example, in translation of a RET protein having one or more of the following amino acid substitutions: M918T, M918V, C634W, V804L, and V804M. In some embodiments of the invention, the dysregulation in the RET gene, RET kinase protein or their expression, or their activity, or the level of any of them is one or more mutations of resistance to RET inhibitors (for example, any combination of one or more described in this document mutations of resistance to RET inhibitors). Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (eg, a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or the use of immunotherapy). In some embodiments, compounds provided herein exhibit penetration into the brain and / or central nervous system (CNS). Such compounds are able to cross the blood-brain barrier and inhibit RET kinase in the brain and / or other structures of the central nervous system. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in a therapeutically effective amount. For example, treating a patient with cancer (eg, RET-associated cancer, such as RET-associated brain or CNS cancer) may include administering (eg, oral administration) of the compound to the patient. In some such embodiments, the compounds provided herein are useful in the treatment of primary brain tumor or brain metastases. For example, these compounds can be used in the treatment of one or more of gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemma) craniopharyngiomas (see, for example, , tumors listed in Louis, DN et al. Acta Neuropathol 131 (6), 803-820 (June 2016)). In some such embodiments, the brain tumor is

- 100 035568 is a primary brain tumor. In some such embodiments, the patient has previously been treated with a different anticancer agent, for example, another RET inhibitor (eg, a compound that is not a compound of general formula I) or a multikinase inhibitor. In some such embodiments, the brain tumor is a metastatic brain tumor. In some such embodiments, the patient has previously been treated with a different anticancer agent, for example, another RET inhibitor (eg, a compound that is not a compound of general formula I) or a multikinase inhibitor.

Also provided are methods (eg, in vitro methods) of selecting a treatment option for a patient who has been identified or diagnosed as having RET-associated cancer. Some embodiments of the invention may further include administering the selected treatment option to a patient who has been identified or diagnosed as having RET-associated cancer. For example, a selected treatment option may include administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. Some embodiments of the invention may further include the step of analyzing a sample from a patient to determine if the patient has a dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them, and determining and diagnosing the patient with the presence of dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them as having RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer having one or more RET inhibitor resistance mutations. In some embodiments, a patient has been identified or diagnosed as having a RET-associated cancer using an approved regulatory body, such as an FDA-approved kit for determining the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in the body patient or biopsy sample from a patient. In some embodiments, the RET-associated cancer is as described herein or known in the art. In some embodiments, the assay is an in vitro assay. For example, this is an assay that uses next-generation sequencing, immunohistochemistry, or FISH separation. In some embodiments, the assay is approved by a regulatory authority, such as an FDA-approved kit.

Also provided herein are methods for selecting a treatment option for a patient, the methods comprising the step of analyzing a sample from the patient to determine if the patient has dysregulation of the RET gene, RET kinase or their expression, or their activity, or any level of any of these (eg, one or more resistance mutations to RET inhibitors), and identifying and diagnosing a patient with dysregulation of the RET gene, RET kinase or their expression, or their activity, or level of any of them as having RET-associated cancer. Some embodiments of the invention further comprise administering the selected treatment option to a patient who has been identified or diagnosed as having RET-associated cancer. For example, a selected treatment option may include administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a patient who has been identified or diagnosed with RET-associated cancer. In some embodiments, the assay is an in vitro assay. For example, this is an assay that uses next-generation sequencing, immunohistochemistry, or FISH separation. In some embodiments, the assay is approved by a regulatory authority, such as an FDA-approved kit.

Also provided are methods for selecting a patient for treatment, comprising selecting, identifying or diagnosing a patient with RET-associated cancer and selecting a patient for treatment comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, determining or diagnosing a patient as having a RET-associated cancer may include the step of analyzing a sample from the patient to determine if the patient has dysregulation of the RET gene, RET kinase, or their expression, or their activity, or level. any of them, and identifying and diagnosing a patient with dysregulation of the RET gene, RET kinase or their expression, or their activity, or level of any of them as having RET-associated cancer. In some embodiments, the method for selecting a treatment option can be used as part of a clinical trial that includes administering various treatment options for RET-associated cancer. In some embodiments, the RET-associated cancer is a cancer having one or more RET inhibitor resistance mutations. In some embodiments, the assay is an in vitro assay. For example, this is an assay that uses next-generation sequencing, immunohistochemistry, or FISH separation. In some embodiments, the assay is approved by a regulatory authority, such as an FDA-approved kit. In some embodiments of the invention, dysregulation of the RET gene, RET kinase, or their ex

- 101 035568 pressure, or their activity, or the level of any of them, includes the presence of one or more mutations of resistance to RET inhibitors.

In some embodiments of any of the methods or uses described herein, an assay used to determine if a patient has an RET gene or RET kinase dysregulation or expression or activity or level of any of them, using a sample from the patient, can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, FISH separation, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR amplification (e.g. RT-PCR and quantitative RT-PCR in real time) ... As is well known in the art, the assay is typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can use other detection methods known in the art to detect dysregulation of the RET gene, RET kinase or their expression, or their activity, or levels of any of them (see, for example, references cited herein). In some embodiments, the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them comprises the presence of one or more RET inhibitor resistance mutations. In some embodiments, the sample is a biological sample or a biopsy sample (eg, a paraffin-embedded biopsy sample) from a patient. In some embodiments, the patient is a patient with suspected RET-associated cancer, a patient with one or more symptoms of an RET-associated cancer, and / or a patient at an increased risk of developing an RET-associated cancer.

In the field of medical oncology, it is common practice to use a combination of different forms of treatment to treat each cancer patient. In medical oncology, other components of such co-treatment or therapy in addition to the compositions provided herein may be, for example, surgery, radiation therapy, and the use of chemotherapeutic agents such as kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. Therefore, the compounds of formula I can also be used as adjuvants for the treatment of cancer, i.e. they can be used in combination with one or more additional therapy options or therapeutic agents, for example, a chemotherapeutic agent that has the same or different mechanism of action. In some embodiments of any of the methods described herein, a compound of Formula I (or a pharmaceutically acceptable salt or solvate thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapeutic or therapeutic options (e.g., chemotherapy) agents. Non-limiting examples of additional therapeutic agents include other therapeutic agents targeting RET (i.e., a first or second RET kinase inhibitor), therapeutic agents targeting a receptor tyrosine kinase, signaling pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g. obataclax ); cytotoxic chemotherapeutic agents targeting angiogenesis therapy options, immune agents including immunotherapy, and radiation therapy.

In some embodiments, another RET targeting drug is a multikinase inhibitor exhibiting RET inhibitory activity. In some embodiments, another RET targeting therapeutic inhibitor is selective for RET kinase. Typical RET kinase inhibitors may exhibit an inhibition activity (IC ₅₀ ) against RET kinase of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less less than about 25 nM, less than about 10 nM, or less than about 1 nM as defined in the assay described herein. In some embodiments, RET kinase inhibitors may exhibit an inhibition activity (IC ₅₀ ) against RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as defined in the this analysis document.

Non-limiting examples of RET-targeted therapeutic agents include alectinib, apatinib, cabozantinib (XL-184), dovitinib, lenvatinib, motesanib, nintedanib, ponatinib, regoraphenib, citravatinib (MGCD516), sunitinib, soravatinib, vatandinib (2,4 dihydroxy-5-isopropylphenyl) -N-ethyl-4- [4- (morpholinomethyl) phenyl] isoxazole-3-carboxamide), BLU6864, BLU-667, DCC-2157, GSK3179106, NVP-AST487 (1- [ 4 - [(4-ethylpiperazin-1-yl) methyl] -3 (trifluoromethyl) phenyl] -3- [4- [6- (methylamino) pyrimidin-4-yl] oxyphenyl] urea), PZ-1, RPI- 1 (1,3dihydro-5,6-dimethoxy-3 - [(4-hydroxyphenyl) methylene] -Н-indol-2-one), RXDX-105 (1- (3 - ((6,7dimethoxyquinazolin-4-yl ) oxy) phenyl) -3- (5- (1,1,1-trifluoro-2-methylpropan-2-yl) isoxazol-3yl) urea), SPP86 (1-isopropyl-3- (phenylethynyl) -S-pyrazolo [3,4D] pyrimidin-4-amine) and TG101209 (No. (1,1-dimethylethyl) -3 - [[5-methyl-2 - [[4- (4-methyl-1-piperazinyl) phenyl] amino] -4pyrimidinyl] amino] benzenesulfonamide).

Additional examples of other RET kinase inhibitors include those described in US patents

- 102 035568 No. 9150517 and 9149464 and international publication WO No. 2014075035, all of which are incorporated herein by reference. For example, in some embodiments, another RET inhibitor is a compound of Formula I

where R1 represents a C ₆ -C ₂₄ -alkyl or polyethylene glycol; or a pharmaceutically acceptable salt form thereof. In some embodiments, the other RET inhibitor is 4- {5- [bis (chloroethyl) amino] -1-methyl-N-benzimidazol-2-yl} butyric acid dodecyl ester.

Additional examples of other RET kinase inhibitors include those described in International Publication No. WO 2016127074, which is incorporated herein by reference. For example, in some embodiments, the other RET inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein (R ^B ) _n * Ν ')] ^(I) wherein rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

each L ¹ and L ^{2 are} independently selected from a bond, - (C1-C6 alkylene) -, - (C2-C6 alkenylene) -, - (C2-C6 alkynylene) -, - (C1-C6 haloalkylene) -, - (C1-C6-heteroalkylene) -, -C (O) -, -O-, -S-, -S (O), -S (O) 2-, -N (R ¹ ) -, -O- ( C1-C ₆ -alkylene) -, - (C ₁ -C ₆ -alkylene) -O-, -N (R1) -C (O) -, -C (O) N (R ¹ ) -, - (C1 -C6-alkylene) -N (R ¹ ) -, -N (R ¹ ) - (C1-C6-alkylene) -, -N (R ¹ ) -C (O) - (C1-C6-alkylene) -, - ( C1-C6 alkylene) -N (R ¹ ) -C (O) -, -C (O) -N (R ¹ ) - (C1-C6-alkylene) -, - (C1-C6-alkylene) -C (O) -N (R ¹ ) -, -N (R ¹ ) -S (O) 2-, -S (O) 2-N (R ¹ ) -, -N (R ¹ ) -S (O) 2- (C1-C6-alkylene) -, uS (O) 2-N (R ¹⁾ (C1-C ₆ alkylene) -; where each alkylene, alkenylene, alkynylene, haloalkylene and heteroalkylene are independently substituted with 0-5 R ¹ ;

each R ^a and R ^{B is} independently selected from ^ - ^ - alkyl, ^ - ^ - alkoxy, halogen, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -hydroxyalkyl, C ₁ -C ₆ -heteroalkyl and -N ( R ¹ ) (R ¹ ); where each alkyl, alkoxy, haloalkyl, hydroxyalkyl and hydroxyalkyl are independently substituted with 0-5 Ra;

each R ^C and R ^{d is} independently selected from ^ - ^ - alkyl, ^ - ^ - alkenyl, ^ - ^ - alkynyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ -heteroalkyl, C ₁ -C ₆ - haloalkyl, ^ - ^ - haloalkoxy, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, -C (O) R ¹ , -OC (O) R ¹ , - C (O) OR ¹ , - (C1-C6-alkylene) -C (O) R ¹ , -SR ¹ , -S (O) 2R ¹ , -S (O) 2-N (R ¹ ) (R ¹ ), - (C1-C6-alkylene) -S (O) 2 (R ¹ ), - (C1-C6-alkylene) -S (O) 2 -N (R ¹ ) (R ¹ ), -N (R ¹ ) (R ¹ ) -C (O) -N (R ¹ ) (R ¹ ) -N (R ¹ ) -C (O) R ¹ , -N (R ¹ ) -C (O) OR ¹ , - (C ₁ -C ₆ alkylene) -N (R ¹ ) -C (O) R ¹ , -N (R ¹ ) S (O) 2R ¹ and -P (O) (R ¹ ) (R ¹ ); where each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl and heterocyclylalkyl is independently substituted with 05 R ^a ; or 2 R ^C or 2 R ^D together with the carbon atom (s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 R ^a ;

each R ^{1 is} independently selected from hydrogen, hydroxyl, halogen, thiol, C ₁ -C ₆ -alkyl, C ₁ -C ₆ thioalkyl, ^ - ^ - alkoxy, C ₁ -C ₆ -halogenoalkyl, ^ - ^ - hydroxyalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, thioalkyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl is independently substituted with 0-5 R ^b, or 2 R ¹ together with the carbon atom (s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 R ^b ;

each R ^a and R ^{b is} independently C ₁ -C ₆ -alkyl, halogen, hydroxyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ -heteroalkyl, C ₁ -C ₆ -hydroxyalkyl, ^ - ^ - alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and heterocyclyl is independently substituted with 0-5 R ';

each R 'is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, halogen, hydroxyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl or cyano; or 2 R 'together with the atom (s) to which they are attached form a cycloalkyl or heterocyclyl ring;

m is 0, 1, 2 or 3;

n is 0, 1 or 2; and p and q are each independently 0, 1, 2, 3, or 4.

- 103 035568

For example, a RET inhibitor can be selected from the group consisting of:

- 104 035568

- 105 035568

or a pharmaceutically acceptable salt thereof.

In some embodiments, the RET inhibitor is selected from the group consisting of: ABT-348 (K- [4- [4-amino-7- [1- (2-hydroxyethyl) -III-pyrazol-4-yl] thieno [3, 2-c] pyridin-3-yl] phenyl] -No- (3fluorophenyl) urea); AD-57 which has the structure

- 106 035568

AD-80 (1- (4- (4-amino-1-isopropyl-III-pyrazolo [3,4 ^] pyrimidin-3-yl) phenyl) -3- (2-fluoro-5 (trifluoromethyl) phenyl) urea ); ALW-II-41-27 (\ - (5 - ((4 - ((4-ethylpiperazin-1-yl) methyl) -3 (trifluoromethyl) phenyl) carbamoyl) -2-methylphenyl) -5- (thiophen-2 -yl) nicotinamide); Amuvatinib (MP470) (No. (benzo ^] [1,3] dioxol-5-ylmethyl) -4- (benzofuro [3.2 ^] pyrimidin-4-yl) piperazine-1-carbothioamide); BPR1J373 (5-phenylthiazol-2-ylamine pyriminide derivative); CLM3; doramapimoda (BIRB-796) (1- (3 (tert-butyl) -1 - (p-tolyl) -Sh-pyrazol-5-yl) -3- (4- (2-morpholinoethoxy) naphthalene-1-yl) urea); DS5010; famitinib (5- [2- (diethylamino) ethyl] -2 - [(Z) - (5-fluoro-2-oxo-1 H-indol-3-ylidene) methyl] -3-methyl6,7-dihydro-1H -pyrrolo [3,2-c] pyridin-4-one); fedratinib (SAR 302503, TG101348) (X- (tert-butyl) -3 ((5-methyl-2 - ((4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl ) amino) benzenesulfonamide); GSK3179106; GSK3352589; HG-6-63-01 ((E) -3- (2- (4-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) vinyl) ^ - (4 ((4-ethylpiperazine- 1-yl) methyl) -3- (trifluoromethyl) phenyl) -4-methylbenzamide); NVP-BBT594 (5 - ((6acetamidopyrimidin-4-yl) oxy) -X- (4 - ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) indoline-1-carboxamide); PP2 (4-amino-5- (4-chlorophenyl) -7- (dimethylethyl) pyrazolo [3.4 ^] pyrimidine); PP242 (2- (4-amino-1-isopropyl-1H-pyrazolo [3,4 ^] pyrimidin-3-yl) -III-indol-5-ol); quizartinib (AC220) (1- (5- (tert-butyl) isoxazol-3-yl) -3- (4- (7- (2-morpholinoethoxy)) benzo ^] imidazo [2,1-b] thiazol-2yl ) phenyl) urea); Semaxanib (SU5416, VEGFR2 III kinase inhibitor) (^) - 3 - ((3,5-dimethyl-1Hpyrrol-2-yl) methylene) indolin-2-one); SU4984 (3- [4- (1-formylpiperazin-4-yl) benzylidenyl] -2indolinone); Vitaferin A ((4β, 5β, 6β, 22R) -4,27-dihydroxy-5,6,22,26-diepoxyergosta-2,24-diene-1,26dione); XL-999 (^) - 5 - ((1-ethylpiperidin-4-yl) amino) -3 - ((3-fluorophenyl) (5-methyl-III-imidazol-2yl) methylene) indolin-2-one); XMD15-44 (No. (4 - ((4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -4methyl-3- (pyridin-3-ylethynyl) benzamide); Y078-DM1 (an antibody-drug conjugate consisting of an RET antibody (Y078) coupled to a derivative of the cytotoxic agent maytansine); and Y078-DM1 (an antibody-drug conjugate consisting of an RET antibody (Y078) coupled to a derivative of the cytotoxic agent maytansine). Additional examples of RET inhibitors include: No. (2-fluoro-5-trifluoromethylphenyl) -No- {4 '- [(2-benzamido) pyridin-4-ylamino] phenyl} urea; 1isopropyl-3- (phenylethynyli) -1H-pyrazolo [3.4 ^] pyrimidin-4-amine; 3 - ((6,7-dimethoxyquinazoline-4yl) amino) -4-fluoro-2-methylphenol; N- (5- (tert-butyl) isoxαzol-3-yl) -2- (4- (imidαzo [1,2-a] pyridin-6yl) phenyl) acetamide; N- (5- (tert-butyl) isoxazol-3-yl) -2- (3- (imidazo [1,2-b] pyridazin-6-yloxy) phenyl) acetamide; 2-amino-6 - {[2- (4-chlorophenyl) -2-oxoethyl] sulfanyl} -4- (3-thienyl) pyridine-3,5-dicarbonitrile; and 3-arylureidobenzylidene-indolin-2-ones. Other drugs include RET inhibitors such as those described, for example, in US Pat. Nos. 7,504,509; 8299057; 8399442; 8067434; 8937071; 9006256; and 9035063; US Patent Publications No. 2014/0121239; 20160176865; 2011/0053934; 2011/0301157; 2010/0324065; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195; international patent publications WO 2016/037578; WO 2016/038519; WO 2016/038552; WO 2014/184069; WO 2014/072220; WO 2012/053606; WO 2009/017838; WO 2008/031551; WO 2007/136103; WO 2007/087245; WO 2007/057399; WO 2005/051366; WO 2005/062795; and WO 2005/044835; and J. Med. Chem. 2012, 55 (10), 4872-4876, all of which are incorporated herein by reference in their entirety.

Non-limiting examples of drugs targeting a receptor tyrosine kinase (e.g., Trk) include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinibu, pantinibazumibitum 1 - ((3S, 4R) -4- (3-fluorophenyl) -1- (2-methoxyethyl) pyrrolidin-3-yl) -3- (4methyl-3- (2-methylpyrimidin-5-yl) -1- phenyl-III-pyrazol-5-yl) urea, AG 879, AR-772, AR-786, AR256, AR-618, AZ-23, AZ623, DS-6051, Go 6976, GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101, TPX-0005 and TSR-011. Additional drugs targeting Trk include those described in US Pat. Nos. 8,450,322; 8513263; 8933084; 8791123; 8946226; 8450322; 8299057; and 8912194; US Patent Publications No. 2016/0137654; 2015/0166564; 2015/0051222; 2015/0283132; and 2015/0306086; international patent publications WO 2010/033941; WO 2010/048314; WO 2016/077841; WO 2011/146336; WO 2011/006074; WO 2010/033941; WO 2012/158413; WO 2014078454; WO 2014078417; WO 2014078408; WO 2014078378; WO 2014078372; WO 2014078331; WO 2014078328; WO 2014078325; WO 2014078323; WO 2014078322; WO 2015175788; WO 2009/013126; WO 2013/174876; WO 2015/124697; WO 2010/058006; WO 2015/017533; WO 2015/112806; WO 2013/183578; and WO 2013/074518, all of which are incorporated herein by reference

- 107 035568 in full.

Further examples of Trk inhibitors can be found in U.S. Patent No. 8637516, International Publication No. WO 2012/034091, U.S. Patent No. 9102671, International Publication No. WO 2012/116217, U.S. Publication No. 2010/0297115, International Publication No. WO 2009/053442, U.S. Patent No. 8642035, international publication No. WO 2009092049, US patent No. 8691221, international publication No. WO 2006131952, all of which are incorporated herein by reference in their entirety. Typical Trk inhibitors include GNF-4256, described in Cancer Chemother publications. Pharmacol. 75 (1): 131-141, 2015; and GNF-5837 (No. [3 - [[2,3-dihydro-2-oxo-3- (1H-pyrrol2-ylmethylene) -1H-indol-6-yl] amino] -4-methylphenyl] -No- [ 2-fluoro-5- (trifluoromethyl) phenyl] urea) described in ACS Med. Chem. Lett. 3 (2): 140-145, 2012, (each of which is incorporated herein by reference in its entirety). Additional examples of Trk inhibitors include those disclosed in US Patent Publication No. 2010/0152219, US Patent No. 8114989 and International Patent Publication No. WO 2006/123113, all of which are incorporated herein by reference in their entirety. Examples of Trk inhibitors include AZ623, described in Cancer 117 (6): 1321-1391, 2011; AZD6918 described in Cancer Biol. Ther. 16 (3): 477-483, 2015; AZ64 described in Cancer Chemother. Pharmacol. 70: 477-486, 2012; AZ-23 (^) - 5-chloro-N- (1- (5-fluoropyridin-2-yl) ethyl) N- (5-isopropoxy-1H-pyrazol-3-yl) pyrimidine-2,4-diamine) described in Mol. Cancer Ther. 8: 18181827, 2009; and AZD7451; each of which is incorporated herein by reference in its entirety. A Trk inhibitor can include those described in US Pat. Nos. 7,615,383; 7384632; 6153189; 6027927; 6025166; 5910574; 5877016; and 5844092, each of which is incorporated herein by reference in its entirety. Additional examples of Trk inhibitors include CEP751 described in Int. J. Cancer 72: 672-679,1997; CT327 described in Acta Derm. Venereol. 95: 542-548, 2015; compounds described in International Patent Publication No. WO 2012/034095; compounds described in US patent No. 8673347 and international publication No. WO 2007/022999; compounds described in US patent No. 8338417; compounds described in International Publication No. WO 2016/0277'54; compounds described in US patent No. 9242977; compounds described in US Patent Publication No. 2016/0000783; sunitinib (N- (2-diethylaminoethyl) -5 - [^) - (5-fluoro-2-oxo-III-indol3 ylidene) methyl] -2,4-dimethyl-III-pyrrole-3-carboxamide) as described in PLoS One 9: e95628, 2014; compounds described in International Patent Publication No. WO 2011/133637; compounds described in US patent No. 8637256; connections described in Expert. Opin. Ther. Pat. 24 (7): 731-744, 2014; connections described in Expert Opin. Ther. Pat. 19 (3): 305-319, 2009; da-2-phenylpyrrolidine-substituted imidazopyridazines, e.g. GNF-8625, ^) - 1- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2b] pyridazine-3- yl) - [2,4'-bipyridin] -2'-yl) piperidin-4-ol as described in ACS Med. Chem. Lett. 6 (5): 562567, 2015; GTx-186 and others as described in PLoS One 8 (12): e83380, 2013; K252a ((9S- (9a, 10β, 12α)) 2,3,9,10,11,12-hexahydro-10-hydroxy-10- (methoxycarbonyl) -9-methyl-9,12-epoxy-III-diindolo [1,2,3fg: 3 ', 2', 1'-kl] pyrrolo [3,4-i] [1,6] benzodiazocin-1-one) as described in Mol. Cell Biochem. 339 (1-2): 201-213,2010; 4-aminopyrazolylpyrimidines, for example, AZ-23 ((^) - 5-chloro-N- (1- (5-fluoropyridin-2-yl) ethyl) N4- (5-isopropoxy-III-pyrazol-3-yl) pyrimidine -2,4-diamine) as described in JJ. Med. Chem. 51 (15): 46724684, 2008; PHA-739358 (danusertib) as described in Mol. Cancer Ther. 6: 3158, 2007; Go 6976 (5,6,7,13 tetrahydro-13-methyl-5-oxo-12H-indolo [2,3-a] pyrrolo [3,4-c] carbazole-12-propanenitrile) as described in J. Neurochem ... 72: 919-924,1999; GW441756 ((3Z) -3 - [(1-methylindol-3-yl) methylidene] -1H-pyrrolo [3.2b] pyridin-2-one) as described in IJAE 115: 117, 2010; milcyclib (PHA-848125AC) described in J. Carcinog. 12:22, 2013; AG-879 ((2E) -3- [3,5-bis- (1,1-dimethylethyl) -4-hydroxyphenyl] -2-cyano-2-propenthioamide); altiratinib (No. (4 - ((2- (cyclopropanecarboxamido) pyridin-4-yl) oxy) -2.5 difluorophenyl) -No (4-fluorophenyl) cyclopropane-1,1-dicarboxamide); cabosantinib (N- (4 - ((6,7dimethoxyquinolin-4-yl) oxy) phenyl) -No- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide); letaurtinib (^^^) - 6-hydroxy-6- (hydroxymethyl) -5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b, 8а, 14-triase-5.8methanodibenzo [b , h] cycloocta [jkl] cyclopent [e] -indacene-13 (6H) -one); dovatinib (4-amino-5-fluoro-3- [6- (4methylpiperazin-1-yl) -1H-benzimidazol-2-yl] quinolin-2 (1H) -one mono-2-hydroxypropanoate hydrate); citravatinib (No. (3-fluoro-4 - ((2- (5 - (((2-methoxyethyl) amino) methyl) pyridin-2-yl) thieno [3,2-b] pyridin-7yl) oxy) phenyl) -No (4-fluorophenyl) cyclopropane-1,1-dicarboxamide); ONO-5390556; regoraphenib (4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy | -Nomethylpyridine-2carboxamide hydrate); and BCP-902A; each of which is incorporated herein by reference in its entirety.

The ability of a Trk inhibitor to act as an inhibitor of TrkA, TrkB and / or Trk C can be tested using the assays described in Examples A and B in US Pat. No. 8,513,263, which is incorporated herein by reference in its entirety.

In some embodiments, signaling pathway inhibitors include inhibitors of the Ras-Raf-MEK-ERK pathway (e.g., binimetinib, selemetinib, encorafinib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., everolimus, rapamycin, perifosin, temsirolimus) and other kinase inhibitors such as baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semaxanib, AP32788, BLU285,

- 108 035568

BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS1286937, PF 477736 ((^) - amino-H- [5.6-dihydro-2- (1-methyl-1H-pyrazol-4-yl ) -6-oxo-1H-pyrrolo [4,3.2eP | 2,3 | benzodiazepin-8-yl | cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX 103, RXDX 106, RXDX 108 and TG101209 ^ -tert-butyl-3- (5-methyl-2- (4- (4methylpiperazin-1-yl) phenylamino) pyrimidin-4-ylamino) benzenesulfonamide).

Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolumab.

In some embodiments of the invention, the cytotoxic chemotherapeutic agents are selected from arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etocystabine spp. oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

Non-limiting examples of angiogenesis-targeted therapy options include aflibercept and bevacizumab.

The term immunotherapy refers to an agent that modulates the immune system. In some embodiments of the invention, immunotherapy may increase the expression and / or activity of an immune system regulator. In some embodiments, immunotherapy can reduce the expression and / or activity of an immune system regulator. In some embodiments of the invention, immunotherapy can target an immune cell and / or increase its activity. In some embodiments, the immunotherapy is cellular immunotherapy (eg, adoptive T cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge ™; Plosker (2011) Drugs 71 (1): 101-108). In some embodiments, cellular immunotherapy includes cells that express a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah ™).

In some embodiments, the immunotherapy is an antibody-based therapy (eg, monoclonal antibodies, conjugated antibodies). In some embodiments, the antibody-based therapy is the use of bevacizumab (mvasti ™, avastin®), trastuzumab (herceptin®), avelumab (bavenzio®), rituximab (mabthera ™, rituxan®), edrecolomab (panorex), daratuzumab ®), olaratumab (lartruvo ™), ofatumumab (arserra®), alemtuzumab (campat®), cetuximab (erbitux®), oregovomab, pembrolizumab (keyruda®), dinutiximab (unituxin®), cp (obinutivuelimab -675.206), ramucirumab (tsiramza®), ublituximab (TG-1101), panitumumab (vectibix®), elotuzumab (empicity ™), avelumab (bavenzio®), nesitumumab (portrazza ™) (tsirmutuzumab) (UC-961) Zevalin®), Isatuximab (SAR650984), Nimotuzumab, Fresolimumab (GC1008), Lirilumab (INN), Mogamulizumab (Poteligeo®), Ficlatuzumab (AV-299), Denosumab (X-Geva®), Ganitumaba, or Peliucimaba

In some embodiments, the immunotherapy is the use of an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (mylotarg ™), inotuzumab ozogamicin (besponza®), brentuximab vedotin (adcetris®), ado-trastuzumab emtansine (TDM-1; cadcilab®), mirvettanzim3 ) or anetumab ravtanzine.

In some embodiments, the immunotherapy comprises the use of blinatumomab (AMG103; blincyto®) or midostaurin (readapt).

In some embodiments, the immunotherapy comprises the use of a toxin. In some embodiments of the invention, the immunotherapy is the use of denileukin diphtox (ontac®).

In some embodiments, the immunotherapy is a cytokine-based therapy. In some embodiments, the cytokine therapy is interleukin 2 (IL-2) therapy, interferon alpha (IFNa) therapy, granulocyte colony stimulating factor (G-CSF) therapy, interleukin 12 (IL-12) therapy, interleukin 15 ( IL-15), interleukin 7 (IL-7) therapy, or erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNa therapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®).

In some embodiments, the immunotherapy is the use of

- 109 035568 immune checkpoint inhibitors. In some embodiments, the immunotherapy comprises the use of one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (ervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PDL1 inhibitor is atezolizumab (tecentrik®), avelumab (bavenzio®), or durvalumab (imfinzi ™).

In some embodiments, the immunotherapy is mRNA-based immunotherapy. In some embodiments, mRNA-based immunotherapy is the use of CV9104 (see, e.g., Rausch et al. (2014), Human Vaccin Immunother 10 (11): 3146-52; and Kubler et al. (2015) J. Immunother Cancer 3:26).

In some embodiments, the immunotherapy is a Calmette-Guerin (BCG) bacillus therapy.

In some embodiments, the immunotherapy is an oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is the use of talimogene alherparepvec (T-VEC; Imlygic®).

In some embodiments, the immunotherapy is the use of a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9®, or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is engerix-B®, recombivax HBV®, or GI-13020 (tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is Biovax ID®, Oncophage®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, Rindopepimut®, Cimavax-EGF, Lapuleucel-T (APC8024; Neuvenge ™), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlizimut-L (hepco-U5). DCVAX®, SCI-B1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac or Viagenpumatucel-L (HS-110).

In some embodiments, the immunotherapy is the use of a peptide vaccine. In some embodiments, the peptide vaccine is non-lipimut-S (E75) (Neuwax ™), IMA901, or Survax M (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic autologous neo-antigen vaccine (see, for example, Ott et al. (2017), Nature 547: 217-221; Sahin et al. (2017) Nature 547: 222-226). In some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA vaccine. In some embodiments, the DNA vaccine is a mammaglobin-A DNA vaccine (see, e.g., Kim et al. (2016), Oncolmmunology 5 (2): e1069940).

In some embodiments, the immune agents are selected from aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

Non-limiting examples of radiation therapy include radioactive iodine therapy, external beam radiation therapy, and radium 223 therapy.

Additional kinase inhibitors include those described, for example, in US Pat. Nos. 7,514,446; 7863289; 8026247; 8501756; 8552002; 8815901; 8912204; 9260437; 9273051; US Publication No. US 2015/0018336; International Publications No. WO 2007/002325; WO 2007/002433; WO 2008/080001; WO 2008/079906; WO 2008/079903; WO 2008/079909; WO 2008/080015; WO 2009/007748; WO 2009/012283; WO 2009/143018; WO 2009/143024; WO 2009/014637; 2009/152083; WO 2010/111527; WO 2012/109075; WO 2014/194127; WO 2015/112806; WO 2007/110344; WO 2009/071480; WO 2009/118411; WO 2010/031816; WO 2010/145998; WO 2011/092120; WO 2012/101032; WO 2012/139930; WO 2012/143248; WO 2012/152763; WO 2013/014039; WO 2013/102059; WO 2013/050448; WO 2013/050446; WO 2014/019908; WO 2014/072220; WO 2014/184069; and WO 2016/075224, which are hereby incorporated by reference in their entirety. Additional examples of kinase inhibitors include those described, for example, in WO 2016/081450; WO 2016/022569; WO 2016/011141; WO 2016/011144; WO 2016/011147; WO 2015/191667; WO 2012/101029; WO 2012/113774; WO 2015/191666; WO 2015/161277; WO 2015/161274; WO 2015/108992; WO 2015/061572; WO 2015/058129; WO 2015/057873; WO 2015/017528; WO / 2015/017533; WO 2014/160521; and WO 2014/011900, all of which are incorporated herein by reference in their entirety. Accordingly, this document also provides a method for treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination that contains (a) a compound of Formula I or a pharmaceutically acceptable administration thereof

- 110 035568 lem salt or solvate, (b) an additional therapeutic agent and, (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of cancer, wherein the amount of a compound of formula I or a pharmaceutically acceptable thereof a salt or solvate and an additional therapeutic agent together are effective in treating cancer.

In some embodiments, the additional therapeutic agent (s) include (s) any of the above therapy options or therapeutic agents that meet cancer treatment standards, wherein the cancer is characterized by dysregulation of the RET, RET protein, or expression thereof, or their activity, or the level of any of them.

These additional therapeutic agents can be administered with one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as part of one or as separate dosage forms, by one or more routes of administration and / or according to the same or different administration regimens in accordance with standard pharmaceutical practice known to the person skilled in the art.

In addition, this document provides (i) a pharmaceutical combination for the treatment of cancer in a patient in need thereof, which contains (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (b) at least one additional therapeutic agent (for example, any of the exemplary additional therapeutic agents described herein or known in the art), and, (c) optionally, at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of cancer, wherein the amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and an additional therapeutic agent are together effective in the treatment of cancer; (ii) a pharmaceutical composition containing such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product containing such a combination as a combination preparation for simultaneous, separate or sequential use; and a method for treating cancer in a patient in need thereof. In one embodiment, the patient is a human. In some embodiments, the cancer is a RET-associated cancer. For example, it is a RET-associated cancer that has one or more RET inhibitor resistance mutations.

In the context of this document, the term pharmaceutical combination refers to a pharmaceutical therapeutic agent obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term “fixed combination” means that a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional therapeutic agent (eg, a chemotherapeutic agent) is administered to a patient simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are formulated as separate compositions or dosages such that they can be administered simultaneously to a patient in need thereof. , in parallel or sequentially at various intermediate intervals, and such administration provides effective levels of two or more compounds in the patient's body. This also applies to cocktail therapy, for example, the administration of three or more active ingredients.

Accordingly, this document also provides a method for treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination for the treatment of cancer, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally, at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use in the treatment of cancer, wherein the amounts of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent together are effective in the treatment of cancer. In one embodiment, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously in divided doses. In one embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent are administered in divided doses, sequentially in any order, in co-therapeutically effective amounts, for example, daily dosages or intermittently. In one embodiment of the invention, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the cancer is a RET-associated cancer. For example, it is a RET-associated cancer that has one or more RET inhibitor resistance mutations.

This document also provides a method of treating a disease or disorder mediated by RET in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or salt thereof

- 111 035568 that, or a pharmaceutical composition thereof. In some embodiments, the RET-mediated disease or disorder is dysregulation of a RET gene, a RET kinase or their expression, or their activity, or the level of any of them. For example, dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them includes the presence of one or more mutations of resistance to RET inhibitors. A disease or disorder mediated by RET can include any disease, disorder, or pathological condition that is directly or indirectly associated with the expression or activity of RET, including overexpression and / or abnormal levels of activity. In one embodiment, the disease is cancer (eg, RET-associated cancer). In one embodiment, the cancer is any of the cancers or RET-associated cancers described herein. Although the genetic basis of tumorigenesis may differ for different types of cancer, the cellular and molecular mechanisms required for metastasis seem to be the same for all types of solid tumors. During the metastatic cascade, cancer cells lose growth inhibitory responses, undergo changes in adhesion and produce enzymes that can degrade extracellular matrix components. This leads to the separation of tumor cells from the original tumor, infiltration into the bloodstream through the newly formed vasculature, migration and extravasation of tumor cells to favorable distant sites where they can form colonies. A large number of genes have been identified as promoters or suppressors of metastasis. For example, overexpression of glial cell neurotrophic factor (GDNF) and its receptor RET tyrosine kinase correlates with cancer proliferation and metastasis. See, for example, Zeng, Q. et al. J. Int. Med. Res. (2008) 36 (4): 656-64.

Accordingly, this document also provides methods of inhibiting, preventing, helping to prevent or reduce the symptoms of cancer metastasis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. Such methods can be used in the treatment of one or more of the cancers described herein. See, for example, US publication No. 2013/0029925; International Publication No. WO 2014/083567; and US patent No. 8568998. In some embodiments, the cancer is a RET-associated cancer. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with adjunctive therapy or other therapeutic agent, including a chemotherapeutic agent such as a kinase inhibitor. For example, it is the first or second RET kinase inhibitor.

The term metastasis is a term known in the art and refers to the formation of an additional tumor (e.g., a solid tumor) at a site distant from the primary tumor in a subject or patient, the additional tumor containing the same or similar cancer cells as the primary tumor ...

Also provided are methods of reducing the risk of metastasis or additional metastasis in a patient with RET-associated cancer, comprising selecting, identifying or diagnosing the patient as having RET-associated cancer and administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a patient who has been is selected, identified, or diagnosed as having a RET-associated cancer. Also provided are methods of reducing the risk of metastasis or additional metastasis in a patient with RET-associated cancer, comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a patient with RET-associated cancer. The reduced risk of metastasis or additional metastasis in a patient with RET-associated cancer can be compared with the risk of metastasis or additional metastasis in a patient before treatment, or compared to a patient or patient population with a similar or the same RET-associated cancer who has not received any treatment or received other treatment. In some embodiments, the RET-associated cancer is a RET-associated cancer having one or more RET inhibitor resistance mutations.

The expression risk of metastasis means the risk that a subject or patient with a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from the primary tumor in the subject or patient for a specified period of time, with an additional the tumor contains the same or similar cancer cells as the primary tumor. Methods for reducing the risk of metastasis in a subject or patient with cancer are described herein. The expression risk of developing additional metastases means the risk that a subject or patient with a primary tumor and one or more additional tumors in areas distant from the primary tumor (where one or more additional tumors contain the same or similar cancer cells as the primary tumor), one or more other tumors distant from the primary tumor will develop, with the additional tumors containing the same or similar cancer cells as the primary tumor. The ways

- 112 035568 risk reduction of additional metastases is described in this document.

In the context of this document, the first RET kinase inhibitor or the first RET inhibitor is an RET kinase inhibitor as defined herein, but which does not contain a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. In the context of this document, the second RET kinase inhibitor or the second RET inhibitor is a RET kinase inhibitor as defined herein, but which does not contain a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. When both the first and second RET inhibitors are present in the method provided herein, the first and second RET kinase inhibitors are different.

In some embodiments, the presence of one or more RET inhibitor resistance mutations in the tumor results in the tumor becoming more resistant to treatment with the first RET inhibitor. Methods useful when mutation of resistance to RET inhibitors causes an increase in tumor resistance to treatment with the first RET inhibitor are described below. For example, provided herein are methods of treating a subject having cancer, comprising defining a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to a designated subject a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. Also provided are methods of treating a subject that has been identified as having a cancer cell that has one or more RET inhibitor resistance mutations comprising administering to the subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. For example, provided herein are methods of treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, the first RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation; and (d) administering to the subject a compound of Formula I or a pharmaceutically acceptable solvate salt thereof as monotherapy or in combination with another anti-cancer agent if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor from step (b) to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments, provided herein are methods of treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting dysregulation of a RET gene, RET kinase, or expression, or activity, or level of any of them in a sample from the subject ; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, the first RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent, to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor from step (b) to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating RET

- 113 035568 associated cancer in a subject in need of such treatment, comprising (a) identifying one or more fusion proteins from table. 1 and / or one or more point mutations / insertions / deletions in the RET kinase protein from table. 2 in a sample from a subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, the first RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation from Table 1. 3 or 4; and (d) administering a compound of formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent, to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor from step (b) to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting a KIF5B-RETB fusion protein in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, the first RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has a resistance mutation to V804M RET inhibitors; and (d) administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent, to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor from step (b) to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation.

As another example, provided herein are methods of treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, the second RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864, as monotherapy or in combination with another an anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering to the subject an additional dose of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof from step (b), if the subject has a cancer cell that does not have a resistance mutation to RET inhibitors. In some embodiments, provided herein are methods of treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix)

- 114 035568 example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, the second RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864, as monotherapy or in combination with another an anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering to the subject an additional dose of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof from step (b), if the subject has a cancer cell that does not have a resistance mutation to RET inhibitors. In some embodiments, the invention provides methods for treating RET-associated cancer in a subject in need of such treatment, comprising (a) identifying one or more fusion proteins from Table. 1 and / or one or more point mutations / insertions / deletions in the RET kinase protein from table. 2 in a sample from a subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation from Table 1. 3 or 4; and (d) administering a second RET inhibitor, the second RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864, as monotherapy or in combination with another an anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering to the subject an additional dose of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof from step (b), if the subject has a cancer cell that does not have a resistance mutation to RET inhibitors. In some embodiments, provided herein are methods for treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting a KIF5B-RET fusion protein in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has a resistance mutation to V804M RET inhibitors; and (d) administering a second RET inhibitor, the second RET inhibitor being selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864, as monotherapy or in combination with another an anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering to the subject an additional dose of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof from step (b), if the subject has a cancer cell that does not have a resistance mutation to RET inhibitors.

Also provided herein are methods of treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting dysregulation of the RET gene, RET kinase, or expression, or activity, or level of any thereof in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation; and (d) administering additional doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof from step (b), to the subject as monotherapy or in combination with another anti-cancer agent (e.g., a second RET inhibitor,

115 035568 a second compound of formula I, or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (eg, surgery or radiation) if the subject has a cancer cell that has at least one mutation in resistance to RET inhibitors. In some embodiments, provided herein are methods of treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in a sample from the subject ; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation; and (d) administering additional doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof from step (b) to the subject as monotherapy or in combination with another anti-cancer agent (e.g., a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt thereof, or immunotherapy) or anti-cancer therapy (eg, surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, the invention provides methods for treating RET-associated cancer in a subject in need of such treatment, comprising (a) identifying one or more fusion proteins from Table. 1 and / or one or more point mutations / insertions / deletions in the RET kinase protein from table. 2 in a sample from a subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has at least one RET inhibitor resistance mutation from Table 1. 3 or 4; and (d) administering additional doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof from step (b) to the subject as monotherapy or in combination with another anti-cancer agent (e.g., a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt thereof, or immunotherapy) or anti-cancer therapy (eg, surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, a second RET inhibitor selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864 is administered in step (d). In some embodiments, provided herein are methods for treating RET-associated cancer in a subject in need of such treatment, comprising (a) detecting a KIF5B-RET fusion protein in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from a subject has a resistance mutation to V804M RET inhibitors; and (d) administering additional doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof from step (b) to the subject as monotherapy or in combination with another anti-cancer agent (e.g., a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt thereof, or them

- 116 035568 moonotherapy) or anti-cancer therapy (eg, surgery or radiation), if the subject has a cancer cell that has at least one mutation in resistance to RET inhibitors. In some embodiments, a second RET inhibitor selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, fortinib, BLU667, and BLU6864 is administered in step (d).

Also provided are methods of selecting a treatment for a subject having cancer, comprising identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting a treatment that comprises administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with a first RET inhibitor. Also provided are methods of selecting a treatment for a subject having cancer, comprising selecting a treatment that comprises administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of selecting a subject having cancer for treatment that does not include the use of a first RET inhibitor as monotherapy, comprising identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting a specific subject for treatment which comprises administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of selecting a subject having cancer for treatment that does not include the use of a first RET inhibitor as monotherapy, comprising selecting a subject that has been identified as having a cancer cell that has one or more RET inhibitor resistance mutations for treatment that comprises administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. In some embodiments, one or more RET inhibitor resistance mutations may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E.

Also provided are methods for determining the likelihood that a subject having cancer (e.g., RET-associated cancer) will respond positively to treatment with a first RET inhibitor as monotherapy, comprising determining the presence in a cancer cell in a sample obtained from the subject of one or more mutations of resistance to RET inhibitors; and determining that a subject having a cancer cell that has one or more resistance mutations to RET inhibitors is less likely to respond positively (ie, more likely to not respond) to treatment with the first RET inhibitor as monotherapy. Also provided are methods for determining the likelihood that a subject having cancer (e.g., RET-associated cancer) will respond positively to treatment with a first RET inhibitor as monotherapy, comprising determining the presence in a cancer cell in a sample obtained from the subject of one or more mutations of resistance to RET inhibitors; and determining that a subject lacking a cancer cell that has one or more resistance mutations to RET inhibitors is more likely to respond positively to treatment with a first RET inhibitor as monotherapy than a subject having a cancer cell that has one or more mutations of resistance to RET inhibitors. Also provided are methods for predicting the efficacy of treatment with a first RET inhibitor as monotherapy in a subject having cancer, comprising determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that treatment with the first RET inhibitor as monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from a subject that has one or more RET inhibitor resistance mutations. Also provided are methods for predicting the effectiveness of treatment with a first RET inhibitor as monotherapy in a subject having cancer, comprising determining that treatment with a first RET inhibitor as monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from a subject who has one or more RET inhibitor resistance mutations. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E.

Also provided are methods of treating a subject having cancer, comprising (a) administering to the subject one or more doses of a first RET inhibitor over a period of time; (b) after (a) determining if a cancer cell in a sample obtained from a subject has at least one mutation

- 117 035568 resistance to RET inhibitors; and (c) administering to the subject a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent if the subject has a cancer cell that has at least one mutation in resistance to RET inhibitors; or (d) administering additional doses of the first RET inhibitor from step (a) to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments of the invention, in which the subject is administered additional doses of the first RET inhibitor from step (a), the subject can also be administered another anti-cancer agent (for example, a second RET inhibitor or a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) ... In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments of step (c), another RET inhibitor may be the first RET inhibitor administered in step (a). In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E.

Also provided are methods of treating a subject having cancer, comprising (a) administering to the subject one or more doses of a first RET inhibitor over a period of time; (b) after (a) determining whether the cancer cell in the sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) administering a second RET inhibitor as monotherapy or in combination with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (d) administering additional doses of the first RET inhibitor from step (a) to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments of the invention in which additional doses of the first RET inhibitor from step (a) are administered to the subject, another anti-cancer agent may also be administered to the subject. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anti-cancer agent is immunotherapy.

Also provided are methods of treating a subject having cancer (e.g., RET-associated cancer), comprising (a) determining whether a sample obtained from a subject who has cancer and who has previously received one or more doses of a first RET inhibitor has a cancer cell, one or more RET inhibitor resistance mutations; and (b) administering to the subject a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent if the subject has a cancer cell that has at least one mutation in resistance to RET inhibitors; or (c) administering additional doses of a first RET inhibitor that has previously been administered to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments of the invention, in which the subject is administered additional doses of a first RET inhibitor that was previously administered to him, the subject can also be administered another anti-cancer agent (for example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments of step (b), another

118 035568 the anticancer agent may be the first RET inhibitor administered in step (a).

Also provided are methods of treating a subject having cancer, comprising (a) determining if a cancer cell in a sample obtained from a subject who has cancer and who has previously been administered one or more doses of a first RET inhibitor, one or more mutations of resistance to RET inhibitors ; and (b) administering a second RET inhibitor as monotherapy or in combination with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) administering additional doses of a first RET inhibitor that has previously been administered to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments of the invention, in which the subject is administered additional doses of the first RET inhibitor that was previously administered to him, the subject can also be administered another anti-cancer agent. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments (b) the other anti-cancer agent may be the first RET inhibitor administered in step (a).

Also provided are methods for selecting a treatment for a subject having cancer, comprising (a) administering to the subject one or more doses of a first RET inhibitor over a period of time; (b) after (a) determining whether the cancer cell in the sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) selecting a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent for the subject if the subject has a cancer cell that has one or more RET inhibitor resistance mutations; or (d) selecting additional doses of the first RET inhibitor from step (a) for the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments, if additional doses of the first RET inhibitor from step (a) are selected for a subject, the method may further include selecting doses of a different anti-cancer agent for the subject. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments of step (c), another RET inhibitor may be the first RET inhibitor administered in step (a).

Also provided are methods for selecting a treatment for a subject having cancer, comprising (a) administering to the subject one or more doses of a first RET inhibitor over a period of time; (b) after (a) determining whether the cancer cell in the sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) selecting a second RET inhibitor as monotherapy or in combination with another anticancer agent if the subject has a cancer cell that has one or more RET inhibitor resistance mutations; or (d) selecting additional doses of the first RET inhibitor from step (a) for the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments, if additional doses of the first RET inhibitor from step (a) are selected for a subject, the method may further include selecting doses of a different anti-cancer agent for the subject. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art.

- 119 035568 in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments, the other RET inhibitor may be the first RET inhibitor administered in step (a). Also provided are methods for selecting a treatment for a subject having cancer, comprising (a) determining if a cancer cell in a sample obtained from a subject who has cancer and who has previously been administered one or more doses of a first RET inhibitor, one or more mutations of resistance to RET inhibitors; (b) selecting a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as monotherapy or in combination with another anticancer agent for the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) selecting additional doses of a first RET inhibitor that has previously been administered to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments, if additional doses of a first RET inhibitor that have previously been administered to the subject are selected for a subject, the method may further include selecting doses of another anti-cancer agent (e.g., a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof) for the subject. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments of step (c), another RET inhibitor may be the first RET inhibitor administered in step (a).

Also provided are methods for selecting a treatment for a subject having cancer, comprising (a) determining if a cancer cell in a sample obtained from a subject who has cancer and who has previously been administered one or more doses of a first RET inhibitor, one or more mutations of resistance to RET inhibitors; (b) selecting a second RET inhibitor as monotherapy or in combination with another anticancer agent for the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) selecting additional doses of a first RET inhibitor that has previously been administered to the subject if the subject has a cancer cell that does not have the RET inhibitor resistance mutation. In some embodiments, if additional doses of a first RET inhibitor that have previously been administered to the subject are selected for a subject, the method may further include selecting doses of another anti-cancer agent (e.g., a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) for the subject. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments, the other RET inhibitor may be the first RET inhibitor administered in step (a).

Also provided are methods for determining the risk of a subject developing cancer that has some resistance to a first RET inhibitor, comprising determining whether a cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and defining a subject having a cell that has one or more mutations of resistance to RET inhibitors as having an increased likelihood of developing cancer that has some resistance to the first RET inhibitor. Also provided are methods for determining the risk of a subject developing cancer that has some resistance to a first RET inhibitor, comprising defining a subject having a cell that has one or more mutations in resistance to RET inhibitors as having an increased likelihood of developing a cancer that has some resistance to the first a RET inhibitor. Also provided are methods for determining the presence of cancer that has some resistance to a first RET inhibitor, comprising determining whether a cancer cell in a sample obtained from a subject has one or more mutations in resistance to RET inhibitors; and

- 120 035568 determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations has cancer that has some resistance to the first RET inhibitor. Also provided are methods for determining whether a subject has cancer that has some resistance to a first RET inhibitor, comprising determining that a subject having a cancer cell that has one or more mutations of resistance to RET inhibitors has cancer that has some resistance to the first inhibitor RET. In some embodiments, one or more RET inhibitor resistance mutations impart increased resistance to treatment with the first RET inhibitor in a cancer cell or tumor. In some embodiments, one or more RET inhibitor resistance mutations comprise one or more RET inhibitor resistance mutations listed in Table 1. 3 and 4. For example, one or more mutations of resistance to RET inhibitors may include a substitution at amino acid position 804, for example, V804M, V804L, or V804E.

In some embodiments of any of the methods described herein, a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with a first RET inhibitor can be any of the RET inhibitor resistance mutations listed in Table 1. 3 or 4 (eg, substitution at amino acid position 804, eg V804M, V804L, or V804E). In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor makes the tumor more resistant to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. Methods useful in the event that a mutation of resistance to RET inhibitors results in the tumor becoming more resistant to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof are described below. For example, provided herein are methods of treating a subject having cancer, comprising defining a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the designated subject a drug that does not contain a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as monotherapy (eg, a second RET kinase inhibitor). Also provided are methods of treating a subject that has been identified as having a cancer cell that has one or more RET inhibitor resistance mutations, comprising administering to the subject a drug that does not contain a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy (e.g. , a second RET kinase inhibitor). In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor.

Also provided are methods of selecting a treatment for a subject having cancer, comprising identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting a drug that does not contain a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy for a particular subject (eg, a second RET kinase inhibitor). Also provided are methods of selecting a treatment for a subject having cancer, comprising selecting a drug that does not contain a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy (e.g., a second RET kinase inhibitor) for a subject that has been determined to have a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of selecting a subject having cancer for treatment that does not include the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy (e.g., a second RET kinase inhibitor), comprising defining a subject having a cancer cell that has one or more mutations of resistance to RET inhibitors; and selecting a specific subject for treatment that does not include the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy (eg, a second RET kinase inhibitor). Also provided are methods of selecting a subject with cancer for treatment that does not include the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy (e.g., a second RET kinase inhibitor), comprising selecting a subject that has been determined to have a cancer cell which has one or more RET inhibitor resistance mutations for treatment that does not involve the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor.

Also provided are methods for determining the likelihood that a subject having cancer will respond positively to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as monotherapy, comprising determining whether a cancer cell in a sample obtained from the subject has one or more mutations of resistance to RET inhibitors; and determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations is less likely to respond positively to treatment with a compound of formula I

- 121 035568 or a pharmaceutically acceptable salt or solvate thereof as monotherapy. Also provided are methods for determining the likelihood that a subject having cancer will respond positively to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as monotherapy, comprising determining that a subject having cancer cells that has one or more mutations of resistance to RET inhibitors, the likelihood of a positive response to treatment with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof as monotherapy is reduced. Also provided are methods for predicting the effectiveness of treatment with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy in a subject having cancer, comprising determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from a subject that has one or more RET inhibitor resistance mutations. Also provided are methods for predicting the effectiveness of treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy in a subject having cancer, comprising determining that treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as monotherapy is less likely to be effective when a subject having a cancer cell in a sample obtained from a subject that has one or more RET inhibitor resistance mutations. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor.

Also provided are methods of treating a subject having cancer, comprising (a) administering to the subject one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, over a period of time; (b) after (a) determining whether the cancer cell in the sample obtained from the subject has one or more RET inhibitor resistance mutations; and (c) administering a second RET inhibitor or a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent, to a subject having a cancer cell that has one or more RET inhibitor resistance mutations; or (d) administering additional doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof from step (a), to a subject having a cancer cell that does not have a resistance mutation to RET inhibitors. In some embodiments, in which additional doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof from step (a), are administered to the subject, another anti-cancer agent or a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, may also be administered to the subject. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments, the other RET inhibitor may be a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, administered in step (a). Also provided are methods of treating a subject having cancer, comprising (a) determining whether a cancer cell in a sample obtained from a subject who has cancer and who has previously been administered one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, has one or more mutations of resistance to RET inhibitors; (b) administering a second RET inhibitor or a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent to a subject having a cancer cell that has one or more RET inhibitor resistance mutations; or (c) administering additional doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, which have previously been administered to a subject having a cancer cell that does not have a resistance mutation to RET inhibitors. In some embodiments of the invention in which additional doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof from step (a), are administered to the subject, another anti-cancer agent may also be administered to the subject. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments, the other RET inhibitor may be a compound of Formula I, or pharmaceutically, when

- 122 035568 The salt or solvate introduced in step (a).

Also provided are methods of selecting treatment for a subject having cancer, comprising (a) administering one or more doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, over a period of time; (b) after (a) determining whether the cancer cell in the sample obtained from the subject has one or more RET inhibitor resistance mutations; and (c) selecting a second RET inhibitor or a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent for the subject if the subject has a cancer cell that has a resistance mutation to RET inhibitors; or (d) selecting additional doses of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, from step (a) for the subject if the subject has a cancer cell that does not have a resistance mutation to RET inhibitors. In some embodiments of the invention in which additional doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof from step (a) are selected for a subject, the method may also include the additional selection of another anti-cancer agent. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments, the other RET inhibitor may be a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, administered in step (a).

Also provided are methods for selecting a treatment for a subject having cancer, comprising (a) determining whether a sample obtained from a subject who has cancer and who has previously been administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof has a cancer cell one or more RET inhibitor resistance mutations; (b) selecting a second RET inhibitor or a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent for the subject if the subject has a cancer cell that has a mutation for resistance to RET inhibitors; or (c) selecting additional doses of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, that have previously been administered to the subject if the subject has a cancer cell that does not have a resistance mutation to RET inhibitors. In some embodiments of the invention in which additional doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof from step (a) are selected for a subject, the method may also include the additional selection of another anti-cancer agent. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor. In some embodiments, the additional anti-cancer agent is any anti-cancer agent known in the art. For example, the additional anti-cancer agent is another RET inhibitor (eg, a second RET inhibitor). In some embodiments, the additional anti-cancer agent is immunotherapy. In some embodiments, the other RET inhibitor may be a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, administered in step (a).

Also provided are methods for determining the risk of a subject developing cancer that has some resistance to a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising determining whether a cell in a sample obtained from the subject has one or more mutations of resistance to RET inhibitors; and defining the subject if the subject has a cell that has one or more mutations of resistance to RET inhibitors as having an increased likelihood of developing cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods for determining the risk of developing a cancer subject in a subject who has some resistance to a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising defining a subject having a cell that has one or more RET inhibitor resistance mutations as having an increased likelihood of developing cancer which has some resistance to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods for determining the presence of cancer that has some resistance to a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, comprising determining whether a cancer cell in a sample obtained from a subject has one or more mutations in resistance to RET inhibitors; and determining that a subject having a cancer cell that has one or more mutations in resistance to RET inhibitors has cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods for determining whether a subject has cancer that has some resistance to a compound of Formula I or its pharmaceutical

- 123 035568 a ceutically acceptable salt or solvate, comprising determining that a subject having a cancer cell that has one or more mutations in resistance to RET inhibitors has cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, one or more RET inhibitor resistance mutations confer increased resistance to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in a cancer cell or tumor.

In some embodiments of any of the methods described herein, a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, may be any of the RET inhibitor resistance mutations listed in tab. 3 or 4.

Methods for determining the level of resistance of a cancer cell or tumor to RET inhibitors (eg, any RET inhibitors described herein or known in the art) can be determined by methods known in the art. For example, the level of resistance of a cancer cell to a RET inhibitor can be assessed by determining the IC50 of a RET inhibitor (eg, any RET inhibitor described herein or known in the art) for the viability of the cancer cell. In other examples, the level of resistance of a cancer cell to an RET inhibitor can be assessed by determining the growth rate of a cancer cell in the presence of a RET inhibitor (eg, any RET inhibitor described herein). In other examples, the level of resistance of a tumor to a RET inhibitor can be assessed by determining the mass or size of one or more tumors in a subject during treatment with a RET inhibitor (eg, any RET inhibitor described herein). In other examples, the level of resistance of a cancer cell or tumor to an RET inhibitor can be indirectly assessed by determining the activity of a RET kinase containing one or more mutations of resistance to RET inhibitors (i.e. the same RET kinase that is expressed in a cancer cell or tumor in the subject's body). The level of resistance of a cancer cell or tumor having one or more RET inhibitor resistance mutations to a RET inhibitor is assessed in relation to the level of resistance in a cancer cell or tumor that does not have a resistance mutation to RET inhibitors (for example, a cancer cell or tumor that does not have such the mutations of resistance to RET inhibitors, cancer cells or tumors that do not have any mutations of resistance to RET inhibitors, or cancer cells or tumors that express wild-type RET protein). For example, the determined level of resistance of a cancer cell or tumor having one or more resistance mutations to RET inhibitors may be greater than about 1%, more than about 2%, more than about 3%, more than about 4%, more than about 5 %, more than about 6%, more than about 7%, more than about

8%, more than about 9%, more than about 10%, more than about 11%, more than about 12%, more than about 13%, more than about 14%, more than about 15%, more than about 20% , more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 60%, more than about 70%, more more than about 80%, more than about 90%, more than about 100%, more than about 110%, more than about 120%, more than about 130%, more than about 140%, more than about 150%, more than about 160%, more than about 170%, more than about 180%, more than about 190%, more than about 200%, more than about 210%, more than about 220%, more than about 230%, more than about 240% more than about 250%, more than about 260%, more than about 270%, more than about 280%, more than about 290%, or more than about 300% of the level of resistance in a cancer cell or tumor that does not have a resistance mutation RET inhibitors (e.g. measures, a cancer cell or tumor that does not have the same resistance mutations to RET inhibitors, a cancer cell or tumor that does not have any resistance mutations to RET inhibitors, or a cancer cell or tumor that expresses wild-type RET protein). RET is thought to play an important role in the development and survival of afferent nociceptors in the skin and intestines. RET kinase knockout mice lack enteral neurons and have other nervous system abnormalities, suggesting the need for a functional RET kinase protein product during development (Taraviras, S. et al., Development, 1999, 126: 2785-2797 ). In addition, in population studies of patients with Hirschsprung's disease, characterized by obstruction of the colon due to the lack of normal energy supply to the colon, there is a higher proportion of both familial and sporadic RET mutations with loss of function (Butler Tjaden N., et al., Transl. Res. 2013, 162: 1-15). Irritable bowel syndrome (IBS) is a common disease affecting 10-20% of people in developed countries and is characterized by abnormal bowel movements, bloating and increased sensitivity (Camilleri, M., N. Engl. J. Med., 2012, 367: 1626-1635). Although the etiology of IBS is unknown, it is believed to be the result of impaired communication between the brain and the gastrointestinal tract, abnormalities in the gut microbiome, or increased inflammation. The resulting gastrointestinal changes interfere with normal intestinal transit, resulting in diarrhea or constipation. In addition, in many patients with IBS, sensitization of the peripheral nervous system leads to visceral hypersensitivity or allodynia (Keszthelyi, D., Eur. J. Pain, 2012, 16: 1444-1454).

- 124 035568

See, for example, US publication number 2015/0099762.

Accordingly, this document provides methods of treating a patient who is diagnosed with (or identified as having) irritable bowel syndrome (IBS), including a diarrhea-dominant, constipation-dominant or intermittent bowel movement, functional bloating, functional constipation, functional diarrhea , unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain and inflammatory bowel disease, which comprise administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. This document also provides methods of treating a patient who has been identified or diagnosed as having RET-associated irritable bowel syndrome (IBS) (e.g., a patient who has been identified or diagnosed as having RET-associated irritable bowel syndrome (IBS) using an approved regulatory body, for example, an FDA-approved kit for determining the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in the patient's body or a biopsy sample from the patient), which include administering to the patient a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt or solvate thereof.

Also provided herein are methods of treating pain associated with IBS that comprise administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with another therapeutic agent useful to treat one or more symptoms of IBS. Also provided are methods of treating irritable bowel syndrome (IBS) in a patient in need, comprising (a) determining if irritable bowel syndrome (IBS) in a patient is RET-associated with IBS (e.g., using an approved regulatory body, e.g., an FDA-approved kit for determining the dysregulation of the RET gene, RET kinase or their expression, or their activity, or the level of any of them in the patient's body or a biopsy sample from the patient, or by performing any of the non-limiting examples of analysis described herein); and (b) in the case of defining CPK as RET-associated CPK, administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds of this invention are useful for treating irritable bowel syndrome (IBS) in combination with one or more additional therapeutic agents or therapy options effective in treating irritable bowel syndrome that have the same or different mechanism of action. At least one additional therapeutic agent can be administered with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in one or separate dosage forms, one or different routes of administration and according to one or different administration regimens in accordance with standard pharmaceutical practice known to the skilled person in the art.

Non-limiting examples of additional therapeutic agents for irritable bowel syndrome (IBS) include probiotics, dietary fiber supplements (eg, psyllium, methylcellulose), antidiarrheals (eg, loperamide), bile acid binders (eg, cholestyramine, colestipol, colesevelam) , anticholinergics and antispasmodics (eg, hyoscyamine, dicyclomine), antidepressants (eg, a tricyclic antidepressant, such as imipramine or notriptyline, or a selective serotonin reuptake inhibitor (SSRI), such as fluoxetine, paroxetine, rifaximin), antibiotics (eg, alosetron and lyubiproston.

Accordingly, this document also provides methods of treating irritable bowel syndrome (IBS), comprising administering to a patient in need of a pharmaceutical combination for treating IBS that comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent and, (c) optionally, at least one pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for treating IBS, wherein the amounts of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are together effective in treating IBS. In one embodiment, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously in divided doses. In one embodiment, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent are administered in divided doses, sequentially in any order, in co-therapeutically effective amounts, for example, daily dosages or intermittently. In one embodiment of the invention, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and an additional therapeutic agent are administered simultaneously as a combined dosage.

In addition, this document provides (i) a pharmaceutical combination for the treatment of syn

- 125 035568 irritable bowel nucleus in a patient in need thereof, which contains (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) at least one additional therapeutic agent (for example, any of the typical additional therapeutic agents described in this document or known in the art), and, (c) optionally, at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of irritable bowel syndrome, the amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or the solvate and the complementary therapeutic agent are together effective in treating irritable bowel syndrome; (ii) a pharmaceutical composition containing such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of irritable bowel syndrome; and (iv) a commercial package or product containing such a combination as a combination preparation for simultaneous, separate or sequential use; and a method for treating irritable bowel syndrome in a patient in need thereof. In one embodiment, the patient is a human.

In the context of this document, the term pharmaceutical combination refers to a pharmaceutical therapeutic agent obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional therapeutic agent (eg, an agent effective in treating irritable bowel syndrome) is administered to a patient simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional therapeutic agent (e.g., an agent effective in treating irritable bowel syndrome) are formulated as separate compositions or dosages such that they can be to be administered to a patient in need thereof simultaneously, in parallel or sequentially at various intermediate intervals, such administration providing effective levels of two or more compounds in the patient's body. In one embodiment of the invention, the compound of Formula I and the additional therapeutic agent are formulated in separate unit dosage forms, the separate dosage forms being suitable for sequential or simultaneous administration. This also applies to cocktail therapy, for example, the administration of three or more active ingredients.

In some embodiments, a compound provided herein can be used as a maintenance agent for a patient undergoing cancer treatment. For example, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, can be used to reduce one or more symptoms associated with treatment with one or more anti-cancer therapy options, such as complications of diarrhea or constipation and / or abdominal pain. See, for example, U.S. Publication No. 2015/0099762 and Hoffman, J.M. et al. Gastroenterology (2012) 142: 844854. Accordingly, a compound or a pharmaceutically acceptable salt or composition provided herein can be administered to a patient to alleviate one or more complications associated with cancer treatment (eg, gastrointestinal complications such as diarrhea, constipation, or abdominal pain).

In some embodiments, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, can be administered to a patient undergoing cancer treatment (e.g., a patient experiencing adverse events associated with cancer treatment, such as immune adverse events or gastrointestinal complications, including diarrhea, constipation, and abdominal pain). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used to treat colitis or IBS associated with the administration of a checkpoint inhibitor; see, for example, Postow, M.A. et al. Journal of Clinical Oncology (2015) 33: 1974-1982. In some such embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be formulated to exhibit low bioavailability and / or target delivery to the gastrointestinal tract. See, for example, U.S. Patent No. 6,531,152.

Also provided is a method of inhibiting RET kinase activity in a cell, comprising contacting the cell with a compound of formula I. In one embodiment, the contacting occurs in vitro. In one embodiment of the invention, the contacting occurs in vivo. In one embodiment, the contacting occurs in vivo, the method comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a subject having a cell having RET kinase activity. In some embodiments, the cell is a cancer cell. In one embodiment, the cancer cell is any cancer described herein. In some embodiments, the cancer cell is a RET-associated cancer cell. In some embodiments, the cell is gastrointestinal

- 126 035568 intestinal cell. Also provided is a method for inhibiting RET kinase activity in a mammalian cell comprising contacting the cell with a compound of formula I. In one embodiment, the contacting occurs in vitro. In one embodiment of the invention, the contacting occurs in vivo. In one embodiment, the contacting takes place in vivo, the method comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a mammal having a cell having RET kinase activity. In some embodiments, the mammalian cell is a mammalian cancer cell. In one embodiment, the mammalian cancer cell is any cancer described herein. In some embodiments, the mammalian cancer cell is a RET-associated cancer cell. In some embodiments, the mammalian cell is a gastrointestinal cell.

In the context of this document, the term contacting refers to the bringing of the specified fragments in an in vitro system or in vivo system. For example, contacting a RET kinase with a compound provided herein includes administering a compound provided herein to an individual or patient, such as a human, having RET kinase as well as, for example, administering a compound provided herein. , into a sample containing a cellular or purified preparation containing RET kinase.

In addition, provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

The expression effective amount means the amount of a compound that, when administered to a patient in need of such treatment, is sufficient to (i) treat a RET-associated disease or disorder, (ii) ameliorate, ameliorate, or eliminate one or more symptoms of a particular disease, condition or disorder. or (iii) delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of formula I, which will correspond to this amount, will vary depending on factors such as the particular compound, the condition and severity of the disease, the individual characteristics (for example, the weight) of the patient in need of treatment, but it can be easily determined by a person skilled in the art. this field of technology.

When used as pharmaceuticals, the compounds of Formula I may be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered in a variety of ways, depending on whether topical or systemic treatment is desired and the area to be treated. Administration can be local (including transdermal, epidermal, ophthalmic and mucosal delivery, including intranasal, vaginal and rectal), pulmonary (for example, by inhalation or insufflation of powders or aerosols, including by means of a nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration may include the use of a dosage form formulated to be administered once a day or twice a day (BID). Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, for example, intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or can be carried out, for example, using a continuous perfusion pump. Pharmaceutical compositions and formulations for topical use may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powdery or oily bases, thickeners, and the like may be necessary or desirable.

This document also provides pharmaceutical compositions which contain, as an active ingredient, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In the preparation of the compositions provided herein, the active ingredient is usually mixed with an excipient, diluted with an excipient, or enclosed in such a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a stock solution, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, starch capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in the form of a solid or in a liquid medium), ointments containing, for example, up to 10 wt% active compound, soft and hard gelatine capsules, suppositories, sterile injectable solutions and sterile packaged powders. In one embodiment, the composition is formulated for oral administration.

- 127 035568

In one embodiment, the composition is formulated as a tablet or capsule.

Compositions containing a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, may be formulated in unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more typically from about 100 to about 500 mg, of the active ingredient. The term dosage unit form refers to physically discrete units suitable as unitary dosages for humans and other patients, each unit containing a predetermined amount of active material (i.e., the compound for Formula I provided herein) calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One skilled in the art will understand that this range includes compounds or compositions containing from about 5 to about 10 mg, from about 10 to about 15 mg, from about 15 to about 20 mg, from about 20 to about 25 mg, from about 25 to about 30 mg, about 30 to about 35 mg, about 35 to about 40 mg, about 40 to about 45 mg, or about 45 to about 50 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One of ordinary skill in the art will understand that this range includes compounds or compositions containing from about 50 to about 100 mg, from about 100 to about 150 mg, from about 150 to about 200 mg, from about 200 to about 250 mg, from about 250 to about 300 mg, about 350 to about 400 mg, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about 500 mg to about 1000 mg of the active ingredient. One of ordinary skill in the art will understand that this range includes compounds or compositions containing from about 500 to about 550 mg, from about 550 to about 600 mg, from about 600 to about 650 mg, from about 650 to about 700 mg, from about 700 to about 750 mg, about 750 to about 800 mg, about 800 to about 850 mg, about 850 to about 900 mg, about 900 to about 950 mg, or about 950 to about 1000 mg of the active ingredient.

The active compound can be effective over a wide range of dosages and is usually administered in a pharmaceutically effective amount. However, it should be understood that the actual amount of compound administered will be determined by the physician, taking into account the relevant circumstances, including the pathological condition to be treated, the mode of administration chosen, the actual compound or compounds administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms, etc.

In some embodiments, the compounds provided herein can be administered in an amount of from about 1 to about 100 mg / kg. In some embodiments, a compound provided herein can be administered in an amount of about 1 to about 20 mg / kg, about 5 to about 50 mg / kg, about 10 to about 40 mg / kg, about 15 to about 45 mg / kg, about 20 to about 60 mg / kg, or about 40 to about 70 mg / kg. For example, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 mg / kg. In some embodiments, such administration may be a once daily or twice daily (BID) administration. Provided herein are pharmaceutical kits useful, for example, in the treatment of RET-associated diseases or disorders, such as cancer or irritable bowel syndrome (IBS), which contain one or more containers containing a pharmaceutical composition containing a therapeutically effective amount of a compound provided herein. Such kits may additionally contain, if necessary, one or more different components of conventional pharmaceutical kits, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be obvious to those skilled in the art. ... The kit may also include instructions in the form of inserts or labels indicating the amount of components to be administered, instructions for use and / or guidelines for mixing the components.

One of ordinary skill in the art will appreciate that in vivo and in vitro studies using suitable, known and accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

The person skilled in the art will also understand that clinical studies in humans, including primary studies in humans, dose range studies and efficacy studies in healthy patients and / or patients with a given disorder, can be performed in accordance with methods well known in clinical and medical practice.

- 128 035568

Examples of

The following examples illustrate this invention.

Biological examples.

Example A.

Enzyme RET Assay.

Compounds of formula I were screened for their ability to inhibit wild type RET kinase and V804M mutated RET kinase using CisBio's HTRF® KinEASE ™ -TK assay. Briefly, N-terminal GST-labeled recombinant human RET cytoplasmic domain (a.c. 658-end) from Eurofins (0.25 nM RET; cat # 14-570M) or N-terminal GST-labeled human RET cytoplasmic domain with mutation V804M (a.c. 658-end) from Millipore (0.25 nM enzyme; cat # 14-760) was incubated with 250 nM TK biotin substrate (CisBio, part # 62TK0PEC) and 1 mM ATP together with the test compound in a buffer consisting of 25 mM HEPES pH 7.4, 10 mM MgCl ₂ , 0.01% Triton X-100 and 2% DMSO in a volume of 8 μl. Compounds are usually prepared in three-fold serial dilution in DMSO and added to the assay to obtain the appropriate final concentration. After a 30 minute incubation at 22 ° C, the reaction was quenched by the addition of 8 μl of a quench solution containing 31.25 nM Sa-XL665 and 1XTK-ab-Cryptate in HTRF detection buffer (all from CisBio, part # 62TK0PEK). After 1 h incubation at 22 ° C, the degree of reaction was determined using a PerkinElmer EnVision multimode plate reader by HTRF detection at two wavelengths, and the percentage of control (POC) was calculated using the ratiometric emission factor. 100 POA was determined without the use of the test compounds, and 0 POA was determined using previously quenched control reactions. The POK values were fitted with a 4-parameter logistic curve, and the IC _{50 was} defined as the concentration of inhibitor at which the POK is 50 for the fit curve. The IC ₅₀ values for the compounds tested in this assay are presented in table. five.

Example B.

Cellular RET Assay.

The cellular activity of the RET kinase inhibiting compound was determined in HEK-293 cells expressing the Kif5b-RET fusion protein. Briefly, HEK-293 cells expressing the Kif5b-RET fusion protein were seeded at 50,000 cells / well in 96-well poly-E-lysine coated plates the day before assay. The cells were incubated for 1 h with the test compound in DMEM (Dulbecco's Modified Eagle's Medium) at a final DMSO concentration of 0.5%. Compounds are usually prepared in three-fold serial dilution in DMSO and added to the assay to obtain the appropriate final concentration. After 1 h, the medium was removed, the cells were fixed with 3.8% formaldehyde for 20 min, washed with PBS, and permeabilized for 10 min with 100% methanol. Then the plates were washed with PBS-0.05% Tween 20 and blocked with a blocking solution LI-COR (catalog LI-COR, no. 927-40000) for 1 hour. The plates were washed with PBS-0.05% Tween 20, then incubated with antibodies against phospho-RET (Tyr1062) (Santa Cruz catalog # sc-20252-R) and anti-GAPDH antibody (Millipore catalog # MAB374) for 2 hours. Plates were washed with PBS-0.05% Tween 20 and incubated with anti-rabbit 680 ( Molecular Probes catalog, # A21109) and anti-mouse 800 (LI-COR catalog, # 92632210) secondary antibodies for 1 hour. All antibodies were diluted in LI-COR blocking solution containing 0.05% Tween. The plates were washed with PBS-0.05% Tween 20, 100 μL of PBS was added to each well and the plates were read on a LI-COR Aerius fluorescent plate reader. The phospho-RET signal was normalized to the GAPDH signal. 100 POA (percentage of control) was determined without the use of test compounds, and 0 POA was determined using 1 μM control inhibitor. The POC values were fitted with a 4-parameter logistic curve. The IC ₅₀ value corresponds to the point at which the curve crosses the 50 POC. The IC ₅₀ values for the compounds tested in this assay are presented in table. five.

Example C.

Analysis of the RET G810R mutant.

The potency of a compound inhibiting RET kinase with a mutation of G810R was determined using the CisBio HTRF Kinease TK assay method. Samples for analysis contained RET with the G810R mutation, manufactured by Array Biopharma, Inc. (1 nM enzyme - p1982 lot # 160713. Kinase was incubated with 250 nM TK substrate biotin (CisBio, part # in catalog 62TK0PEC) and 1 mM ATP together with the test compound in a buffer consisting of 25 mM HEPES, pH 7.4, 10 mM MgCl ₂ , 0.01% Triton X-100 and 2% DMSO in a volume of 8 μl Compounds were usually prepared as a three-fold serial dilution in DMSO and added to the assay to obtain the appropriate final concentration. After 60 minutes incubation at 22 ° C, the reaction quenched by the addition of 8 μl of quench solution containing 31.25 nM Sa-XL665 and 1xTK-Ab-Cryptate in HTRF detection buffer (all from CisBio Part # 62TK0PEC) After 1 hour incubation at 22 ° C. the degree of response using a PerkinElmer EnVision multimode plate reader by HTRF detection at two wavelengths, and the percentage of control (POC) was calculated using the ratiometric emission factor.

- 129 035568 was determined without the use of the test compounds, and 0 POK was determined using previously quenched control reactions. The POC values were fitted to a 4-parameter logistic curve as a function of compound concentration, and the IC ₅₀ value corresponded to the point at which the best fit curve intersected the 50 POC.

Table 5

The IC _{50 of the} compounds tested in the assay c. examples A, B and C

Example p # RET enzyme (wild type) 1C ₅₀ (nM) RET enzyme (V804M) IC50 (nM) 1C ₅₀ cells KIF5BRET PTYR1062 (nM) RET enzyme (G810R) IC50 (nM) 1 24.0 145.2 1074.2 N / A 2 32.1 176.2 70.3 202.3 3 16.1 90.2 37.8 N / A 4 92.1 10000.0 437.2 N / A five 15.4 66.9 30.8 N / A 6 16.8 61.8 22.4 N / A 7 25.2 141.4 23.3 N / A 8 66.2 315.7 95.2 N / A nine 14.9 95.8 32.6 N / A ten 110.1 492.8 N / A N / A eleven 42.5 143.1 89.7 N / A 12 9.5 46.6 24.0 N / A 13 19.2 95.6 38.6 N / A fourteen 165.4 1135.1 N / A N / A 15 264.0 1839.1 N / A N / A sixteen 14.1 45.0 133.9 N / A 17 18.1 62.8 And, 8 N / A 18 11.7 116.4 37.4 N / A nineteen And, 4 40.0 40.6 N / A 20 30.9 127.7 39.4 N / A 21 20.2 94.2 14.5 255.1 22 50.3 239.1 100.2 N / A

- 130 035568

23 39.9 463.1 111.5 N / a 24 31.0 241.5 99.7 611.3 25 258.8 1693.0 n / a N / a 26 4048.1 5174.2 n / a N / a 27 3545.8 10000.0 n / a N / a 28 1314.8 10000.0 N / a N / a 29 345.1 2124.0 n / a N / a thirty 433.8 4733.4 n / a N / a 31 13.5 88.2 26.5 N / a 32 69.6 409.7 85.6 N / a 33 9.9 88.1 21.1 N / a 34 19.7 138.2 19.9 N / a 35 209.8 1263.8 n / a N / a 36 62.4 534.0 120.0 N / a 37 80.4 963.4 160.5 N / a 38 353.4 3915.7 n / a N / a 39 15.1 97.2 23.5 N / a 40 63.2 802.4 193.7 N / a 41 25.2 208.7 54.1 N / a 42 33.0 188.5 107.8 N / a 43 25.9 59.1 1991.1 N / a 44 54.5 396.5 175.0 N / a 45 138.2 901.3 N / a N / a 46 60.8 735.8 88.6 N / a 47 29.5 239.7 50.5 N / a 48 22.1 44.3 5.4 182.4 49 12.5 101.3 24.1 N / a 50 12.6 60.7 18.9 N / a 51 14.0 62.0 46.6 N / a 52 15.4 80.6 59.8 N / a 53 15.6 181.0 54.8 N / a 54 16.6 84.4 40.8 N / a 55 17.2 89.1 202.1 N / a 56 20.3 222.0 99.6 N / a 57 22.3 131.0 92.1 N / a 58 23.2 225.2 68.0 N / a 59 24.3 147.6 95.0 N / a 60 32.4 220.9 125.1 N / a 61 34.6 254.8 129.3 N / a 62 38.1 253.9 133.7 N / a 63 18.5 67.1 12.9 550.1 64 73.1 644.9 241.3 N / a 65 208.7 1451.6 N / a N / a 66 54.6 250.1 157.2 N / a 67 6588.9 10000.0 N / a N / a 68 166.2 1329.1 N / a N / a 69 222.7 678.9 N / a N / a 70 469.9 3978.2 N / a N / a

- 131 035568

71 56.4 341.5 165.7 N / a 72 36.3 271.3 89.0 N / a 73 107.8 601.8 N / A N / a 74 76.3 492.4 287.0 N / a 75 128.2 768.6 N / A N / a 76 133.0 656.6 N / A N / a 77 277.0 1133.2 N / A N / a 78 180.1 920.8 N / A N / a 79 241.6 968.2 N / A N / a 80 1212.3 5647.2 N / A N / a 81 728.9 4512.1 N / A N / a 82 2656.5 8939.1 N / A N / a 83 72.7 410.3 382.8 N / a 84 124.1 748.4 N / A N / a 85 209.6 1003.6 n / a N / a 86 120.8 696.6 N / A N / a 87 215.6 1075.5 N / a N / a 88 34.3 151.2 30.0 N / a 89 261.7 1190.6 N / a N / a 90 454.6 1712.2 N / a N / a 91 163.3 764.6 N / a N / a 92 32.2 152.5 35.9 N / a 93 157.5 771.8 N / a N / a 94 88.1 702.5 370.6 N / a 95 136.6 952.6 N / a N / a 96 62.8 593.9 271.5 N / a 97 39.1 255.9 90.1 487.0 98 21.4 152.1 269.8 N / a 99 20.0 125.2 20.7 N / a one hundred 14.1 91.3 43.4 N / a 101 60.4 465.3 346.3 N / a 102 69.0 535.9 149.7 N / a 103 95.2 786.8 224.0 N / a 104 476.6 3574.3 N / a N / a 105 45.4 237.2 138.3 N / a 106 33.3 360.8 58.5 N / a 107 47.2 457.7 67.4 N / a 108 54.6 543.1 102.95 N / a 108 25.2 n / a 91,7 N / a BY 8.1 18.5 4.5 90.0 111 16.4 74.9 10.5 N / a 112 25.7 162.9 40.4 N / a 113 614.9 4754.7 N / a N / a 114 109.9 843.6 N / a N / a 115 15.0 70.5 16.6 54.3 116 103.8 1255.1 221.8 N / a 117 51.6 322.0 135.9 N / a 118 19.2 103.8 32.8 N / a

- 132 035568

119 32.1 147.9 48.3 n / a 120 37.3 275.1 72.3 N / A 121 34.3 181.8 20.3 N / a 122 80.4 790.4 213.8 N / a 123 36.8 276.9 50.0 N / a 124 152.6 1075.5 294.6 N / a 125 27.5 310.4 69.2 N / a 126 91.5 708.9 181.3 N / a 127 41.9 228.5 201.5 N / a 128 10.2 24.0 2.5 575.7 129 21.6 179.2 24.1 N / a 130 30.9 183.7 20.1 n / a 131 41.5 422.5 113.5 N / a 132 256.3 1332.2 593.3 n / a 133 124.4 914.8 n / a n / a 134 33.1 398.3 109.7 N / a 135 77.0 756.1 173.9 n / a 136 13.1 26.1 3.9 386.6 137 43,7 252.0 27.1 n / a 138 41.9 360.9 87.7 N / a 139 237.5 1733.1 N / A n / a 140 23.5 219.7 96.2 n / a 141 85.5 651.3 159.0 n / a 142 51.0 319.0 59.1 n / a 143 36.3 276.0 46.5 n / a 144 39.3 220.6 37.4 N / a 145 55.1 560.5 115.5 N / a 146 113.7 712.2 N / A N / a 147 84.2 867.7 256.2 N / a 148 144.5 1206.0 N / A N / a 149 49.4 328.1 100.8 N / a 150 432.5 5390.5 N / A N / a 151 490.4 5556.6 n / a N / a 152 122.8 1986.9 n / a N / a 153 36.7 283.5 69.7 N / a 154 26.2 180.3 26.8 N / a 155 28.0 146.1 45.0 N / a 156 31.9 157.6 20.5 N / a 157 35.0 346.0 72.3 N / a 158 100.6 703.4 130.9 N / a 159 270.8 1356.1 N / A N / a 160 34.8 397.3 86.6 N / a 161 86.3 634.0 119.6 N / a 162 67.0 562.6 246.7 N / a 163 14.0 24.1 4.2 530.7 164 18.6 154.0 22.1 N / a 165 25.3 123.1 21.6 N / a 166 29.3 84.2 22.6 N / a

- 133 035568

167 35.3 320.9 89.5 N / a 168 50.4 212.9 50.8 N / a 169 63.0 299.4 109.3 N / a 170 68.6 426.2 146.2 N / a 171 144.4 912.1 n / a N / a 172 268.6 1788.4 N / A N / a 173 46.9 244.2 44.8 N / a 174 13.3 52.2 6.8 847.2 175 19.9 37.9 2.9 N / a 176 24.5 74.5 Yu, 1 N / a 177 134.4 839.7 N / A N / a 178 28.4 79.8 12.2 N / a 179 32.1 110.8 25.4 N / a 180 23.2 63.2 15.7 N / a 181 91.0 674.8 165.4 N / a 182 634.3 3688.8 N / A N / a 183 15.1 34.1 6.4 472.6 184 21.6 82.5 17.0 3097.4 185 27.0 185.2 36.6 N / A 186 20.2 149.0 36.9 n / a 187 56.2 499.6 254.5 N / a 188 69.2 692.5 160.5 N / a 189 82.7 789.6 211.3 N / a 190 443.6 5301.9 N / A N / a 191 37.3 207.3 111.6 N / a 192 12.3 282.3 44.7 N / a 193 38.3 372.5 38.6 N / a 194 57.8 610.2 106.8 N / a 195 30.5 178.1 73.6 N / a 196 78.1 567.2 238.3 N / a 197 149.4 1533.8 N / A N / a 198 59.1 356.1 193.0 N / a 199 50.3 449.9 91.5 N / a 200 461.7 5324.1 N / A N / a 201 59.0 273.6 90.0 N / a 202 278.2 2284.8 N / A N / a 203 253.6 3034.5 n / a N / a 204 103,7 581.8 131.7 N / a 205 18.2 89.0 And, 7 N / a 206 61.3 519.1 78.0 N / a 207 27.4 123.0 18.8 N / a 208 33.3 234.5 40.4 N / a 209 41.3 288.1 39,7 N / a 210 34.5 196.7 57.2 786.7 211 113.5 901.6 N / A N / a 212 222.7 2022.5 N / A N / a 213 25.2 253.7 78.3 N / a 214 54.4 338.0 148.8 N / a

- 134 035568

215 108.5 753.1 N / A N / A 216 29.1 211.8 73.3 N / A 217 27.0 189.9 68.4 N / A 218 85.6 499.9 194.1 N / A 219 77.8 423.7 92.3 N / A 220 101.8 661.0 181.7 N / A 221 54.9 293.0 55.0 N / A 222 40.8 273.9 40.9 N / A 223 57.1 438.6 62.1 N / A 224 125.7 1033.3 N / A N / A 225 56.7 447.9 101.7 N / A 226 36.3 382.8 95.6 N / A 227 49.8 379.7 76.3 N / A 228 45.3 388.9 76.4 N / A 229 100.0 946.3 124.3 N / A 230 908.8 9120.4 N / A N / A 231 398.9 2999.9 N / A N / A 232 41.9 223.7 60.0 N / A 233 194.3 1040.2 N / A N / A 234 533.5 4156.4 N / A N / A 235 306.4 3651.1 N / A N / A 236 348.3 3801.2 N / A N / A 237 37.7 213.2 28.7 N / A 238 42.4 347.8 87.5 N / A 239 48.9 498.9 125.6 N / A 240 62.4 566.0 137.0 N / A 241 69.6 560.0 142.1 N / A 242 30.5 161.4 21.3 N / A 243 46.3 150.4 70.2 N / A 244 107.4 476.9 N / A N / A 245 543.5 10000.0 N / A N / A 246 413.8 7839.8 N / A N / A 247 49.6 324.3 33.8 N / A 248 21.8 42.0 7.3 N / A 249 10.6 37.3 8.1 N / A 250 19.8 62.6 10.5 N / A 251 35.0 222.7 22.1 1828.5 252 29.9 59.0 10.9 3738.7 253 51.3 1141.8 85.5 N / A 254 14.8 85.7 36.8 104.5 255 14.4 128.3 22.2 80.1 256 39.3 512.3 445.1 N / A 257 483.3 6165.2 N / A N / A 258 660.5 1914.1 N / A N / A 259 74.9 930.5 251.5 N / A 260 240.5 3455.9 N / A N / A 261 30.7 61.4 10.7 58.7 262 92.8 549.5 58.9 872.3

- 135 035568

263 93.2 1133.3 173.0 N / a 264 117.2 1326.1 n / a 938.2 265 156.5 1451.0 n / a N / a 266 643.9 3333.3 n / a N / a 267 121.7 1293.1 n / a N / a 268 2835.2 8899.5 n / a N / a 269 3789.0 10000.0 n / a N / a 270 271.5 2977.8 1667.0 N / a 271 514.0 4965.8 n / a N / a 272 69.8 982.3 673.4 N / a 273 109.4 1109.1 N / A N / a 274 223.4 1756.1 n / a N / a 275 965.2 9236.5 n / a N / a 276 63.2 274.7 64.3 N / a 277 9.7 80.8 76.6 N / a 278 35.6 237.8 47.3 N / a 279 64.9 704.7 136.8 N / a 280 10.2 90.4 9.0 N / a 281 9.4 19.3 5.4 N / a 282 20.0 49.1 8.1 N / a 283 31.9 107.5 8.1 N / a 284 13.8 55.5 13.3 N / a 285 13.1 84.9 24.1 N / a 286 28.9 150.9 27.7 N / a 287 17.9 121.9 30.1 N / a 288 26.5 215.5 47.3 N / a 289 36.8 209.1 54.8 N / a 290 52.2 393.1 84.6 N / a 291 43.4 547.9 86.2 N / a 292 43.8 177.8 99.8 N / a 293 47.7 487.0 129.3 N / a 294 59.3 430.5 134.2 N / a 295 53.4 181.3 195.8 N / a 296 83.7 448.4 300.8 N / a 297 102.3 1091.2 787.6 N / a 298 33.9 234.8 31.4 N / a 299 33.5 302.0 29.5 N / a 300 31.0 257.6 50.2 N / a 301 24.0 181.0 113.1 N / a 302 65.1 504.4 158.5 N / a 303 75.0 605.4 264.1 N / a 304 100.2 652.5 383.3 N / a 305 108.1 680.5 N / A N / a 306 125.4 881.5 n / a N / a 307 229.0 1552.5 n / a N / a 308 255.8 2199.0 n / a N / a 309 140.5 1056.1 N / a N / a 310 319.2 3631.3 n / a N / a

- 136 035568

311 117.4 215.0 n / a N / a 312 20.8 287.9 26.1 N / a 313 13,7 132.1 9.2 N / a 314 28.9 308.4 36.1 N / a 315 9.6 23.2 4.9 N / a 316 31.9 221.4 38.2 N / a 317 20.7 196.6 44.3 N / a 318 69.5 345.6 142.7 N / a 319 53.5 674.9 166.2 N / a 320 88.8 701.8 1667.0 N / a 321 94.7 757.0 1667.0 N / a 322 223.4 1490.6 N / A N / a 323 9.9 21.6 4.0 N / a 324 11.4 15.5 10.9 N / a 325 24.2 103.6 27.8 N / a 326 41.1 368.2 78.8 N / a 327 94.7 517.6 314.1 N / a 328 82.4 586.8 444.5 N / a 329 106.7 337.0 N / A N / a 330 45.4 372.1 93.2 N / a 331 9.4 30.8 10.3 N / a 332 14.6 75.5 24.4 N / a 333 29.4 218.1 33.2 N / a 334 38.5 251.0 46.0 N / a 335 39.4 218.5 47.1 N / a 336 45.3 334.8 164.0 N / a 337 12.6 30.0 4.6 N / a 338 33.6 568.2 70.4 N / a 339 51.7 756.7 236.9 N / a 340 65.1 582.7 769.3 N / a 341 79.2 397.2 1667.0 N / a 342 63.8 309.7 1667.0 N / a 343 55.3 329.9 970.1 N / a 344 65.6 552.2 175.1 N / a 345 26.8 140.5 37.5 N / a 346 35.2 172.7 45.9 N / a 347 77.9 832.3 161.1 N / a 348 183.9 1196.6 N / A N / a 349 55,7 348.7 260.8 N / a 350 77.2 225.7 96.1 N / a 351 313.9 2730.6 N / A N / a 352 2379.9 10000.0 N / A N / a 353 89.3 570.5 128.6 N / a 354 3347.1 10000.0 N / A N / a 355 405.4 5472.6 n / a N / a 356 242.1 2291.9 n / a N / a 357 154.1 2082.0 n / a N / a 358 50.3 710.0 150.6 N / a

- 137 035568

359 60.7 1477.2 100.2 N / a 360 190.6 2393.4 n / a N / a 361 62.5 288.0 102.7 N / a 362 170.0 732.6 N / A N / a 363 31.7 88.9 24.8 N / a 364 257.3 1895.7 N / A N / a 365 47.8 187.1 61.0 N / a 366 22.3 47.5 19.3 N / a 367 109.1 1098.7 N / A N / a 368 19.8 47.2 30.3 N / a 369 16.2 36.9 12.1 N / a 370 19.4 56.5 13.5 N / a 371 28.9 147.3 35,7 N / a 372 33.9 78.7 35,7 N / a 373 277.5 2974.6 N / A N / a 374 581.6 6256.9 n / a N / a 375 113.1 1561.6 n / a N / a 376 164.8 2788.1 n / a N / a 377 69.9 977.2 149.0 N / a 378 110.3 1374.6 N / A N / a 379 474.9 4809.7 n / a N / a 380 127.5 1994.2 n / a N / a 381 147.5 1714.8 n / a N / a 382 31.2 134.0 28.9 N / a 383 32.8 257.8 55.3 N / a 384 77.4 598.8 381.7 N / a 385 59.5 401.8 112.0 N / a 386 193.8 2911.9 N / A N / a 387 355.0 4202.6 n / a N / a 388 72.6 551.6 223.5 N / a 389 44.3 236.7 50.2 N / a 390 69.2 621.2 231.1 N / a 391 459.9 5367.8 N / A N / a 392 170.9 3419.8 n / a N / a 393 706.7 7376.4 n / a N / a 394 111.6 887.1 n / a N / a 395 365.2 2494.9 n / a N / a 396 110.9 1859.9 n / a N / a 397 75.6 668.0 51.9 N / a 398 197.0 3411.4 N / A N / a 399 86.8 1309.2 129.2 N / a 400 110.0 1427.0 N / A N / a 401 94.9 1249.8 261.5 N / a 402 114.1 1349.6 N / A N / a 403 50.3 738.7 105.0 N / a 404 293.8 6841.7 N / A N / a 405 48.2 331.7 70.0 N / a 406 46.5 299.7 46.2 N / a

- 138 035568

408 159.2 3136.0 N / A n / a 409 502.1 5012.6 N / A N / A 410 69.6 1038.4 1667.0 N / a 411 264.3 2912.5 1667.0 N / a 412 184.1 2524.7 N / A N / a 413 388.6 3712.7 N / A N / a 414 298.0 3136.0 990.0 N / a 415 61.6 767.8 146.5 N / a 416 14.1 48.3 9.3 N / a 417 109.3 974.6 N / A N / a 418 340.4 3890.4 N / A N / a 419 402.4 5308.7 N / A N / a 420 280.2 4516.5 N / A N / a 421 135.3 685.8 N / A N / a 422 27.4 101.6 256.9 N / a 423 15.0 82.9 13,7 N / a 424 102.3 736.4 N / A N / a 425 21.2 162.0 49.7 3238.7 426 24.5 157.0 23.5 1489.0 427 38.7 448.8 51.1 3764.4 428 24.1 135.4 33.4 1742.5 429 38.5 452.6 34.2 5466.1 430 45.1 333.2 25.1 4137.1 431 4.5 12.3 2.4 N / a 432 29.5 155.5 20.8 N / a 433 14.2 28.4 3.3 246.8 434 9.3 18.1 2.8 N / a 435 9.5 25.0 6.5 N / a 436 34.3 117.9 And, 5 351.1 437 19.0 138.8 And, 1 278.0 438 10.4 53.4 5.2 104.8 439 22.6 47.0 5.7 128.1 440 13.2 32.6 36.4 N / a 441 45.3 433.6 63.2 N / a 442 13.8 21.5 2.0 100.6 443 6.5 11.9 0.8 N / a 444 7.8 16.1 3.6 68.5 445 8.2 24.0 2.5 N / a 446 9.5 44.7 10.0 119.7 447 18.2 32.1 2.7 213.4 448 9.6 20.4 94.5 N / a 449 11.9 28.7 2.9 400.8 450 11.4 31.3 12.6 112.7 451 8.3 14.7 7.6 52.4 452 12.4 28.4 2.9 281.7 453 9.2 29.3 227.2 n / a 454 16.3 47.9 8.2 1938.2 455 23.2 53.3 5.5 904.7

- 139 035568

456 14.7 30.0 6,7 N / a 457 22.4 35.4 2.8 521.9 458 59.0 210.4 29.7 4116.7 459 10.6 56.1 15.5 123.0 460 12.9 27.4 2,3 207.5 461 5.6 16.4 90.8 N / a 462 9.0 11.9 17.5 84.8 463 22.8 158.5 256.1 N / a 464 38.8 252.8 61.3 N / a 465 48.5 289.1 103.2 N / a 466 9.7 46.4 19.3 N / a 467 13.5 31.8 10.2 N / a 468 4.8 10.2 6.0 N / a 469 12.0 27.3 17.6 N / a 470 5.5 10.4 4.0 41.0 471 18.3 29.5 10.6 175.3 472 14.5 77.0 30.1 N / a 473 17.4 58.4 8.2 642.2 474 33,7 88.3 22.1 N / a 475 20.0 50.0 3.4 252.5 476 20.0 55.1 21.3 N / a 477 35.4 95.0 28.9 N / a 478 18.3 39.9 3.2 208.3 479 12.6 51.4 10.4 242.0 480 7.4 29.3 8.3 n / a 481 28.4 65.4 18.8 N / a 482 9.1 22.9 25.9 N / a 483 19.4 28.3 6.8 159.2 484 38.2 75.2 14.4 814.4 485 289.6 4217.1 n / a N / a 486 21,7 162.4 101.8 N / a 487 64.7 632.9 134.6 N / a 488 80.7 321.9 144.4 N / a 489 12.5 35.9 2.7 614.5 490 28.2 67.5 13.2 N / a 491 19.7 75.5 38.0 N / a 492 86.1 518.8 122.8 N / a 493 15.3 74.6 35.2 N / a 494 76.8 269.4 195.4 N / a 495 20.6 139.9 37.5 N / a 496 30.1 114.1 34.8 N / a 497 23.5 115.9 29.3 N / a 498 41.4 48.9 57.3 N / a 499 42.5 70.2 49.5 N / a 500 170.3 325.4 n / a N / a 501 102.4 298.9 100.7 N / a 502 487.6 931.3 n / a N / a 503 692.5 6084.2 n / a N / a

- 140 035568

504 25 140 88 > 10000 505 256 4286 ΝΑ 2662 506 213 638 ΝΑ 3427 507 ten 77 15 79 508 28 117 64 143 509 fourteen 91 ΝΑ 147 510 18 111 ΝΑ 192 511 61 514 ΝΑ 841 512 38 224 ΝΑ 380 513 276 2250 ΝΑ 3009 514 572 2430 ΝΑ 2231 515 108 1122 ΝΑ 1990 516 93 885 ΝΑ 1117 517 295 1766 ΝΑ 2474 518 28 579 192 476 519 235 2386 ΝΑ 1487 520 730 5111 ΝΑ 6810 521 78 695 170 1329 522 81 695 ΝΑ 1290 523 51 483 96 473 524 314 2114 ΝΑ 2780 525 1415 3518 ΝΑ 3633 526 90 817 ΝΑ 997 527 292 4765 ΝΑ 2041 528 148 1541 ΝΑ 1392 529 66 584 73 839 530 70 698 94 941 531 58 1322 176 2327 532 301 5330 ΝΑ 8885 533 124 767 ΝΑ 876 534 104 625 ΝΑ 1051 535 18 54 sixteen 1534 536 43 256 18 1761 537 371 5945 ΝΑ ΝΑ 538 172 1489 ΝΑ ΝΑ 539 35 250 127 ΝΑ 540 72 559 210 ΝΑ 541 170 1253 ΝΑ ΝΑ 542 12 150 18 229 543 7 31 nine 102 544 4 28 8 65 545 12 74 51 1136 546 23 77 28 284 547 five sixteen five 39 548 17 153 35 374 549 ten 144 13 535 550 12 62 17 433 551 3 eleven 7 323

- 141 035568

552 1 7 15 101 553 2 eleven 39 153 554 nineteen 207 28 727 555 nineteen 114 33 868 556 4 91 162 153 557 2529 1372 NA 3679 558 230 585 NA 3621 559 ten 88 23.8 301.8 560 43.5 334.7 105.35 1462.9 561 165.3 972.7 292.65 2461.5

N / A = not available.

Synthetic examples.

Synthesis of intermediates.

Intermediate P1.

4-Bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile.

Part A: Preparation of O- (mesitylsulfonyl) hydroxylamine.

Stage 1: obtaining tert-butyl (mesitylsulfonyl) oxycarbamate. To a solution of 2,4,6trimethylbenzene-1-sulfonyl chloride (10.0 g, 45.72 mmol) and tert-butyl hydroxycarbamate (6.088 g, 45.72 mmol) in MTBE (100 ml) at 0 ° C was added TEA (14, 46 ml, 48.01 mmol) dropwise with stirring. The resulting suspension was stirred at 0 ° C for an additional 30 min and then warmed to ambient temperature, Then the reaction mixture was diluted with water (100 ml), brought to pH 4 with 1N. HC1 ( _VODN .). The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound first as a yellowish oil which, after drying overnight under high vacuum, became a white solid (12.89 g, 89% yield).

¹ H NMR (CDCl3) δ 7.66 (br s, 1H), 6.98 (s, 2H), 2.67 (s, 6H), 2.32 (s, 3H), 1.31 (s , 9H).

Stage 2: preparation of O- (mesitylsulfonyl) hydroxylamine. To TPA (117 ml, 1521 mmol) at 0 ° C was slowly added tert-butyl (mesitylsulfonyl) oxycarbamate (39.0 g, 124 mmol) over 25 min. The reaction mixture was stirred at 0 ° C for 1.5 h and then quenched by successive addition of crushed ice and water. The resulting thick slurry was vigorously stirred at ambient temperature for 5 minutes. Without allowing the filter cake to dry, the solid was collected by careful filtration under reduced pressure followed by washing with water (4 L) until the filtrate reached pH 6 (Caution: Risk of dry compound explosion at ambient temperature). The wet filter cake was dissolved in DCM (150 ml) and the resulting biphasic solution was separated. The DCM layer was dried over MgSO ₄ for 30 min and then filtered and washed with DCM (420 ml) to give the title compound as a 0.22M solution in DCM.

Part B: Preparation of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: Preparation of 2,4,6-trimethylbenzenesulfonate of 1-amino-3-bromo-5-methoxypyridinium. To a solution of O- (mesitylsulfonyl) hydroxylamine (part A, 26.6 g, 117 mmol) in DCM (570 ml) cooled to 0 ° С, 3-bromo-5-methoxypyridine (22.1 g, 117 mmol ). The reaction mixture was stirred for 1 h at 0 ° C, then additionally 3-bromo-5-methoxypyridine (250 mg, 1.39 mmol) was added and stirred for an additional 2 h at 0 ° C. The reaction mixture was diluted with Et ₂ O (600 ml), stirred at 0 ° C for 10 min, and then filtered under reduced pressure, washed with Et ₂ O (3x250 ml). With a decrease in volume of about 1/3, the filtrate gives additional precipitate which was collected by filtration. Both filter cakes were dried under reduced pressure to give the title compound (39.3 g, 83% yield).

1H NMR (CDCl ₃ ) δ 9.25 (br s, 1H), 8.99 (m, 1H), 8.74 (m, 1H), 7.46 (m, 1H), 6.83 (s , 2H), 3.92 (s, 3H) 2.65 (s, 6H), 2.22 (s, 3H).

Step 2: Preparation of ethyl 6-bromo-4-methoxypyrαzolo [1,5-a] pyridine-3-carboxylate and ethyl 4-bromo6-methoxypyrαzolo [1,5-a] pyridine-3-carboxylate. TEA ( 22.98 ml, 164.8 mmol) followed by the dropwise addition of ethyl propiolate (16.71 ml, 164.8 mmol). After stirring vigorously for 2 days, the reaction was slowly stopped by adding portionwise to rapidly stirring ice water (820 ml). The mixture was stirred at ambient temperature

- 142 035568 medium for 10 minutes, and then filtered under reduced pressure. The collected solid was washed with water and air dried to give the title compounds as an orange solid in about 4: 1 isomeric ratio (as measured by 1H NMR) with 6-Br isomer as major isomer (21 g). The wet solid mixture of isomers (about 75% w / w) was used directly in step 3 without further purification. MS (apci) m / z = 298.9, 300.9 (M + H). The ratio of regioisomers was determined from the chemical shift of MeO in ¹ H NMR (CDCl ₃ ) δ 3.98 (6-Br isomer) versus 3.83 (4-Br isomer).

Step 3: Preparation of 6-bromo-4-methoxypyrazolo [1,5-a] pyridine (P1) and 4-bromo-6methoxypyrazolo [1,5-a] puridine. Isomeric mixture of ethyl 6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carboxylate and ethyl 4-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carboxylate from step 2 (15 g, 50, 1 mmol) was added to 48% HBr (114 ml) with stirring, then heated at 80 ° C for 90 min, followed by stirring at ambient temperature overnight. The resulting suspension was filtered under reduced pressure and washed with water. The aqueous filtrate and filter cake were worked up independently. The filter cake was suspended in MTBE and filtered under reduced pressure to remove insoluble impurities. The MTBE filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give 6-bromo-4methoxypurazolo [1,5-a] puridine as a beige solid (about 98: 2 6- / 4-Br; 5.08 g). MS (apci) m / z = 226.9, 228.9 (M + H).

1H NMR (CDCls) δ 8.26 (m, 1H), 7.82 (d, 1H), 6.61 (m, 1H), 6.43 (m, 1H), 3.94 (s, 3H) ...

The original aqueous filtrate of the reaction mixture was independently extracted with EtOAc (2x500 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure. The crude residue was dissolved in DCM (50 ml) and then filtered to remove insoluble impurities.

Concentration of the DCM filtrate under reduced pressure, followed by chromatography on silica gel (0-50% EtOAc / hexane isomer mixture) gave a second batch of 6-bromo-4methoxypyrαzolo [1,5-a] puridine (intermediate P1) as a white solid (spot c higher Rf, 2.06 g), as well as the title minor isomeric compound 4-bromo-6methoxypyrαzolo [1,5-a] puridine (intermediate P2) also as a white solid (lower Rf spot, 1, 32 g). MS (apci) m / z = 226.9, 228.9 (M + H).

1H NMR (CDCl ₃ ) δ 8.02 (m, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 6.55 (m, 1H), 3.80 (s, 3H ).

Step 4: Preparation of 4-bromo-6-methoxypyrαzolo [1,5-a] pyridine-3-carbαldehyde. A solution of 4-bromo-6methoxypyrazolo CD-pyridine (5.0 g, 22 mmol) in DMF (220 ml) was cooled to 0 ° C and then POCl ₃ (6.2 ml, 66 mmol) was added slowly. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was cooled to 0 ° C, quenched with water (220 ml) and podslushivaet 6 M NaOH _H. ,, _ull to pH 9-10. The reaction mixture was stirred for 1 hour and then filtered under reduced pressure. The solid was washed sequentially with water (3x50 ml) and MTBE (3x50 ml). The collected solid was suspended in DCM (500 ml), stirred in an ultrasonic bath for 30 minutes, and then filtered under reduced pressure. The filtrate was saved and the filter cake was dissolved in water (300 ml) and extracted with DCM. The organic extracts together with the remaining DCM filtrate were combined and dried over anhydrous Na ₂ SO ₄ , then filtered and evaporated under reduced pressure to give the title compound (4.84 g, 86% yield). MS (apci) m / z = 256.9 (M + H).

Step 5: Preparation of 4-bromo-6-methoxypyrazolo [1,5-a] pyridine-3-carbaldehyde oxime. To a suspension of 4-bromo-6-methoxypyrαzolo [1,5-a] puridine-3-carbaldehyde (4.84 g, 19.0 mmol) in EtOH (253 ml) at ambient temperature were added water (127 ml) and the hydrochloride hydroxylamine (1.98 g, 28.5 mmol). After stirring at 50 ° C overnight, the reaction mixture was cooled to ambient temperature and evaporated under reduced pressure. The residue was suspended in water (150 ml) and then saturated NaHCOj ^^.) (30 ml) was added slowly. After stirring for 1 h at ambient temperature, the suspension was filtered under reduced pressure and the filter cake was washed sequentially with H2O (500 ml) and MTBE (100 ml) to give the title compound as a 2: 1 E / Z isomer mixture (5 , 13 g, quantitative yield), which was used in the next step without further purification. MS (apci) m / z = 271.9 (M + H).

Step 6: Preparation of 4-bromo-6-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile. E / Z mixture of 4-bromo6-methoxypyrαzolo [1,5-a] pyridine-3-carbaldehydoxyme (4.95 g, 18.33 mmol) in acetic anhydride (172.9 ml, 1833 mmol) was stirred at 140 ° С in for 25 hours, and then cooled to ambient temperature. The resulting suspension was further cooled in an ice bath for 15 minutes and then filtered under reduced pressure and washed sequentially with water (200 ml) and MTBE (300 ml) to give the title compound (3.74 g, 81% yield).

1H NMR (d6-DMSO) δ 8.70 (s, 1H), 8.60 (s, 1H), 7.78 (s, 1H), 3.83 (s, 3H).

Step 7: Preparation of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile. To a suspension of 4-bromo-6-methoxypyrαzolo [1,5-a] puridine-3-carbonitrile (50.0 g 198.4 mmol) in DCE (500 ml) was added

- 143 035568

AlCl ₃ (79.34 g, 595.1 mmol). The resulting mixture was stirred for 19 h at 76 ° C under N2 ( _r ) atmosphere and then cooled to room temperature. Using THF (1750 ml) as washing solvent, the reaction mixture was poured into a mechanically stirred suspension of sodium sulfate decahydrate (10 eq., 639 g) in THF (1000 ml). After stirring overnight at ambient temperature, the resulting suspension was filtered and the solid washed with additional THF (2x250 ml). The filtrate was evaporated under reduced pressure and the resulting solid was dried under high vacuum for 3 days to give the title compound (46.18 g, 98% yield), sufficient purity for later use.

1H NMR (d-DMSO) δ 10.48 (s, 1H), 8.58 (s, 1H), 8.38 (d, 1H), 7.64 (3, 1H).

Intermediate P2.

6-methoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride.

Step 1: Preparation of tert-butyl 4- (5- (3-cyano-6-methoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate. To a stirred solution of 4-bromo-6-methoxypyrazolo [1,5-a] pyridine 3-carbonitrile (intermediate P1, step 6 part B; 425 mg, 1.69 mmol) in dioxane (33.7 mL) was added tert-butyl 4 - (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1-carboxylate (985 mg, 2.53 mmol) and 2 M K ₂ CO ₃ ( _BogH .) (1.69 ml, 3.37 mmol). After purging with N ^ r) for 5 min, X-phos (161 mg, 0.337 mmol) and Pd ₂ (dba) ₃ (77.2 mg, 0.0843 mmol) were added to the mixture and again purged with N ^ r) for additional 5 min. The resulting reaction mixture was stirred overnight at 80 ° C, then cooled to ambient temperature and diluted with water. The biphasic mixture was extracted with EtOAc, and the combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% 20% MeOH / DCM in EtOAc as gradient eluent) to afford the purified title compound (842 mg, quantitative yield).

Step 2: Preparation of 6-methoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride. In a solution of tert-butyl 4- (5- (3-cyano-6-methoxypyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate (842 mg, 1.94 mmol) in 20% MeOH / DCM (20 ml) was added 56N. HCl in iso-PrOH (5 ml, 1.94 mmol). After stirring for 6 hours at ambient temperature, the suspension was filtered under reduced pressure. The filter cake was washed with water to give the purified title compound as the hydrochloride salt (459 mg, 71% yield).

Intermediate P3.

tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1carboxylate.

A mixture of 4-bromo-6-hydroxypyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 1.20 g, 5.04 mmol) and tert-butyl 4- (5- (4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) piperazine-1carboxylate (2.36 g, 6.05 mmol) in 2 M Na ₂ CO ₃ ( _BogH .) (2, 63 ml, 5.25 mmol) and dioxane (2 ml) were purged with N ₂ (j-) for 5 min. Pd (PPh ₃ ) ₄ (121 mg, 0.105 mmol) was added to the mixture and N (r) was blown through it for an additional 5 min. The resulting mixture was stirred for 16 h at 80 ° C under N ₂ (r). The mixture was cooled to ambient temperature and water (100 ml) was added. The resulting biphasic mixture was extracted with DCM. The combined organic extracts were dried over anhydrous MgSO (TO), filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-90% ACN / water as eluent gradient). The purified yellow residue was dissolved in DCM and then activated carbon was added. The charcoal mixture was filtered through Celite®, washed with additional DCM before concentrating the filtrate under reduced pressure to afford the purified title compound (1.55 g, 73% yield). MS (apci) m / z = 421.1 (M + H).

- 144 035568

Intermediate P4.

N = \

ΦγΟχΖ

O tert-butyl 3- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6 diazabicyclo [3.1.1] heptane-6-carboxylate ...

In a pressure vessel, to a solution of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 181 mg, 0.761 mmol) in dioxane (7.61 ml) was added (6- (6- (tert-butoxycarbonyl) -3.6 diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (intermediate R4; 243 mg, 0.761 mmol), Pd (PPh ₃ ) ₄ (44.0 mg , 0.0381 mmol) and 2 M L ₂ CO ₃ ( _VOD n.) (381 μL, 0.761 mmol). The resulting mixture was purged with AG ( _D ), and then the vessel was sealed and the mixture was stirred overnight at 80 ° C. Then the reaction mixture was diluted with water and was extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (25-100% EtOAc in hexane isomers as gradient eluent) to afford the purified title compound (72 mg, 22% yield). MS (apci) m / z = 433.2 (M + H).

Intermediate P5.

ν = λ

Jf t

4-bromo-6-ethoxypyrazolo [1,5-a] pyrigine-3-carbonitrile.

A solution of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 4.0 g, 16.80 mmol) in DMA (100 ml) was added K2CO ₃ ( _ra ) (7.0 g, 51 mmol) and iodoethane (2.0 ml, 25 mmol), and then stirred for 3 h at 60 ° C. The reaction mixture was cooled to ambient temperature and then poured into 1: 1 Na ^ H / water. The resulting slurry was filtered and the solid was isolated to give the title compound (4.35 g, 97% yield) of sufficient purity for later use.

Intermediate P6.

N = \ ί I _F

6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a pressure vessel, to a solution of 4-bromo-6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P5; 500 mg, 1.88 mmol) in dioxane (9.40 ml) was successively added 2-fluorine -5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (629 mg, 2.82 mmol), Pd (PPh ₃ ) ₄ (217 mg, 0.188 mmol) and 2 MJa ₂ CO ₃ ( _aq .) (4.70 ml, 9.40). The resulting mixture was purged with Ar _(d) and then the vessel was sealed. The mixture was stirred for 8 h at 90 ° C, and then overnight at ambient temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (25-100% EtOAc in hexane isomers as gradient eluent) to afford the purified title compound (500 mg, 94% yield). MS (apci) m / z = 283.1 (M + H).

Intermediate P7.

N = \

Ji ϊ

4- (6- (3,6-Diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5а] pyridine-3-carbonitrile dihydrochloride HCl.

Were used two methods (method A and method B, as described below) to obtain this intermediate.

- 145 035568

Method A.

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) 3,6-diazabicyclo [3.1.1] heptane -6-carboxylate. A mixture of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P6; 347 mg, 1.23 mmol), tert-butyl 3,6 diazabicyclo [3.1.1 ] heptane-6-carboxylate (365.6 mg, 1.844 mmol) and K ₂ CO ₃ (. _ib ,) (1.699 g, 12.29 mmol) in DMSO (6.15 ml) were stirred for 3 days at 80 ° FROM. The reaction mixture was cooled to ambient temperature, then diluted with water and extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (50-100% EtOAc in hexane isomer gradient eluent) to afford the purified title compound (434.5 mg, 77% yield). MS (apci) m / z = 461.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride. A solution of tert-butyl 3- (5- (3-cyano-6-ethoxypyrazolo [1.5а] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (44 mg, 0.096 mmol) vDCM (2 ml) was added 4N. HCl in dioxane (2 ml). The resulting mixture was stirred for 2 h at ambient temperature, after which additional 4N. HCl in dioxane (2 ml). After stirring for an additional 1 hour at ambient temperature, the reaction mixture was evaporated under reduced pressure to give the purified title compound (34 mg, quantitative yield). MS (apci) m / z = 361.1 (M + H).

Method B.

Stage 1: preparation of tert-butyl-3- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -3,6-diazabicyclo [3.1.1] heptane -6-carboxylate. In a pressure vessel, to a solution of 4-bromo-6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P5; 38 mg, 0.14 mmol) in dioxane (1.4 mL) was successively added (6- (6 - (tert-butoxycarbonyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) boric acid (intermediate R4; 50 mg, 0.16 mmol), Pd (PPh ₃ ) ₄ (8 , 2 mg, 0.007 mmol) and 2 M ZhCO3 (aq.) (0.7 ml, 0.14 mmol). The resulting mixture was purged with Ar ( _d ), then the vessel was sealed. The mixture was stirred for 8 h at 90 ° C, and then overnight at ambient temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO _{4 (TB)} , filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (25-100% EtOAc in hexane isomers as gradient eluent) to afford the purified title compound (44 mg, 67% yield). MS (apci) m / z = 461.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride. Same as step 2 of method A above.

Intermediate P8.

6- (2,2-difluoroethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile dihydrochloride.

Stage 1: preparation of 2,2,2-trifluoroacetate tert-butyl 4- (5- (3-cyano-6- (2,2difluoroethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl ) piperazine-1-carboxylate. A mixture of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 88 mg, 0.21 mmol), 2-bromo-1,1-difluoroethane (36.4 mg, 0.251 mmol) and K ₂ CO _{3 (TB)} (86.78 mg, 0.6279 mmol) in DMF (2.09 ml) were stirred 24 h at 50 ° C. Then 2-bromo1,1-difluoroethane (36.40 mg, 0.2512 mmol) was added and the resulting mixture was stirred for another 6 h at 50 ° C. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with saturated sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the purified title compound as 2,2,2-trifluoroacetate salt (30 mg, 26 % output). MS (apci) m / z = 485.2 (M + H).

Step 2: Preparation of 6- (2,2-difluoroethoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride. In a solution of tert-butyl 4- (5- (3-cyano-6- (2,2 difluoroethox ^ pyrazole D ^ pyridinL-yl ^ iridinL-yl ^ iperazine L-carboxylate 2,2,2 trifluoroacetate (30 mg, 0.0619 mmol) in DCM (1 ml) was added dropwise with 4M HCl in dioxane (1 ml, 4.00 mmol) The resulting mixture was stirred overnight at ambient temperature and then

- 146 035568 was added another 4 M HCl in dioxane (1 ml, 4.00 mmol). The end of the reaction was monitored by LCMS and upon completion, evaporated under reduced pressure, azeotropically with Et2O (3x10 mL) to give the title compound as the dihydrochloride salt (23.8 mg, quantitative yield). MS (apci) m / z = 385.1 (M + H).

Intermediate P9.

4- (6- (piperazin-1-yl) pyridin-3-yl) -6- (2,2,2-trifluoroethoxy) pyrazolo [1,5a] pyridine-3-carbonyl-yl dihydrochloride.

Stage 1: preparation of tert-butyl-4- (5- (3-cyano-6- (2,2,2-trifluoroethoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1 -carboxylate. In a solution of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperαzine-1-kαrboxylate (intermediate P3; 100 mg, 0.238 mmol) in DMF (1.19 ml) DIEA (124.6 μl, 0.7135 mmol) and 2.2.2 trifluoroethyl trifluoromethanesulfonate (51.40 μl, 0.3567 mmol) were added. The resulting mixture was stirred for 4 hours at ambient temperature and then water was added. The reaction mixture was partitioned between EtOAc, water and saturated aqueous sodium chloride solution. The resulting organic extracts were washed with a saturated aqueous sodium chloride solution, then dried over anhydrous MgSO ^), filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to afford the purified title compound (30 mg, 25% yield). MS (apci) m / z = 503.2 (M + H).

Stage 2: Obtaining 4- (6- (piperazin-1-yl) pyridin-3-yl) -6- (2,2,2trifluoroethoxy) nyrazolo [1,5-a] pyridine-3-carboninyryl dihydrochloride A solution of p-butyl 4- (5- (3-cyano-6- (2,2,2trifluoroethox ^ pyrazoloC ^^ pyridine ^ -yl ^ iridin ^ -n ^ piperazine-b-carboxylate (30 mg, 0.060 mmol) in DCM (1 ml) was added dropwise 4 M HCl in dioxane (1 ml, 4.00 mmol) The resulting mixture was stirred overnight at ambient temperature and then additional 4 M HCl in dioxane (1 ml, 4.00 mmol) was added. The end of the reaction was monitored by LCMS and upon completion, evaporated under reduced pressure, azeotropically with Et2O (3x10 mL) to afford the title compound as the dihydrochloride salt (24 mg, quantitative yield) MS (apci) m / z = 403.1 (M + H).

Intermediate P10.

4- (6- (piperazin-1-yl) pyridin-3-yl) -6-propoxypyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 4- (5- (3-cyano-6-propoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate To a stirred mixture of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 101.3 mg, 0.2409 mmol) and K ₂ CO _{3 (solid)} (66.59 mg, 0.4818 mmol) in DMF (1.21 mL) was slowly added 1brompropan (24.1 uL, 0.265 mmol). The resulting mixture was stirred for 3 h at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, then washed with water and saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous № ^ O4 _(TV), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-6% MeOH in DCM as eluent gradient) to afford the purified title compound (100 mg, 90% yield). MS (apci) m / z = 463.2 (M + H).

Step 2: Preparation of 4- (6- (piperazin-1-yl) pyridin-3-yl) -6-propoxypyrazolo [1,5-a] pyridine-3carbonitrile. To a solution of tert-butyl 4- (5- (3-cyano-6-propoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (100 mg, 0.216 mmol) in DCM ( 1.08 ml) was added TFA (1.08 ml, 0.2162 mmol) and stirred for 3 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated \ a2C (') _{3i: i! LullJ} and saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous № ^ O4 _(TV), filtered and evaporated under reduced pressure to give the pure title compound (78 mg, yield 100%). MS (apci) m / z = 363.2 (M + H).

All intermediate compounds in the table. AA and their Boc-protected piperazine-containing starting compounds were prepared and purified using a method similar to that described for the synthesis

- 147 035568 intermediate P10. In each case, the 1-bromopropane was replaced with a suitable alkyl halide and an appropriate gradient eluent was used for chromatographic purification of each starting compound for t-butyl carbamate. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly.

Table AA

Inter mediat no. Structure Chemical name MS (apci) ιη / ζ P11 N = \ J I l ^ / NH 6-isobutoxy-4- (6 (piperazin-1-yl) pyridin3-i l) pyrazolo [1,5а] pyridine-3-carbonitrile 377.2 (M + H) P12 T 0 / * 0 44 0 y 6- (neopentyloxy) -4- (6 (piperazin-1-yl) pyridin3-i l) pyraz olo [1,5а] pyridine-3-carbonitrile 391.2 (M + H) P13 I 0/0 0 6- (2-methylbutoxy) -4- (6 (piperazin-1-yl) pyridin3-yl) pyrazolo [1,5а] pyridine-3-carbonitrile 391.2 (M + H) P14 4 0 P 1 0 I 6- (2-ethylbutoxy) -4- (6 (piperazin-1-yl) pyridin3-yl) pyrazolo [1,5а] pyridine-3-carbonitrile 405.2 (M + H). P15 T 0/0 0 s 6- (cyclobutylmethoxy) -4 (6- (piperazin-1 yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3-carbonitrile 389.2 (M + H)

Intermediate P16.

6-hydroxy-4- (6- (4- (pyridin-2-ylmethyl) piperαzin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

In a pressure vessel through a mixture of 4-bromo-6-hydroxypyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 100 mg, 0.420 mmol) and 1- (pyridin-2-ylmethyl) -4- (5 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) piperazine (intermediate R9; 192 mg, 0.504 mmol) in dioxane (4 ml) and 2 M Na ₂ CO ₃ ( _Bogn .) (1.05 ml, 2.10 mmol) was purged with N ₂ ( _g ) for 5 min. Pd (PPh ₃ ) ₄ (48.5 mg, 0.0420 mmol) was added to the mixture and purged with N _2fr) for an additional 5 min. The vial was sealed and the mixture was stirred for 15 h at 80 ° C. The mixture was cooled to ambient temperature, then diluted with water (5 ml) and 2 M HCl ^^) (0.9 ml) was added. The resulting biphasic mixture was extracted with DCM. The combined organic extracts were dried over anhydrous MgSO ^), filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to afford the title compound (34 mg, 20% yield). MS (apci) m / z = 412.1 (M + H).

Intermediate P17.

6- (2-morpholinoethoxy) -4- (6- (piperαzin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

- 148 035568

Step 1: Preparation of tert-butyl 4- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate. DIAD (333 μL, 1.69 mmol) was added to a cold (0 ° С) solution of PPh ₃ (444 mg, 1.69 mmol) in 1: 1 DCM: THF (10.0 ml) and stirred for 15 min at 0 ° C. To the resulting mixture at 0 ° C was added a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 356 mg, 0.847 mmol) and 2morpholinoethan-1-ol (207 μl, 1.69 mmol) in 1: 1 DCM: THF (20.0 ml). After stirring overnight at room temperature, the reaction mixture was evaporated under reduced pressure and purified by silica gel chromatography (5-30% MeOH in EtOAc as eluent gradient) to afford the title compound (303 mg, 67% yield). MS (apci) m / z = 534.2 (M + H).

Step 2: Preparation of 6- (2-morpholinoethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile. In a solution of tert-butyl 4- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperαzine-1-carboxylate (303 mg, 0.568 mmol) in DCM (4.0 ml) was added TFA (2.0 ml). The resulting mixture was stirred for 30 min at ambient temperature and then purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to provide the title compound as a TFA salt ... The salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ^ (.). The combined organic extracts were separated, dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure to give the purified title compound (100 mg, 41% yield) MS (apci) m / z = 434.1 (M + H).

Intermediate P18.

6- (2- (4-methylpiperazin-1-yl) ethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [^^ pyridine3-carbonitrile.

Stage 1: preparation of tert-butyl-4- (5- (3-cyano-6- (2- (4-methylpiperazin-1-yl) ethoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2- yl) piperαzine-1-carboxylate. DIAD (175.6 μL, 0.8919 mmol) was added to a cold (0 ° C) solution of PPh ₃ (233.9 mg, 0.8919 mmol) in 1: 1 DCM: THF (6.0 ml) and stirred in for 15 minutes at 0 ° C. To the resulting mixture at 0 ° C was added a solution of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 250.0 mg, 0.5946 mmol) and 1- (Nhydroxyethyl) -4-methylpiperazine (102.9 mg, 0.7135 mmol) in 1: 1 DCM: THF (12.0 ml). After stirring overnight at room temperature, the reaction mixture was evaporated under reduced pressure and purified by silica gel chromatography (1-30% DCMMeOH with 2% NH4OH as gradient eluent) to afford the title compound, which was immediately transferred to Step 2. MS (apci) m / z = 547.2 (M + H).

Stage 2: Preparation of 6- (2- (4-methylpiperazin-1-yl) ethoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile ... A solution of tert-butyl 4- (5- (3-cyano-6- (2- (4-methylpiperazin-1yl) ethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine- 1-carboxylate in 1: 1 DCM: TFA (6.0 ml) was stirred for 15 min at ambient temperature, then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% water ACN with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ^ (.). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure to give the title compound (146.4 mg, 55% yield). MS (apci) m / z = 447.2 (M + H).

Intermediate P19.

6- (oxαzol-2-ylmethoxy) -4- (6- (piperαzin-1-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3carbonitrile.

Stage 1: preparation of tert-butyl 4- (5- (3-cyano-6- (oxazol-2-ylmethoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ... To a mixture of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 77.5 mg, 0.184 mmol) and K ₂ CO ₃ ( _TB ) (50.9 mg, 0.369 mmol) in DMF (1.84 ml) 2 (chloromethyl) oxazole (43.3 μl, 0.369 mmol) was added at room temperature. The resulting mixture was stirred for 1 h at 80 ° C, and

- 149 035568 then additional 2- (chloromethyl) oxazole (10 μl, 0.0852 mmol) was added. After stirring for 3 days at 80 ° C, the reaction mixture was cooled to ambient temperature. The mixture was diluted with EtOAc and washed with water and saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous Na ₂ SO4 ( _ra ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (10-90% EtOAc in hexane isomer as gradient eluent) to afford the purified title compound (44 mg, 48% yield). MS (apci) m / z = 501.8 (M + H).

Step 2: Preparation of 6- (oxazol-2-ylmethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile. In a solution of tert-butyl 4- (5- (3-cyano-6- (oxazol-2-ylmethoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (44 mg , 0.088 mmol) in DCM (880 μl) was added TFA (880 μl, 0.088 mmol), then stirred for 1 h at ambient temperature. The resulting mixture was diluted with DCM and neutralized with saturated Na ^ O ^ (.). The biphasic mixture was extracted with DCM. The combined organic extracts were washed with saturated NaHCO ^^.) And saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the purified title compound (30 mg, 85% yield) ... MS (apci) m / z = 401.8 (M + H).

Intermediate P20.

6 - ((3-methyl-1,2,4-oxadiazol-5-yl) methoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridin-3 -carbonitrile.

Stage 1: preparation of tert-butyl 4- (5- (3-cyano-6 - ((3-methyl-1,2,4-oxadiazol-5yl ^ ethox ^ pyrazolo ^ D ^ pyridinD-yl ^ iridin ^ -yl ^ iperazine I-carboxylate To a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 83 mg, 0.120 mmol) and K ₂ CO ₃ ( _ra ) (54.6 mg, 0.395 mmol) in DMF (1.97 ml) at room temperature was added 5- (chloromethyl) -3-methyl-1,2,4 α-oxadiazole (40.5 μL, 0.395 mmol) and stirred for 3.5 h at 80 ° C. The resulting mixture was cooled to ambient temperature, diluted with EtOAc and washed with water and saturated aqueous sodium chloride The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure.The crude residue was purified by silica gel chromatography (10-90% EtOAc in hexane isomer as gradient eluent) to afford the purified title compound (70.9 mg, yield 70 %) MS (apci) m / z = 516.8 (M + H).

Stage 2: preparation of 6 - ((3-methyl-1,2,4-oxadiazol-5-yl) methoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. In a solution of tert-butyl 4- (5- (3-cyano-6 - ((3-methyl-1,2,4oxadiazol ^ -yl ^ ethox ^ pyrazolo DD ^ pyridinD yl) pyridin-2-yl) piperazine-1-carboxylate (70.9 mg, 0.137 mmol) in DCM (1.37 ml) was added TFA (1.37 ml, 0.137 mmol), and then stirred for 1 h at ambient temperature.The resulting mixture was diluted with DCM and neutralized with saturated L3CO ^ The biphasic mixture was extracted with DCM The combined organic extracts were washed with saturated NaHCO (^ () and saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the purified title compounds (21 mg, 37% yield). MS (apci) m / z = 416.8 (M + H).

Intermediate P21.

4- (6- (piperazin-1-yl) pyridin-3-yl) -6- (pyridin-3-ylmethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 4- (5- (3-cyano-6- (pyridin-3-ylmethoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ... To a mixture of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 0.1002 g, 0.2383 mmol) and pyridin-3-ylmethanol (25.45 μl, 0.2621 mmol) in THF (1.19 ml) was added PPh ₃ (125.0 mg, 0.4766 mmol). The resulting mixture was purged with Ar _(D ) for 3 min before adding DIAD (92.67 μL, 0.4766 mmol).

After blowing A ( _D ) for an additional 1 min, the reaction mixture was stirred for 1 h at ambient temperature. The mixture was diluted with water and extracted with DCM. The combined organic extracts were sequentially washed with water and a saturated aqueous solution of sodium chloride, then with

- 150 035568 sewn over anhydrous Na2SO4 ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (1-6% MeOH in DCM as gradient eluent) to afford the purified title compound (107 mg, 88% yield). MS (apci) n / 2 = 412.2 [(M-Boc) + H].

Step 2: Preparation of 4- (6- (piperazin-1-yl) pyridin-3-yl) -6- (pyridin-3-ylmethoxy) pyrazolo [1,5a] pyridine-3-carbonitrile. In a solution of tert-butyl 4- (5- (3-cyano-6- (pyridin-3-ylmethoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (107 mg , 0.209 mmol) in DCM (1.05 ml) was added TFA (48.3 μl, 0.627 mmol), and then stirred for 30 min at ambient temperature. The resulting mixture was diluted with DCM and neutralized with saturated Na2CC) _{3ll! (UIIJ} . The two-phase mixture was diluted with saturated Na2CC) _{3 (} aq _{|| 1} and extracted with DCM. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na2CO4 _(solid), filtered and evaporated under reduced pressure to give the purified title compound (86 mg, 100% yield). MS (apci) m / z = 412,2 ( M + H).

Intermediate P22.

6- (2- (1H-imidazol-1-yl) ethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

Stage 1: preparation of tert-butyl-4- (5- (6- (2- (1H-imidazol-1-yl) ethoxy) -3-cyanopyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl ) piperazine-1-carboxylate. To a mixture of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 0.1002 g, 0 , 2383 mmol) and 2- (1H-imidazol-1-yl) ethan-1-ol (23.04 μl, 0.2383 mmol) in THF (1.19 ml) was added PPh ₃ (78.13 mg, 0 , 2979 mmol).

The resulting mixture was purged with Ab _(g ) for 3 min before adding DIAD (57.92 μl, 0.2979 mmol). After purging AG ( _g) for an additional 2 min, the reaction mixture was stirred for 15 h at ambient temperature. To the reaction mixture was additionally added 2- (1H-imidazol-1-yl) ethan1-ol (23.04 μl, 0.2383 mmol), PPh ₃ (62.50 mg, 0.2383 mmol) and DIAD (46.34 μl, 0.2383 mmol) and allowed to stir for 4 h at ambient temperature. The mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na2SO4 ( _TB ), filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (1-9% MeOH in DCM as gradient eluent) to afford the purified title compound (24 mg, 20% yield). MS (apci) m / z = 515.2 (M + H).

Stage 2: preparation of 6- (2- (1H-imidazol-1-yl) ethoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile ... In a solution of tert-butyl 4- (5- (6- (2- (1H-imidazol-1-yl) ethoxy) 3-cyanopyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine -1-carboxylate (24 mg, 0.0466 mmol) in DCM (933 μl) was added TFA (933 μl, 0.0466 mmol), and then stirred for 1 hour at ambient temperature. The resulting mixture was diluted with DCM and added dropwise (αΥΌχ,. ,, ^.) Until gas evolution from the solution ceased. The biphasic mixture was diluted with saturated Nal 1CC) _{3 (1 || water} and extracted with DCM. The combined organic extracts were washed with saturated sodium chloride solution, then dried over anhydrous Na2SO4 (τ _B), filtered and evaporated under reduced pressure to give the purified title compound ( 19.4 mg, quantitative yield) MS (apci) m / z = 415.2 (M + H).

Intermediate P23.

6- (2-Hydroxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile hydrochloride.

Stage 1: preparation of tert-butyl 4- (5- (6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -3 cyanopyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine -1-carboxylate. A mixture of tert-butyl 4- (5- (3cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 250 mg, 0.595 mmol) (2-bromoethoxy) (tert-butyl) dimethylsilane (128 uL, 0.743 mmol) and K ₂ CO _{3 (solid)} (247 mg, 1.78 mmol) in DMF (2.97 mL) was stirred for 1 day at 50 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by chromatography on

151 035568 silica gel (0-100% EtOAc / hexane isomer mixture as gradient eluent) to give the purified title compound (30 mg, 26% yield). MS (apci) m / z = 579.8 (M + H).

Step 2: Preparation of 6- (2-hydroxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride. In a solution of tert-butyl 4- (5- (6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -3-cyanopyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1carboxylate (325 mg, 0.562 mmol) in DCM (2.81 ml) was added dropwise 4 M HCl in dioxane (2.81 ml, 11.2 mmol). The resulting mixture was stirred for 1 hour at ambient temperature. The resulting white precipitate was evaporated under reduced pressure to give the title compound as hydrochloride salt (225 mg, quantitative yield). MS (apci) m / z = 364.9 (M + H).

Intermediate P24.

2,2,2-trifluoroacetate 6-hydroxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Via a mixture of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 100 mg, 0.420 mmol), 1 - ((6-methoxypyridin-3-yl) methyl) -4- ( 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridin-2-yl) piperazine (intermediate R10; 207 mg, 0.504 mmol), Pd (PPh ₃ ) ₄ (19, 4 mg, 0.0168 mmol), 2 M Na ^ O ^^.) (630 μl, 1.26 mmol) and 1,4-dioxane (2.80 ml) were purged with Ν _{2 (γ)} , and then stirred in overnight at 85 ° C in an atmosphere of N ₂ ( _d ). The mixture was cooled to ambient temperature, filtered through a syringe filter, and purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as eluent gradient) to afford the title compound as 2.2 , 2-trifluoroacetate salt (145 mg, 62% yield). MS (apci) m / z = 442.2 (M + H).

Intermediate P25.

4-bromo-6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A mixture of (2-bromoethoxy) (tert-butyl) dimethylsilane (451 μL, 2.10 mmol), 4-bromo-6hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 500 mg, 2.10 mmol ) and K ^ CO ^ (871 mg, 6.30 mmol) in DMF (10.5 ml) were stirred for 1 day at 50 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water and saturated sodium chloride solution. The resulting organic extracts were directly purified by silica gel chromatography (0-100% EtOAc / hexane isomer mixture as gradient eluent) to afford the purified title compound (420 mg, 49% yield).

Intermediate P26.

6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

In a pressure vessel into a solution of 4-bromo-6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P25; 420 mg, 1.06 mmol) in dioxane (10.6 ml), 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (355 mg, 1.59 mmol) was successively added, Pd (PPh ₃ ) ₄ (61.2 mg, 0.530 mmol) and 2 M Na ^ O ^^) (2.65 ml, 5.30). The resulting mixture was purged with _AG ( _D ) and the vessel was sealed. The mixture was stirred for 8 h at 90 ° C, and then overnight at ambient temperature. The reaction mixture was diluted with water and extracted with EtOAc.

The combined organic extracts were washed with water (10 ml) and saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-15% MeOH in DCM as gradient eluent) to afford the contaminated title compound. The contaminated compound was re-purified by silica gel chromatography (050% EtOAc in hexane isomer as gradient eluent) to afford the purified title compound (351 mg, 80% yield).

1H NMR (400 MHz, DMSO-06) δ: 8.81 (d, 1H, J = 2.0 Hz), 8.61 (s, 1H), 8.48 (d, 1H, J = 2.7 Hz), 8.25 (td,

- 152 035568

1H, J = 7.8, 2.7 Hz), 7.47 (d, 1H, J = 1.9 Hz), 7.38 (dd, 1H, J = 7.8, 2.3 Hz), 4.21 (t, 2H, J = 4.3Hz), 3.97 (t, 2H, J = 4.7Hz), 0.86 (s, 9H), 0.08 (s, 6H).

Intermediate P27.

N = \ ⁿ ° \ ^ _o 2 HCI kJ ^ NH dihydrochloride 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxyethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: obtaining tert-butyl-3- (5- (3-cyano-6- (2-hydroxyethoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3,6-diazabicyclo [ 3.1.1] heptane-6-carboxylate. A mixture of 6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P26; 110 mg, 0.267 mmol) and 3,6-diazabicyclo [3.1.1] heptane-6carboxylic acid tert-butyl ester (159 mg, 0.800 mmol) in DMSO (2.5 ml) was stirred for 1 h at 110 ° C. After cooling to ambient temperature, the mixture was diluted with water and the resulting suspension was filtered. The solid was separated and purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to afford the purified title compound (22 mg, 17% yield) which was transferred to Step 2. MS (apci) m / z = 591.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxyethoxy) pyrazolo [1,5-a] pyridine-3 hydrochloride -carbonitrile. In a solution of tert-butyl-3- (5- (3-cyano-6- (2hydroxyethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1. 1] heptane-6 carboxylate (22 mg, 0.046 mmol) in DCM (2 ml) was added 4N. HCl in dioxane (3 ml, 0.046 mmol). The resulting mixture was stirred overnight at ambient temperature, then evaporated under reduced pressure to give the title compound as the dihydrochloride salt (17 mg, quantitative yield). MS (apci) m / z = 377.2 (M + H).

Intermediate P28.

N = \

HOy _o AAp _N HCI k ^ NH (^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride ...

In a solution of tert-butyl (R) -4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ( example 116; 68.3 mg, 0.143 mmol) in DCM (714 μl) was added TFA (110 μl, 1.43 mmol). The resulting mixture was stirred for 1 day at ambient temperature, then evaporated under reduced pressure to give the TFA salt of the title compound. The TPA salt was converted to the HCl salt by dissolving the salt in 6N. HCl in iso-PrOH, and then evaporating the mixture under reduced pressure to give the title compound as the hydrochloride salt (59.2 mg, quantitative yield). MS (apci) m / z = 379.2 (M + H).

Intermediate P29.

^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [^^ pyridine-3-carbonitrile.

In a solution of tert-butyl (R) -4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ( example 116; 40 mg, 0.084 mmol) in DCM (418 μl) was added TFA (64 μl, 0.84 mmol), then stirred for 1 day at ambient temperature. The resulting mixture was distributed between DCM and 2 M K ^ CO ^^. The aqueous phase was back extracted with DCM. The combined organic extracts were evaporated under reduced pressure to give the purified title compound (7.2 mg, 23% yield). MS (apci) m / z = 379.2 (M + H).

- 153 035568

Intermediate P30.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- () -2-hydroxypropoxy) pyrazolo [1,5-а] pyridine dihydrochloride 3 -carbonitrile.

Stage 1: preparation of tert-butyl-3- (5- (3-cyano-6 - ((R) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridin4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1.] Heptane-6-carboxylate. To a suspension of tert-butyl 3- (5- (3cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6carboxylate (intermediate P4; 40 mg, 0.0925 mmol) in DMF (462 μl) was added K ₂ CO3 ( _TB ) (328.7 mg, 2.378 mmol) and stirred for 15 min at ambient temperature. To the resulting mixture was added a solution of (H) -2-methyloxirane (32.4 μl, 0.462 mmol) in DMF (462 μl). The reaction mixture was stirred for 4 h at ambient temperature, then overnight at 50 ° C before adding more (H) -2-methyloxyrane (130 μl, 1.85 mmol). The resulting mixture was stirred overnight at 50 ° C and cooled to ambient temperature. The reaction mixture was purified directly by silica gel chromatography (0-100% ethyl acetate in hexane as gradient eluent) to afford the purified title compound (16 mg, 28% yield). MS (apci) m / z = 491.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 ((R) -2-hydroxypropoxy) pyrazolo dihydrochloride [1,5- a] pyridine-3-carbonitrile. In a solution of tert-butyl 3- (5- (3-cyano-6 ((R) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6- diazabicyclo [3.1.1] heptane-6 carboxylate (step 1; 16 mg, 0.0254 mmol) in DCM (2 ml) was added 4N. HCl in dioxane (2 ml). The resulting mixture was stirred for 1 hour at ambient temperature and then evaporated under reduced pressure to give the title compound as a dihydrochloride salt (11.8 mg, quantitative yield). MS (apci) m / z = 391.2 (M + H).

Intermediate P31.

^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride.

Stage 1: preparation of tert-butyl (S) -4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1- carboxylate. To a suspension of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 200 mg, 0.476 mmol ) in DMF (2.38 ml) was added to ₂ CO ₃ ( _TB ) (329 mg, 2.38 mmol) and stirred for 15 min at ambient temperature. To the resulting mixture was added a solution of d) - 2-methyloxyrane (138 mg, 2.38 mmol) in DMF (1 ml). The reaction mixture was stirred for 1 day at 50 ° C, then purified directly by chromatography on silica gel (0-100% DCM in a mixture of hexane isomers followed by a gradient of 20% DCM / MeOH as eluents) to afford the purified title compound (176 mg, 77%), MS (apci) m / z = 478.9 (M + H).

Stage 2: preparation of the hydrochloride (^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl ^ irazolo ^^^ pyridine-3-carbonitrile. Tert-butyl ^) - 4 solution - (5- (3-cyano-6- (2hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (step 1) in 1: 1 DCM: TPA (2 ml) was stirred for 30 min at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was added 6N. HCl in iso-PrOH (2 ml). The resulting mixture was stirred for 1 hour at ambient temperature and then evaporated under reduced pressure to give the title compound (153 mg, 100% yield). MS (apci) m / z = 378.9 (M + H).

Intermediate P32.

(S) -6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

- 154 035568

A solution of tert-butyl ^) - 4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-: yl) pyridin2-yl) piperazine-1-carboxylate (intermediate 31, step 1; 17 mg, 0.036 mmol) and TFA (27 μl, 0.36 mmol) in DCM (178 μl) were stirred overnight at ambient temperature. The reaction mixture was partitioned between DCM and 2 M K ₂ CO ₃ ( _WOD n). The aqueous phase was re-extracted with DCM. The combined organic extracts were evaporated under reduced pressure to give the title compound (13 mg, 97% yield). MS (apci) m / z = 379.1 (M + H).

Intermediate RZZ.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2hydroxypropoxy) pyrazolo [1,5-a] pyridine 3-carbonitrile dihydrochloride ...

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6 - (^) - 2-hydroxypropoxy) pyrazolo [1,5-a] pyridin4-yl) pyridin-2-yl) -3,6- diazabicyclo [3.1.1] heptane-6-carboxylate · To a suspension of tert-butyl-3- (5- (3cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3 , 6-diazabicyclo [3.1.1] heptane-6karboksilata (int P4; 40 mg, 0.093 mmol) in DMF (462 .mu.l) was added K ₂ CO _{3 (solid)} (63.9 mg, 0.462 mmol) and stirred for 15 min at ambient temperature. To the resulting mixture was added a solution of N) - 2-methyloxyrane (32.4 μl, 0.462 mmol) in DMF (462 μl). The reaction mixture was stirred for 4 h at ambient temperature, then overnight at 50 ° C before the addition of additional N) - 2-methyloxyrane (97.2 μl, 1.39 mmol). The reaction mixture was stirred overnight at 50 ° C, and then cooled to ambient temperature. The resulting mixture was partitioned between EtOAc and water and was extracted with EtOAc. The combined organic extracts were washed with saturated sodium chloride solution, then dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure. The residue was purified directly by silica gel chromatography (0-100% EtOAc in hexane isomer as gradient eluent) to afford the purified title compound (15 mg, 28% yield). MS (apci) m / z = 491.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 (^) - 2-hydroxypropoxy) pyrazolo [1,5-a) dihydrochloride ] pyridine-3-carbonitrile. In a solution of tert-butyl-3- (5- (3-cyano-6 (^) - 2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6- diazabicyclo [3.1.1] heptane-6 carboxylate (step 1; 15 mg, 0.026 mmol) in DCM (3 ml) was added 4N. HCl in dioxane (3 ml) and stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure to give the title compound (12 mg, quantitative yield). MS (apci) m / z = 391.2 (M + H).

Intermediate P34.

^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride.

Stage 1: preparation of tert-butyl ^) - 4- (5- (3-cyano-6- (2-hydroxybutoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ... In a solution of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate РЗ; 200 mg 0.476 mmol) in DMF (2.38 mL) was added K ₂ CO _{3 (solid)} (329.0 mg, 2.38 mmol) and stirred for 15 minutes at ambient temperature. To the resulting mixture was slowly added a solution of ^) - 2-ethyloxirane (171 mg, 2.38 mmol) in DMF (1 ml). The reaction mixture was stirred for 1 day at 50 ° C, then purified directly by chromatography on silica gel (using a stepwise gradient of 0-100% DCM in a mixture of hexane isomers followed by illumination with 20% DCM / MeOH as eluents) to obtain the purified title compounds (190 mg, 81.4%). MS (apci) m / z = 492.9 (M + H).

Stage 2: preparation of the hydrochloride ^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3yl ^ irazolo ^ D ^ pyridine-3-carbonitrile. (10-tert-butyl 4 - (5- (3-cyano-6- (2hydroxybutox ^ pyrazolo ^ D ^ pyridine ^ -yl ^ iridin ^ -n ^ piperazine D-carboxylate in 1: 1 DCM: TPA (3 ml) was stirred for 30 min at ambient temperature The mixture was evaporated under reduced pressure The residue was dissolved in 6N HCl in iso-PrOH (3 ml), then immediately evaporated under reduced pressure to give the title compound as the hydrochloride salt (166 mg, 100% yield). MS (apci ) m / z = 392.9 (M + H).

- 155 035568

Intermediate P35.

(R) -6- (2-rugpoKCu6yTOKCu) -4- (6- (nunepa3UH-1-yl) pyridin-3-yl) pyrazolo [1.5-a] pyridine-3 carbonitrile.

Into a solution of (K) -tert-butium 4- (5- (3-cyano-6- (2-guproxybytoxy) pyrazolo [1,5-a] pypugin-4yl) pyridin-2-yl) piperazine-1-carboxylate ( intermediate P34, step 1; 52.5 mg, 0.107 mmol) in DCM (1.07 ml) was added TFA (1.07 ml, 0.107 mmol), then stirred for 5 days at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated # ₂ CO ₃ ( _aq ) and saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the title compound (41.9 mg, quantitative yield). MS (apci) m / z = 392.9 (M + H).

Intermediate P36.

^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pypidin-3-carbonitrile hydrochloride.

Stage 1: preparation of tert-butyl (S) -4- (5- (3-cyano-6- (2-gugroxybytoxy) pyrazolo [1,5-a] pypugin-4yl) pyridin-2-yl) piperazine-1- carboxylate. To a solution of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo ^ E ^ pyridine ^ -yl ^ iridin ^ -yl ^ iperazine-b-carboxylate (intermediate P3; 200 mg, 0.476 mmol) in DMF (2.38 ml ) was added K ₂ CO _{3 (solid)} (329.0 mg, 2.38 mmol) and stirred for 15 minutes at ambient temperature, to the resulting mixture was slowly added a solution of ^.) - 2-etiloksirana (171 mg, 2.38 mmol) in DMF (1 ml) After stirring for 1 day at 50 ° C, the reaction mixture was purified directly by chromatography on silica gel (0-100% DCM in a mixture of hexane isomers followed by a gradient of 20% DCM / MeOH as eluents) to obtain purified of the title compound (175 mg, 75% yield) MS (apci) m / z = 492.8 (M + H).

Stage 2: preparation of (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pypidin-3-carbonitrile hydrochloride. A solution of tert-butyl ^) - 4- (5- (3-cyano-6- (2hydroxybutox ^ pyrazolo ^ E ^ pyridine ^ -yl ^ iridin ^ -yl ^ iperazine L-carboxylate in 1: 1 DCM: TPA (3 ml) stirred for 30 min at ambient temperature The mixture was evaporated under reduced pressure The residue was dissolved in 6N HCl in iso-PrOH (3 ml) and then immediately evaporated under reduced pressure to give the title compound as the hydrochloride salt (153 mg , 100% yield) MS (apci) m / z = 392.8 (M + H).

Intermediate P37.

^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3 carbonitrile.

In a solution of tert-butyl (S) -4- (5- (3-cyano-6- (2-hydroxybytoxy) pyrazolo [1,5-a] pypudin-4yl) pyridin-2-yl) piperazine-1-carboxylate ( intermediate P36, step 1; 86 mg, 0.17 mmol) in DCM (1.2 ml) was added TFA (1.2 ml, 0.17 mmol), then stirred for 5 days at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated Na ₂ CO 3 ( _ing .) And saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered, and evaporated under reduced pressure to give the title compound (30 mg, 44% yield). MS (apci) m / z = 392.9 (M + H).

Intermediate P38.

N = \ ^ΗΟ γ ^Α 'οΆΑρ> _Ν but k ^ NH

Hydrochloride 6 - (((2S *, 3R *) - 3-hydroxybutan-2-yl) oxy) -4- (6- (piperazin-1-yl) pyridin-3

- 156 035568 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: obtaining tert-butyl-4- (5- (3-cyano-6 - (((2S *, 5R *) - 3-hydroxybutan-2-yl) oxy) pyrazolo [1,5-a] pyridine- 4-yl) pyridin-2-yl) piperazine-1-carboxylate. To a suspension of tert-butyl 4- (5- (3-cyano-6hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 200 mg, 0.476 mmol ) in DMF (1 ml) was added K ₂ COy _TB ) (329 mg, 2.38 mmol) and stirred for 15 min at ambient temperature. To the resulting mixture was added a solution of (2R *, 3R *) - 2,3-dimethyloxyrane (171 mg, 2.38 mmol) in DMF (1 ml). The reaction mixture was stirred for 2 days at ambient temperature and then purified directly by chromatography on silica gel (using a stepwise gradient of 0-100% DCM in a mixture of hexane isomers, followed by illumination with 20% DCM / MeOH as eluents) to obtain the purified specified in title compound (223 mg, 95.6%). MS (apci) m / z = 492.8 (M + H).

Stage 2: preparation of hydrochloride 6 - (((2S *, 3R *) - 3-hydroxybutan-2-yl) oxy) -4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5- a] pyridine-3-carbonitrile. A solution of tert-butyl 4- (5- (3-cyano-6 - (((2S, 3R) 3-hydroxybutan-2-yl) oxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2 -yl) piperazine-1-carboxylate in a 1: 1 mixture of DCM: TPA (3 ml) was stirred for 30 min at ambient temperature. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in 6N. HCl in iso-PrOH (3 ml), then immediately evaporated under reduced pressure to give the title compound as the hydrochloride salt (195 mg, 100% yield). MS (apci) m / z = 392.9 (M + H).

Intermediate P39.

6- (2-Hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride.

A solution of tert-butyl 4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate (example 152; 234 mg, 0.476 mmol) in a 1: 1 mixture of DCM: TPA (3 ml) was stirred for 30 min at ambient temperature. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in 6N. HCl in iso-PrOH (3 ml), then immediately evaporated under reduced pressure to give the title compound as hydrochloride salt (187 mg, 92% yield). MS (apci) m / z = 393.2 (M + H).

Intermediate P40.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

In a solution of tert-butyl 4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ( example 152; 17 mg, 0.035 mmol) in DCM (173 μl) was added TFA (27 μl, 0.35 mmol), followed by stirring for 1 day at ambient temperature. The reaction mixture was partitioned between DCM (10 ml) and 2 M K ₂ CO ₃ ( _VOD n.) (5 ml). The aqueous phase was extracted with DCM. The organic extracts were combined and evaporated under reduced pressure to give the title compound (14 mg, quantitative yield). MS (apci) m / z = 393.2 (M + H).

Intermediate P41.

4-bromo-6- (2-hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

In a pressure vessel to a mixture of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 10.0 g, 42.0 mmol) and K ₂ CO ₃ ( _TB ) (17, 4 g, 126 mmol) in DMF (50 ml) was added 2,2 dimethyloxirane (36.9 ml, 420 mmol). After the vessel was sealed, the reaction mixture was stirred for 12 h at 60 ° C, then for 12 h at 85 ° C. The mixture was allowed to cool to ambient temperature. The mixture at room temperature was poured into water (400 ml), then stirred for 1 hour at ambient temperature. The resulting suspension was filtered under reduced pressure, and the filter cake was washed with water. The solid was collected and dried under reduced pressure to give the purified title compound (11 g, 84% yield).

- 157 035568

Intermediate P42.

4- (6-fluoropyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a mixture of 4-bromo-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P41; 10.0 g, 32.2 mmol), 2-fluoro-5 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (10.8 g, 48.4 mmol) and Pd (PPh3) 4 (1.12 g, 0.967 mmol ) in dioxane (200 ml), 2 M Na ₂ CO ₃ ( _BODN ) (64.5 ml, 129 mmol) was added. The resulting mixture was purged with Ar ( _r ), then stirred for 12 h at 85 ° C in an atmosphere of Ν ₂ ( _γ) . After cooling to ambient temperature, the resulting mixture was poured into cold water (1.5 L). The pH of the mixture was adjusted to about 6 with 10% citric acid. After stirring for 1 hour at ambient temperature, the suspension was filtered under reduced pressure. The solid was collected and dried under reduced pressure to give the purified title compound (10 g, 95% yield).

Intermediate P43.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy-pyrazolo-D-pyridine 3-carbonitrile dihydrochloride.

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) 3,6- diazabicyclo [3.1.1] heptane-6-carboxylate. A mixture of 4- (6-fluoropyridin3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 1.70 g, 8.55 mmol), tert-butyl ester of 3,6-diazabicyclo [3.1.1] heptane-6-carboxylic acid (1.70 g, 8.55 mmol) and KsCO3 ^) (7.88 g, 57.0 mmol) in DMSO (7 ml) was stirred for 12 h at 90 ° C. The resulting thick suspension was diluted with additional DMSO (2 ml) and stirred for 12 h at 90 ° C. The mixture was cooled to ambient temperature and diluted with water (100 ml). The aqueous mixture was washed with DCM. The combined organic extracts were dried over anhydrous MgSO ^^, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (30-80% EtOAc / hexane isomer mixture as gradient eluent system) to afford the purified title compound (2.87 g, 100% yield). MS (apci) m / z = 505.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo dihydrochloride [1,5-a ] pyridine-3-carbonitrile. In a solution of tert-butyl-3- (5- (3cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6diazabicyclo [ 3.1.1] heptane-6-carboxylate (see step 1; 3.05 g, 6.04 mmol) in DCM (20 ml) was added 4N. HCl in dioxane (15.1 ml, 60.4 mmol). The resulting mixture was stirred for 12 hours at ambient temperature and then evaporated under reduced pressure. The crude residue was diluted with DCM and toluene, and then sonicated before concentration under reduced pressure to give the title compound as the dihydrochloride salt (2.44 g, quantitative yield). MS (apci) m / z = 405.2 (M + H).

Intermediate P44.

4- (6- (3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy ^ pyrazolo ^ D ^ pyridine 3-carbonitrile.

A solution of tert-butyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate P43, step 2; 2.0 g, 4.2 mmol) in DCM (42 ml) was washed with 1N. NaOH ^^ y The combined aqueous extracts were again extracted with DCM. All organic extracts were then combined, washed with saturated aqueous sodium chloride solution, then passed through a PS filter and evaporated under reduced pressure to give the title compound (244 mg). Since a significant amount of the desired product remained in the aqueous extracts, the combined aqueous extracts were subjected to a series of extractions, first with 20% iso-PrOH in DCM (3x50 ml). NaCl was then added to the aqueous extracts and stirred for 3 h with 20% iso

- 158 035568

PrOH in DCM (200 ml). The aqueous extracts were separated and diluted with MeOH (500 ml). The resulting slurry was filtered and all organic extracts from the extraction sequence were combined and evaporated under reduced pressure to give an overall recovery of the title compound of 1.75 g which was contaminated with inorganic salts. The crude compound was triturated with DCM and filtered, and the filtrate was evaporated under reduced pressure to give the purified title compound (1.26 g, 74% yield). MS (apci) m / z = 405.2 (M + H).

Intermediate P45.

4- (6- (3,8-diazabicyclo [3.2.1] octan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2hydrochloride methylpropox-pyrazolo-C-pyridine 3-carbonitrile.

Stage 1: obtaining tert-butyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) -3, 8-dia-zabicyclo [3.2.1] octane-8-carboxylate. Via a mixture of 4-bromo-6- (2 hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P41; 45 mg, 0.145 mmol), (6- (8- (tert-butoxycarbonyl ) -3,8-diazabicyclo [3.2.1] octan-3-yl) pyridin-3-yl) boric acid (intermediate R11; 53.2 mg, 0.160 mmol) and Pd (PPh ₃ ) ₄ (16.8 mg , 0.0145 mmol) in 2 M Na ^ O ^^.) (363 μL, 0.725 mmol) in dioxane (725 μL) was purged with N ₂ ( _r ), then stirred for 3 h at 100 ° C in an atmosphere of N ₂ (r). The mixture was cooled to ambient temperature and evaporated under reduced pressure to give the crude title compound (64 mg), which was used directly in the next step. MS (apci) m / z = 519.2 (M + H).

Stage 2: preparation of 4- (6- (3,8-diazabicyclo [3.2.1] octan-3-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile. A solution of tert-butyl 3- (5- (3-cyano-6 (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,8 diazabicyclo [3.2 .1] octane-8-carboxylate (64 mg, 0.12 mmol) in a 1: 1 mixture of DCM: TFA (1 ml) was stirred for 15 min at ambient temperature and then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the purified title compound as a TFA salt. The residue was dissolved in 6N. HCl in iso-PrOH (2 mL) then evaporated immediately under reduced pressure to give the title compound as hydrochloride salt (24 mg, 43% yield). MS (apci) m / z = 419.2 (M + H).

Intermediate P48.

6- (2-hydroxy-2-methylpropoxy) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a pressure vessel through a mixture of 4-bromo-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1.5a] pyridine-3-carbonitrile (intermediate P41; 2.0 g, 6.4 mmol), bis- ( pinacolato) diborone (2.5 g, 9.7 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ (0.53 g, 0.64 mmol) and KOAc (1.9 g, 19 mmol) in dioxane ( 15 ml) was purged with Ar ( _D ) for 10 min. The vial was sealed and the mixture was stirred overnight at 90 ° C. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 ml). The resulting slurry was filtered and the filter cake was washed with EtOAc. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (25% EtOAc in hexane as eluent) to give the title compound (2.2 g, 91% yield).

¹ H NMR (400 MHz, CDCl3) δ: 8.19 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H ), 3.80 (s, 2H) 1.41 (s, 12H), 1.35 (s, 6H).

Intermediate P49.

N = \ but.

| \ F ^nh

4- (4- (3,6-diazabicyclo [3.1.1] heptan-3-yl) phenyl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridine-3-carbonitrile.

- 159 035568

Stage 1: obtaining tert-butyl 3- (4- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5а] pyridin-4-yl) phenyl) -3,6-diazabicyclo [3.1 .1] heptane-6-carboxylate. In a pressure vessel through a mixture of 6- (2-hydroxy-2-methylpropoxy) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5a] pyridine -3-carbonitrile (intermediate P48; 0.100 g, 0.280 mmol), tert-butyl 3- (4-bromophenyl) -3.6 diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate R14; 98.9 mg, 0.280 mmol ), X-Phos (26.7 mg, 0.0560 mmol) and Pd ₂ (dba) ₃ (12.8 mg, 0.0140 mmol) in dioxane (1.0 mL) were purged with Ar ( _D ) for 1 min. To the mixture was added 2 M K ₃ PO ₄ ( _B od _H ) (420 μl, 0.840 mmol) and then Ar _{(g) was} purged for an additional 3 minutes before the vessel was sealed. The resulting reaction mixture was stirred overnight at 85 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (10% acetone in DCM as eluent) to give the title compound (86 mg, 43% yield). MS (apci) m / z = 404.2 (-Boc M + H).

Stage 2: preparation of 4- (4- (3,6-diazabicyclo [3.1.1] heptan-3-yl) phenyl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile. In a solution of tert-butyl-3- (4- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) phenyl) -3,6-diazabicyclo [3.1. 1] heptane-6 carboxylate (86 mg, 0.17 mmol) in DCM (0.5 ml) was added TFA (26 μl, 3.4 mmol). The resulting mixture was stirred for 2 hours at ambient temperature and then evaporated under reduced pressure. The residue was suspended in 1 M NaOI I _{ll! (UI | l} (pH 14). The resulting aqueous mixture was salted out with NaCl ( _ra ) and extracted with CHCl _{3. The} combined organic extracts were dried over anhydrous MgSO ₄ ( _ra ), filtered, and evaporated under reduced pressure to give the title compound (62 mg, 90% yield) MS (apci) m / z = 404.2 (M + H).

Intermediate P50.

N = \ / ^ \ ° II ^N

4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine 3 -carbonitrile.

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1.5а] pyridin-4-yl) pyrazin-2-yl) -3.6 -diazabicyclo [3.1.1] heptane-6-carboxylate. In a pressure vessel through a mixture of 6- (2-hydroxy-2-methylpropoxy) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) pyrazolo [1,5-a] pyridine -3-carbonitrile (intermediate P48; 0.100 g, 0.280 mmol), tert-butyl 3- (5chloropyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate R15; 91.4 mg, 0.294 mmol), X-Phos (26.7 mg, 0.0560 mmol) and Pd ₂ (dba) ₃ (12.8 mg, 0.0140 mmol) in dioxane (1.0 mL) was purged with Ar ( _D ) for 1 min. To the mixture was added 2M K ₃ PO 4 _(in d _H.) (420 L, 0 840 mmol) and then purged with Ar _(g) for an additional 3 minutes before sealing the container. The resulting reaction mixture was stirred overnight at 85 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (20% acetone in DCM as eluent) to give the title compound (62 mg, 37% yield).

Stage 2: preparation of 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6 carboxylate (68 mg, 0.13 mmol) in DCM (0.5 ml) was added TFA (21 μl, 2.7 mmol). The resulting mixture was stirred for 2 hours at ambient temperature and then evaporated under reduced pressure. The residue was suspended in 1 M NaOI I _{ll! (UI | l} (pH 14). The resulting aqueous mixture was salted out with NaCl ( _ra ) and extracted with DCM. The combined organic extracts were dried over anhydrous \ -lgSO4 C .. ,, filtered and evaporated at reduced pressure to give the title compound (39 mg, 64% yield) MS (apci) m / z = 406.2 (M + H).

Intermediate P51.

N = \ Jf Ύ ^HCI 6- (3-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile hydrochloride.

Stage 1: preparation of tert-butyl 4- (5- (6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -3 cyanopyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine -1-carboxylate. A solution of tert-butyl 4- (5- (3cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 250 mg, 0.595 mmol), (3-bromopropoxy) (tert-butyl) dimethylsilane (136 uL, 0.743 mmol) and K ₂ CO _{3 (solid)}

- 160 035568 (247 mg, 1.78 mmol) in DMF (2.97 ml) was stirred for 1 day at 50 ° C. After cooling to ambient temperature, the mixture was purified directly by silica gel chromatography (0-100% EtOAc in hexane isomer mixture) to afford the purified title compound (334 mg, 95% yield). MS (apci) m / z = 593.8 (M + H).

Step 2: Preparation of 6- (3-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride.

In a solution of tert-butyl-4- (5- (6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -3-cyanopyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine- 1-carboxylate (334 mg, 0.563 mmol) in DCM (2.82 ml) was added 4N. HCl in dioxane (2.82 ml, 11.3 mmol), and then stirred for 1 hour at ambient temperature. The resulting slurry was evaporated to give the title compound as the hydrochloride salt (234 mg, quantitative yield). MS (apci) m / z = 378.9 (M + H).

Intermediate P52.

dihydrochloride (^) - 6- (2,3-dihydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

Stage 1: obtaining tert-butyl ^) - 4- (5- (3-cyano-6 - ((2,2-dimethyl-1,3-dioxolane-4yl ^ ethoxy ^ irazolo ^ A ^ pyridine ^ -yl ^ iridine N-yl-iperazine-b-carboxylate. A mixture of tert-butyl 4 (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate ( intermediate P3; 150 mg, 0.357 mmol), ^) - 4- (chloromethyl) -2,2-dimethyl-1,3-dioxolane (53.4 μL, 0.392 mmol) and Cs ₂ CO ₃ ( _TB ) (389 mg , 1.20 mmol) in DMF (3.57 ml) was stirred overnight at 100 ° C. After cooling to ambient temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure.The crude residue was purified by silica gel chromatography (30-100% EtOAc in hexane isomers as gradient eluent) to afford the title compound (71 mg, 37% yield) MS (apci) m / z = 535.3 (M + H).

Stage 2: preparation of dihydrochloride (^) - 6- (2,3-dihydroxypropoxy) -4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl ^) - 4- (5- (3-cyano-6 ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) pyrazolo [1,5-a] pyridine-4 -yl) pyridin-2-yl) piperazine-1-carboxylate (71 mg, 0.106 mmol) in DCM (2 ml) was added 4N. HCl in dioxane (3 ml), and then stirred for 2 hours at ambient temperature. The resulting mixture was evaporated under reduced pressure to give the title compound as hydrochloride salt (41.9 mg, quantitative yield). MS (apci) m / z = 395.2 (M + H).

Intermediate P53.

dihydrochloride (^) - 6- (2,3-dihydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl ^) - 4- (5- (3-cyano-6 - ((2,2-dimethyl-1,3-dioxolan-4yl) methoxy) pyrazolo [1,5-a] pyridine- 4-yl) pyridin-2-yl) piperazine-1-carboxylate. A mixture of tert-butyl 4 (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (130 mg, 0.309 mmol), ^) -4- (chloromethyl) -2,2-dimethyl-1,3-dioxolane (46.6 μl, 0.340 mmol) and Cs ₂ CO ₃ ( _TB ) (337 mg, 1.04 mmol) in DMF (3.09 ml) was stirred overnight at 100 ° C. After cooling to ambient temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (30-100% EtOAc in hexane isomers as gradient eluent) to afford the title compound (40 mg, 24% yield). MS (apci) m / z = 535.3 (M + H).

Stage 2: preparation of dihydrochloride (^) - 6- (2,3-dihydroxypropoxy) -4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl ^) - 4- (5- (3-cyano-6 - ((2,2dimethyl-1,3-dioxolan-4-yl) methoxy) pyrazolo [1,5-a] pyridine-4- yl) pyridin-2-yl) piperazine-1carboxylate (step 1; 40 mg, 0.075 mmol) in DCM (1 ml) was added 4 N HCl in dioxane (2 ml), and then stirred for 6 h at ambient temperature. The resulting mixture was evaporated at reduced

- 161,035,568 pressure to give the title compound as the hydrochloride salt (30 mg, quantitative yield). MS (apci) m / z = 395.2 (M + H).

Intermediate P54.

hydrochloride 6 - (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3- carbonitrile.

Stage 1: preparation of tert-butyl-4- (5- (3-cyano-6 - (((3S, 4S) -4-hydroxytetrahydrofuran-3yl) oxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate. To a suspension of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 115 mg, 0.274 mmol) in DMF (1.37 ml) was added to ₂ CO ₃ ( _TB ) (189 mg, 1.37 mmol), then stirred for 15 min at ambient temperature before adding (1R, 5S) -3,6 dioxabicyclo [ 3.1.0] hexane (118 mg, 1.37 mmol) as a solution in DMF (1 ml). The resulting mixture was stirred for 1 day at 50 ° C, then purified directly by chromatography on silica gel (0-100% DCM in a mixture of hexane isomers followed by a gradient of 20% DCM / MeOH as eluents) to afford the title compound. MS (apci) m / z = 508.8 (M + H).

Stage 2: preparation of 6 - ((^^) - 4-hydroxytetrahydrofuran-3-yl) oxy) -4- (6 (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine hydrochloride -3-carbonitrile. A solution of tert-butyl 4- (5- (3cyano-6 - (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate in 1: 1 DCM: TPA (2 ml) was stirred for 30 min at ambient temperature, then evaporated under reduced pressure. The residue was dissolved in 6N. HCl in iso-PrOH (2 ml) and then evaporated under reduced pressure to give the title compound as hydrochloride salt (83 mg, 69% yield). MS (apci) m / z = 406.8 (M + H).

Intermediate P55.

6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Step 1: Preparation of tert-butyl 4- (5- (3-cyano-6- (2-methoxyethoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate. DIAD (283.7 μL, 1.441 mmol) was added to a cold (0 ° C) solution of PPh ₃ (377.9 mg, 1.441 mmol) in 1: 1 DCM: THF (10 ml) and stirred for 15 min at 0 ° FROM. To the resulting mixture at 0 ° C was added a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3 ; 403.9 mg, 0.9606 mmol) and 2methoxyethanol (90.90 μl, 1.153 mmol) in 1: 1 DCM: THF (20.0 ml). The reaction mixture was stirred for 30 min at room temperature, then evaporated under reduced pressure and purified by chromatography on silica gel (50-100% hexane-EtOAc as gradient eluent) to give the title compound, which was immediately transferred to Step 2.C (apci) m / z = 547.2 (M + H).

Step 2: Preparation of 6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile. A solution of tert-butyl 4- (5- (3-cyano-6- (2-methoxyethoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate in a 1: 1 mixture of DCM : TPA (10 ml) was stirred for 15 min at ambient temperature, then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ^^. The resulting organic extracts were dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the title compound (196.1 mg, 54% yield). MS (apci) m / z = 479.2 (M + H).

Intermediate P56.

dihydrochloride (^) - 6- (2-methoxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

- 162 035568

Stage 1: preparation of tert-butyl (^) - 4- (5- (3-cyano-6- (2-methoxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ... DIAD (155 μl, 0.799 mmol) was added to a cold (0 ° C) solution of PPh ₃ (210 mg, 0.799 mmol) in 1: 1 DCM: THF (4 ml) and stirred for 15 min at 0 ° C. To the resulting mixture at 0 ° C was added a suspension of ^) - 2-methoxypropan-1-ol (72.0 mg, 0.799 mmol) and tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5- a] pyridin-4-yl) pyridin-2-yl) piperazine-1 carboxylate (intermediate P3; 168 mg, 0.400 mmol) in 1: 1 DCM: THF (4.0 ml). The resulting mixture was stirred for 17 hours at room temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-100% acetone-mixture of hexane isomers as gradient eluent) to give the title compound (242 mg, quantitative yield). MS (apci) m / z = 493.2 (M + H).

Stage 2: Preparation of dihydrochloride (^) - 6- (2-methoxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl (^) - 4- (5- (3-cyano-6- (2methoxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylate (197 mg, 0.400 mmol) in DCM (2 ml) was added 5-6 M HCl in iso-PrOH (4 ml, 20.0 mmol) and stirred for 1 h at ambient temperature. The mixture was evaporated under reduced pressure, re-evaporated with Et ₂ O (5 ml) to give the purified title compound as the dihydrochloride salt (233 mg, quantitative yield). MS (apci) m / z = 393.2 (M + H).

Intermediate P57.

6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 1-amino-3-bromo-5-methoxypyridinium 2,4,6-trimethylbenzenesulfonate (intermediate P1, part B, stage 1, 400 g, 0.99 mol) in acetonitrile (3.2 L) was added 2-chloroacrylonitrile (130 g, 1.49 mol). The reaction mixture was cooled with an ice / water bath to a temperature in the region of 0 ° C, after which DBU (559 g, 3.67 mol) was added dropwise. After warming to room temperature and stirring for 16 hours, the reaction mixture was poured into water (9.6 L) and filtered. The isolated wet solid was dissolved in DCM and the aqueous phase was removed. The organic layer was filtered through a plug of silica gel (800 g) and washed with DCM. The organic filtrate was evaporated under reduced pressure to give a crude product which was triturated with MTBE (450 ml), filtered and dried under reduced pressure to give the title compound as an off-white powder (75 g, 30% yield).

1H NMR (CDC13) δ 8.32 (m, 1H), 8.12 (s, 1H), 6.74 (m, 1H), 4.03 (s, 3H).

Intermediate P58.

Ν = \ ^Η0 ^ <Ά J 1 ν> _Ό ' ^ζ ^ ^ίίί ^ ΒΓ

4-bromo-6 - ((1R, 3R) -3-hydroxycyclobutoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In an inert atmosphere (N ₂ (r)), a mixture of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 0.250 g, 1.05 mmol) and K ₂ CO ₃ ( _solid . ) (0.435 g, 3.15 mmol) in DMF (1 ml) was stirred for 10 min at ambient temperature. To the mixture was added (^^) - 3-hydroxycyclobutyl-4methylbenzenesulfonate (intermediate R18; 0.254 g, 1.05 mmol). The reaction vessel was sealed and the mixture was stirred for 2 days at 50 ° C, then for 2 days at 65 ° C. After cooling to ambient temperature, the reaction mixture was poured into a 1: 1 saturated aqueous sodium chloride / water solution (50 ml), diluted with MTBE (20 ml) and stirred vigorously for 20 minutes. The biphasic suspension was filtered under reduced pressure, the solids were collected and the filtrate was extracted with EtOAc (2x50 ml). The combined organic extracts were dried over anhydrous MgSO (B), filtered and evaporated under reduced pressure. The residue from the filtrate was combined with the solid after filtration and purified by chromatography on silica gel (using EYAc: hexane isomer 1: 1 as eluent) to provide the purified title compound (100 mg, 26% yield).

1H NMR (400 MHz, CDCI3) δ 8.18 (s, 1H), 7.90 (d, 1H), 7.39 (d, 1H), 4.82 (m, 1H), 4.65 (m , 1H), 4.97 (m, 4H).

Intermediate P59.

U) -4-bromo-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a mixture of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 500 mg, 2.10

- 163,035,568 mmol) in DMF (4 ml) were successively added to K ₂ CO ₃ ( _TB ) (1.451 g, 10.5 mmol) and d) - 2-methyloxirane (2.21 ml, 31.5 mmol). The reaction mixture was stirred for 3 days at 50 ° C in a sealed vessel. After cooling to ambient temperature, the reaction mixture was purified directly by C18 reverse phase chromatography (using 5-90% ACN / water as eluent gradient) to afford the purified title compound (365 mg, 59% yield).

1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 8.14 (d, 1H), 7.49 (d, 1H), 4.25 (m, 1H), 3.96 ( dd, 1H), 3.86 (dd, 1H), 1.33 (d, 3H).

Intermediate P60.

(S) -4-bromo-6- (2-hydroxypropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

To a mixture of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 500 mg, 2.10 mmol) in DMF (4 ml), K ₂ CO ₃ ( _TB ) (1451 mg, 10.5 mmol) and ^) - 2-methyloxirane (1830 mg, 31.5 mmol). The reaction mixture was stirred for 3 days at 50 ° C in a sealed vessel. After cooling to ambient temperature, the reaction mixture was diluted with water (50 ml) and extracted with DCM (2x50 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (50 ml). The resulting emulsion was filtered through a coarse glass filter and the two-phase filtrate was separated. The organic extracts were washed again with saturated aqueous sodium chloride solution (50 ml), then dried over anhydrous MgSO ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-90% EtOAc / hexane isomer mixture as eluent gradient) to afford the purified title compound (357 mg, 57% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 8.14 (d, 1H), 7.49 (d, 1H), 4.25 (m, 1H), 3.96 (dd, 1H), 3.86 (dd 1H), 1.33 (d, 3H).

Intermediate P61.

4-bromo-6 - ((1 - ((tert-butyldimethylsilyl) oxy) cyclopropyl) methoxy) pyrazole [1,5-a] pyridine-3carbonitrile.

DIAD (665.0 μL, 3.378 mmol) was added to a cold (0 ° C) solution of PPh ₃ (885.9 mg, 3.378 mmol) in 1: 1 DCM: THF (10 ml) and stirred for 15 min at 0 ° FROM. To the resulting mixture was added a solution of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 536.0 mg, 2.252 mmol) and (1 - ((tert-butyldimethylsilyl) oxy) cyclopropyl) methanol (intermediate R19; 546.8 mg, 2.702 mmol) in 1: 1 THF: DCM (10 ml). After stirring for 1 hour at ambient temperature, the reaction mixture was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 5-75% EtOAc / hexane isomer mixture as eluent gradient) to afford the purified title compound (404.2 mg, 42% yield).

1H NMR (400 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 8.08-8.07 (d, 1H), 7.49-7.48 (d, 1H), 3.95 (s , 2H), 0.94-0.89 (m, 2H), 0.85 (s, 9H), 0.76-0.73 (m, 2H), 0.14 (s, 6H).

Intermediate P62.

1 - ((4-bromo-3-chloropyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol.

Step 1: Preparation of 4-bromo-3-chloro-6-methoxypyrazolo [1,5-a] pyridine. NCS (8.821 g, 66.06 mmol) was added to a suspension of 4-bromo-6methoxypyrazolo ^ D ^ pyridine (intermediate P1, part B, step 3; 15 g, 66 mmol) in DCM (100 ml), and the mixtures were sonicated in within 5 minutes. After stirring the resulting mixture overnight at ambient temperature, additional NCS (1.25 g) was added.

The reaction mixture was stirred for an additional 6 h, then diluted with Et ₂ O (100 ml), stirred for 10 min and sonicated for 2 min at ambient temperature. The resulting suspension was filtered under reduced pressure, washing the solid with Et ₂ O (2x100 ml). The filtrate was diluted with additional Et ₂ O (100 ml), then sonicated and filtered under reduced pressure. The solids from both filters were combined to give the title compound (18.69 g, quantitative yield). MS (apci) m / z = 260.9, 263.0 (M + H).

- 164 035568

Stage 2: preparation of 4-bromo-3-chloropyrazolo [1,5-a] pyridin-6-ol. In an atmosphere of N ₂ ( _r ) (4-bromo-3-chloro6-methoxypyrazolo [1,5-a] pyridine (7.59 g, 29.0 mmol) was suspended in DCE (290 ml), and then slowly (5% ) min) AlCl ₃ (11.6 g, 87.1 mmol) was added. The resulting mixture was stirred overnight at 76 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DMA (75 ml) resulting in a slight exotherm. DCE was removed under reduced pressure and the residue was diluted with water (125 ml). The aqueous suspension was stirred at 0 ° C for 30 min, then cold filtered under reduced pressure. The solids were washed with cold (0 ° C) water (50 ml) and dried under reduced pressure to give the title compound (7.00 g, 98% yield). The crude compound was dissolved in anhydrous DMA (150 ml) and filtered through a pad of silica gel, washing the pad with additional anhydrous DMA (7x50 ml). A portion of the filtrate (300 ml) was transferred to step 3. MS (apci) m / z = 246.9, 248.9 (M + H).

Step 3: Preparation of 1 - ((4-bromo-3-chloropyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol. To a 0.06 M solution of 4-bromo-3-chloropyrazolo [1,5-a] pyridin-6-ol in DMA (300 ml, 17.0 mmol) was added K ₂ CO3 ( _ra ) (23.5 g, 170 mmol) and 2,2-dimethyloxirane (7.45 ml, 84.9 mmol). After stirring the reaction mixture for 3 h at 55 ° C, additional 2,2-dimethyloxirane (7.45 mL, 84.9 mmol) was added. The reaction mixture was stirred overnight at 55 ° C after which a second aliquot of K ₂ CO3 ( _ra ) (10 g, 72.3 mmol) and an additional amount of 2,2-dimethyloxyrane (7.45 ml, 84.9 mmol) were added ... The reaction mixture was stirred for 2 h at 85 ° C to complete the reaction. After cooling to ambient temperature, the reaction mixture was poured into a 1: 1 mixture of saturated NH ₄ Cl ( _βod .): Water (200 ml). The resulting reaction mixture was washed with EtOAc (5x) and the combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The residue was triturated with water (100 ml) and the solid was collected by filtration under reduced pressure to give the purified title compound (2.62 g, 34% yield). MS (apci) m / z = 319.0, 321.0 (M + H).

Intermediate P63.

4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-ίΐ | ι sridi! ι-3 -carbonitrile.

Step 1: Preparation of 6-bromo-4-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile. In an inert atmosphere (N _{2 (f} )), a solution of 6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P57; 200 g, 873 mmol) in DMA (2494 ml) was stirred at 40 ° C and added dropwise (3 drops per second) 2 M NaOH ^ oOT.) (105 ml, 1746 mmol), then water 5 ml; for flushing the dropping funnel. Then, dodecyl mercaptan (418 ml, 1746 mmol) was added dropwise (3 drops per second). The resulting reaction mixture was stirred for 2 h at 40 ° C. After cooling to ambient temperature, the reaction mixture was poured into cold (~ 10 ° C) water (8 L) and the pH was adjusted to ~ 5 by adding 10% aqueous citric acid solution. The resulting reaction mixture was stirred for 4 hours at ambient temperature, then left for 12 hours at ambient temperature to allow more precipitate to form. The mixture was then stirred for 1 hour at ambient temperature, after which it was filtered under reduced pressure, washing with water (1.5 L). The filter cake was dried under reduced pressure for 2 h, then triturated with heptane (2 L), filtered and dried under reduced pressure to give the title compound (181 g, 87% yield).

1 H NMR (400 MHz, d ₆ -DMSO) δ 11.81 (br C, 1H), 8.82 (d, 1H), 8.55 (s, 1H), 6.87 (d, 1H).

Step 2: Preparation of 6-bromo-3-cyanopyrazolo [1,5-a] pyridin-4-yl trifluoromethanesulfonate. Under an inert atmosphere (N ₂ ( _F )) to a cold (4 ° C) suspension of 6-bromo-4-hydroxypyrazolo [1,5-a] pyridine-3carbonitrile (step 1; 100 g, 420.1 mmol) in DMA ( 2100 ml) DIEA (146.7 ml, 840.2 mmol) was added slowly (10 min). To the resulting cold solution (2 ° C) was added dropwise (3 drops per second) a solution of 1,1,1-trifluoro-N-phenyl-N ((trifluoromethyl) sulfonyl) methanesulfonamide (157.6 g, 441.1 mmol) in DMA (80 ml). The reaction mixture was stirred at low temperature (0-13 ° C) for 4 h. The reaction mixture was slowly poured (15 min) into ice water (8 L). The resulting reaction mixture was stirred for 1 hour at ambient temperature. The resulting suspension was filtered under reduced pressure through a paper filter, the cake was compacted on the filter with a spatula and washed with cold water (3 L). The resulting filter cake was dried under reduced pressure for 3 days to give the title compound (148.5 g, 96% yield).

1H NMR (400 MHz, d6-DMSO) δ 9.60 (d, 1H), 8.85 (s, 1H), 8.22 (d, 1H).

Step 3: Preparation of 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. Through a cold (0 ° C) mixture of 6-bromo-3-cyanopyrazolo [1,5-a] pyridin-4-yl trifluoromethanesulfonate (stage 2; 98.5 g, 253 mmol) and 2-fluoro-5- (4, 4 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (56.4 g, 253 mmol) in dioxane (2 L) was purged with LH ( _g ) for 5 min. PdCl ₂ (dppf) -CH ₂ Cl ₂ (8.26 g, 10.1 mmol) was added to the cold mixture, and Lr (g) was purged again for 5 minutes. While stirring the resulting mixture at

- 165 035568

0 ° C to the mixture was added a solution of KOAc (49.6 g, 506 mmol) in water (500 ml) in an inert atmosphere (Ν _{2 (γ)} ). The mixture was stirred mechanically overnight at ambient temperature under positive pressure Ν ₂ ( _Γ ). The reaction mixture was poured into water (7 L) and stirred for 5 h at ambient temperature. The resulting suspension was filtered and washed with MTBE (1 L). The resulting filter cake was dried under reduced pressure to give the title compound (75 g, 94% yield).

Ή NMR (400 MHz, ^ -DMSU) δ 9.49 (d, 1H), 8.73 (s, 1H), 8.50 (m, 1H), 8.27 (m, 1H), 7.86 (d, 1H), 7.40 (m, 1H).

Step 4: Obtaining 4- (6-fluoropyridin-3-yl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyrazolo [1,5-a] pyridine-3 -carbonitrile. Through a suspension of 6-bromo-4- (6-fluoropyridine-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (stage 3; 55.1 g, 174 mmol), bis- (pinacolato) diborone (46, 3 g, 182 mmol) and KOAc (51.2 g, 521 mmol) in DMSO (430 mL) were purged with Ar ( _r ) for 10 min. To the reaction mixture was added with PdCl ₂ (dppf) -CH ₂ Cl ₂ (1.42 g, 1.74 mmol) and purged with Ar _(r) for an additional 10 min. The resulting mixture was mechanically stirred for 16 h at 70 ° C under a positive pressure Ν ₂ ( _Γ ). After cooling to ambient temperature, the reaction mixture was diluted with 1: 1 EtOAc: water (4.0 L) and stirred for 1 hour. The resulting suspension was filtered. The solids were washed sequentially with water (500 ml) and EtOAc (500 ml) and the biphasic filtrate was separated. The organic layer was temporarily set aside while the aqueous layer was extracted with EtOAc (2x1 L). The organic extracts were combined, washed with water (2x1 L) and saturated aqueous sodium chloride solution (500 ml), then dried over anhydrous Na ^ O ^) and filtered. The filtrate was treated with Si-Thiol resin (2 g; to remove residual Pd) and stirred for 16 h at ambient temperature. The suspension was filtered, the resin was washed with EtOAc and the filtrate was evaporated under reduced pressure. The crude compound was purified by silica gel chromatography (using 5-60% hexane-acetone as gradient eluent). Fractions containing the desired compound were combined and evaporated under reduced pressure to give a semi-pure material. The solid was recrystallized in batches by dissolving part of the material (12.3 g) in acetone (120 ml) at 60 ° C. Hexane (120 ml) was added to the hot solution, then allowed to cool to ambient temperature before being placed in a -18 ° C freezer for 2 hours. The cold suspension was filtered under reduced pressure, rinsing the pure solids with hexane at ambient temperature. Repeating this recrystallization procedure on the remaining crude material afforded the pure title compound (46.2 g, 73%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.99-8.98 (d, 1H), 8.77 (s, 1H), 8.49-8.48 (m, 1H), 8.27-8 , 22 (m, 1H), 7.577.56 (d, 1H), 7.38-7.35 (m, 1H), 1.34 (s, 12H).

Stage 5. Obtaining 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile. To a cold (0 ° C) solution of 4- (6-fluoropyridin-3-yl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (step 4; 22.96 g, 57.06 mmol) in THF (315 ml, 0.2 M) was added 2 M CHOH water.) (142.6 ml, 285.3 mmol), and then 35 wt% H ₂ O ₂ ( _aq ) (29.97 mL, 342.3 mmol) was added dropwise. The resulting mixture was stirred for 3 h at 0 ° C, then 3 M No. ₂ 8 ₂ O ₃ ( _Water .) (114.1 ml, 342.3 mmol) was added at 0 ° C. The cooled mixture was stirred for 16 h at ambient temperature, then the mixture was partitioned between MTBE (1 L) and water (200 ml). The biphasic mixture was stirred for 15 minutes and then filtered, washing with additional water. The resulting biphasic filtrate was separated and the organic extracts from the filtrate were washed with 0.1 M NaOI 1 _(aq . _: , (200 ml). The aqueous extracts were combined, washed with MTBE (500 ml), then acidified to pH ~ 5 using solid citric acid. the aqueous suspension was diluted with additional water (250 ml), stirred for 30 min, and then filtered.

The solids were washed with water and dried under reduced pressure to give the title compound (11.3 g, 66% yield). MS (APCI Neg.) M / z = 253.0 (M-H).

Intermediate P64.

4- (6-fluoropyridin-3-yl) -6- (2- (2-oxopyrrolidin-1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3 carbonitrile.

To a solution of 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P63; 200 mg, 0.787 mmol) in DMA (6 ml) was added C ^ CO ^ s) (769 mg, 2.36 mmol) and 1- (2-chloroethyl) pyrrolidin-2-one (139 mg, 0.944 mmol). The reaction mixture was stirred overnight at 100 ° C in a sealed vessel. After cooling to ambient temperature, the resulting mixture was partitioned between water and DCM, then extracted with DCM (3x). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (1x), then dried over anhydrous ZhO ₄ ( _ta ), filtered and evaporated under reduced pressure. The crude residue was purified

166 035568 silica gel chromatography (using 0-10% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the title compound (115 mg, 34% yield). MS (apci) m / z = 366.1 (M + H).

Intermediate P65.

N = \ ^ηο > ρΛ η 1

4- (6-fluoropyridin-3-yl) -6 - ((1R, 3R) -3-hydroxycyclobutoxy) pyrαzolo [1,5-a] pyridine-3carbonitrile.

Through a mixture of 4-bromo-6 - ((1r, 3r) -3-hydroxycyclobutoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P58; 0.100 g, 0.325 mmol), 2-fluoro-5- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) pyridine (629 mg, 2.82 mmol) and Pd (PPh ₃ ) ₄ (217 mg, 0.188 mmol) in dioxane (1 ml) A _{(d) was} purged for 1 min, then 2 M K ₂ CO ₃ ( _VODN .) (0.470 mL, 0.974 mmol) was added. The resulting mixture was purged with AG ( _D ) for 3 min, then the reaction vessel was sealed. The mixture was stirred for 3 days at 90 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 40% EtOAc in hexane as eluent) to afford the purified title compound (96 mg, 91% yield). MS (apci) m / z = 325.1 (M + H).

Intermediate P66.

N == \ ⁿ k.

Ο% | Ν (R) -4- (6-fluoropyridin-3-yl) -6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a tube under pressure, into a solution of (R) -4-bromo-6- (2-hydroxypropoxy) pyrαzolo [1,5-a] pyridine-3carbonitrile (intermediate P59; 365 mg, 1.23 mmol) in dioxane (6 ml ) were added 2-fluoro-5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (330 mg, 1.48 mmol) and 2 M No. 2SKhK _{D! 0DND |} (1849 μl, 3.70 mmol) then purged with N _{2 (r)} for 5 min. Pd (PPh ₃ ) ₄ (35.6 mg, 0.0308 mmol) was added to the resulting mixture, followed by N _{2 (r)} purging again for 5 minutes before sealing the vessel. The reaction mixture was stirred for 22 h at 80 ° C. After cooling to ambient temperature, the mixture was diluted with water (25 ml) and stirred for 1 hour. The resulting slurry was filtered under reduced pressure and the solids were collected to give the purified title compound (229 mg, 60% yield). MS (apci) m / z = 313.1 (M + H).

Intermediate P67.

N = \ ξ | l -J (S) -4- (6-fluoropyridin-3-yl) -6- (2-hydroxypropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

In a tube under pressure, to a solution of (S) -4-bromo-6- (2-hydroxypropoxy) pyrαzolo [1,5-a] pyridine-3carbonitrile (intermediate P60; 357 mg, 1.21 mmol) in dioxane (6 ml ) was added 2-fluoro-5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (323 mg, 1.45 mmol) and 2 M No. 2SKhK _{D! 0DND |} (1808 μL, 3.62 mmol) and purged with N _{2 (r)} for 5 min. Pd (PPh ₃ ) ₄ (34.8 mg, 0.0301 mmol) was added to the resulting mixture, followed by N ₂ ( _r) purging again for 5 minutes before the vessel was sealed. The reaction mixture was stirred for 22 h at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with water (25 ml) and stirred for 1 h. The resulting suspension was filtered under reduced pressure and the solids were collected to give the purified title compound (191 mg, 51% yield). MS (apci) m / z = 313.1 (M + H).

Intermediate P68.

6 - ((1 - ((tert-butyldimethylsilyl) oxy) cyclopropyl) methoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a solution of 4-bromo-6 - ((1 - ((tert-butyldimethylsilyl) oxy) cyclopropyl) methoxy) pyrazolo [1.5a] pyridine-3-carbonitrile (intermediate P61; 404.2 mg, 0.9569 mmol) in a mixture of 4: 1 dioxane: water (10 ml) was added 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (234.8 mg, 1.053 mmol ), Pd (PPh ₃ ) ₄ (110.6 mg, 0.09569 mmol) and K ^ CO ^) (396.8 mg, 2.871 mmol). The resulting mixture was purged

- 167 035568 with argon Ar ( _G ) before sealing the reaction vessel. The mixture was stirred for 16 h at 90 ° C. After cooling to ambient temperature, the reaction mixture was diluted with a 4: 1 mixture of DCM: iso-PrOH, washed with water (1x), then dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 5-75% hexane-EtOAc as gradient eluent) to afford the purified title compound (292.6 mg, 70% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40-8.39 (m, 1H), 8.21 (s, 1H), 8.18-8.17 (d, 1H), 8.04- 8.00 (m, 1H), 7.207.19 (d, 1H), 7.14-7.11 (m, 1H), 4.01 (s, 2H), 0.95-0.92 (m, 2H), 0.85 (s, 9H), 0.80-0.75 (m, 2H), 0.14 (s, 6H).

Intermediate P69.

1 - ((3-chloro-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol.

In a pressure vessel to a mixture of 1 - ((4-bromo-3-chloropyrazolo [1,5-a] pyridin-6-yl) oxy) -2methylpropan-2-ol (intermediate P61; 1.44 g, 4.51 mmol), 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (1.51 g, 6.76 mmol) and Pd (PPh ₃ ) ₄ ( 260 mg 0.225 mmol) in dioxane (50 ml) was added 2 M (CO ^.) (15 ml, 27 mmol). The resulting mixture was purged with 2 ( _Γ ) for 10 min before sealing the vessel. The reaction mixture was stirred overnight at 90 ° C. After cooling to ambient temperature, the resulting mixture was diluted with water (75 ml) and extracted with MTBE (3x75 ml). The combined organic extracts were dried over anhydrous Na2SO _{4 (MW),} filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc / hexane isomer mixture as eluent gradient) to afford the purified title compound (370 mg, 25% yield). MS (apci) m / z = 336.1 (M + H).

Intermediate P70A: 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile and intermediate P70B: dihydrochloride 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -3,6-diazabicyclo [3.1.1] heptane- 6-carboxylate. In a solution of 4- (6-fluoropyridin-3-yl) -6hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P63; 1.256 g, 4.941 mmol) and tert-butyl 3,6-diazabicyclo [3.1.1 ] heptane-6-carboxylate (1.317 g, 6.917 mmol) in DMSO (6 ml), DIEA (1.721 ml, 9.881 mmol) was added. The reaction vessel was sealed and the mixture was stirred for 24 h at 60 ° C. Added additional amount of tert-butyl-3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (0.586 g) and the reaction mixture was stirred 72 h at 60 ° C. After cooling to ambient temperature, the reaction mixture was poured into water (60 ml) and the resulting suspension was filtered under reduced pressure. The solid was collected, then dissolved in EtOAc, dried over anhydrous Na2SO _{4 (MW),} filtered and evaporated under reduced pressure. Separately, the aqueous filtrate was again extracted with a 4: 1 mixture of DCM: iso-PrOH (4x) and the combined organic extracts were evaporated under reduced pressure. The crude residue and solids after filtration were purified by silica gel chromatography (using 0-95% DCM: acetone as gradient eluent) to afford the title compound (1.0 g, 49% yield). MS (apci) m / z = 433.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile idihydrochloride 4- ( 6- (3,6-diazabicyclo [3.1.1] heptan3-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile. A solution of tert-butyl 3- (5- (3cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6carboxylate ( 1.0 g, 2.40 mmol) in 1: 1 TFA: DCM (5 ml), diluted with DCM (5 ml) and stirred for 45 min at ambient temperature. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO (^ ().). The biphasic mixture was extracted with 4: 1 DCM: i-PrOH (3x), and the combined organic extracts were dried over anhydrous Na2SO _{4 (MW),} filtered and evaporated under reduced pressure, yielding intermediate P70A: 4- (6- (3,6diazabitsiklo [3.1 .1] heptan-3-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (322.9 mg, 40% yield). MS (apci) m / z = 333.1 (M + H). Separately, the extracts NaHCO ^ () were evaporated under reduced pressure and the residue was dissolved in 4: 1 DCM: iso-PrOH. The suspension was filtered at reduced

- 168,035568 pressure and the filtrate was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. This residue was dissolved in MeOH and concentrated HCl (10 ml) was added. The suspension was filtered and evaporated under reduced pressure to remove MeOH before diluting with MeOH (10 ml) and MTBE (40 ml). The resulting suspension was sonicated for several minutes, then filtered. The solids were washed with MTBE and dried under reduced pressure to give intermediate P70B: 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6hydroxypyrazolo dihydrochloride [1,5- a] pyridine-3-carbonitrile (450.7 mg, 46% yield). MS (apci) m / z = 333.2 (M + H).

Intermediate P71.

6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

Into a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P70B; 322, 9 mg, 0.9715 mmol) in DCM (10 ml) were successively added 6-methoxy-nicotinaldehyde (137.1 mg, 1.943 mmol) and 2 drops of glacial acetic acid. The mixture was stirred for 15 minutes at ambient temperature, then NaBH (AcO) ₃ (514.8 mg, 2.429 mmol) was added. The resulting mixture was stirred overnight at ambient temperature before adding additional 6-methoxy-nicotinaldehyde (34 mg) and NaBH (AcO) ₃ (103 mg). The resulting mixture was stirred until LCMS indicated complete consumption of starting material, then the mixture was concentrated. The residue was diluted with a 4: 1 mixture of DCM: isoPrOH and extracted with water (2x). The combined aqueous extracts were back extracted 4: 1 with DCM: iso-PrOH (3x). The organic extracts were combined, then dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was diluted 4: 1 with DCM: isoPrOH and extracted with saturated Na1CXC _{1! Od1M} . The aqueous extracts were washed with 4: 1 DCM: isoPrOH (3x), then the combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the purified title compound (27.4 mg, 6% yield). MS (apci) m / z = 454.2 (M + H).

Intermediate P72.

N = \ ί I

Ηο ^^ γ ^ Ν o

6-hydroxy-4- (6- (6- (6-methoxy-nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3- carbonitrile.

Into a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5а] pyridine-3-carbonitrile (intermediate P70B; 187, 7 mg, 0.5647 mmol) in DCM (11.3 ml) was added 2methoxy-5-pyridinecarboxylic acid (86.48 mg, 0.5647 mmol), HATU (257.7 mg, 0.6776 mmol) and DIEA ( 393.5 μl, 2.259 mmol). The resulting mixture was stirred for 16 h at ambient temperature, then additional 2-methoxy-5-pyridinecarboxylic acid (43.23 mg, 0.2824 mmol) and DIEA (199 μl, 1.13 mmol) were added. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NH (1).). The organic extracts were purified directly by silica gel chromatography (using 0-10% MeOH / DCM as gradient eluent) to afford the title compound (68.6 mg, 26% yield). MS (apci) m / z = 468.2 (M + H).

Intermediate P73.

N = \ ί Ύ

Ι \ ^ ΝΗ

6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 255.7 mg, 0.9058 mmol) in DMSO (3.6 ml) tert-butyl 1-piperazinecarboxylate (337.4 mg,

- 169 035568

1.812 mmol) and DIEA (315.6 μl, 1.812 mmol), and then stirred for 16 h at 90 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and sequentially extracted with water (3x) and saturated aqueous sodium chloride solution (1x). The combined organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was dissolved in 1: 1 DCM: TFA (5.0 ml). After stirring for 30 minutes at ambient temperature, the mixture was evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent). Fractions containing the desired compound were combined, dissolved in 4: 1 DCM: iso-PrOH, and then extracted with saturated NaHCO (^ ().). The organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the purified title compound (261.9 mg, 83% yield). MS (apci) m / z = 349.2 (M + H).

Intermediate P74.

bis- (2,2,2-trifluoroacetate) 6-ethoxy-4- (6- (piperαzin-1-ul) pyrudin-3-ul) pyrαzolo [1,5-a] pyridine-3carbonitrile.

In a solution of tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine 1-carboxylate (example 29; 413 mg, 0.921 mmol) in DCM (8 ml) was added TFA (2 ml). After stirring for 1 hour at ambient temperature, the mixture was evaporated under reduced pressure to give the purified title compound (quantitative yield). MS (apci) m / z = 349.2 (M + H).

Intermediate P75.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile.

To a mixture of 6-ethoxy-4- (6-fluoropyridin-3-ul) pyrαzolo [1,5-a] pyrudin-3-carbonitrile (intermediate P6; 347 mg, 1.23 mmol) and tert-butyl-3,6 β-diazabicyclo [3.1.1] heptane-6-carboxylate (176.6 mg, 0.8908 mmol) in DMSO (0.8 ml) was added DIEA (221.7 μl, 1.273 mmol). The mixture was stirred for 3 days at 60 ° C in a sealed vessel. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and extracted with water (3x) and saturated aqueous sodium chloride solution (1x). The organic extracts were then dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc in a mixture of hexane isomers as eluent gradient) to afford pure tert-butyl 3- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridine- 4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane6-carboxylate. This material was suspended in DCM (1.0 ml) and a 1: 1 mixture of TFA: DCM (0.25 ml) was added. After stirring for 7 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in 4: 1 DCM: iso-PrOH and extracted with saturated NaHCO (^ ().). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure to give the purified title compound (67.1 mg, 29% yield) MS (apci) m / z = 361.2 (M + H).

Intermediate P76.

bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

Stage 1: obtaining tert-butyl-3- (5- (3-cyano-6- (2-morpholinoethoxy) pyrαzolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3,6-diazabicyclo [ 3.1.1] heptane-6-carboxylate. In a solution of tert-butyl-3- (5- (3-cyano-6hydroxypyrαzolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6 -carboxylate (in

- 170 035568 thermediat P4; 350 mg, 0.809 mmol) in DMA (4046 μl) were sequentially added with K ₂ CO ₃ ( _TB ) (336 mg, 2.43 mmol) and 4- (2-chloroethyl) morpholine (218 μl 1.62 mmol). The reaction mixture was stirred overnight at 50 ° C in a sealed vessel. The reaction mixture was cooled to ambient temperature, then diluted with water (10 ml). The resulting suspension was filtered under reduced pressure, washing the solid with water (2x10 ml), then Et ₂ O (2x10 ml). The solids were dried under reduced pressure to give the title compound (380 mg, 86% yield). MS (apci) m / z = 546.3 (M + H).

Stage 2: preparation of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl 3- (5- (3cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyrigin-4-yl) pyridin-2-yl) -3,6 diazabicyclo [3.1.1] heptane -6-carboxylate (step 1; 380 mg, 0.696 mmol) in DCM (2 ml) was added TFA (2 ml). The resulting mixture was stirred for 10 minutes at ambient temperature and then evaporated under reduced pressure to give the purified title compound (400 mg, quantitative yield). MS (apci) m / z = 446.2 (M + H).

Intermediate P77.

bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- (2oxopyrrolidin-1- yl) ethoxy) pyrazolo [1,5-a] pyrigine-3-carbonitrile.

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6- (2- (2-oxopyrrolidin-1-yl) ethoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl ) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate. Mixture of 4- (6-fluoropyridin-3-yl) -6- (2- (2-oxopyrrolidin-1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P64; 115 mg, 0.315 mmol) , tert-butyl-3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (93.6 mg, 0.472 mmol) and K ₂ CO ₃ ( _TB ) (218 mg, 1.57 mmol) in DMSO (630 μl) was stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was partitioned between water and DCM, then extracted with DCM (5x). The combined organic extracts were washed with saturated aqueous sodium chloride solution (1x), then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc in hexane isomers followed by 0-10% MeOH in EtOAc as gradient eluent) to afford the title compound (85 mg, 30% yield). MS (apci) m / z = 544.3 (M + H).

Stage 2: preparation of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) -6- (2- (2- oxopyrrolidin-1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl 3- (5- (3-cyano-6- (2- (2-oxopyrrolidin-1-yl) ethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyrigin-2-yl) 3 , 6-diazabicyclo [3.1.1] heptane-6-carboxylate (step 1; 85 mg, 0.094 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure to give the purified title compound (63 mg, quantitative yield). MS (apci) m / z = 444.2 (M + H).

Intermediate P78.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1d, 3r-3-hydroxycyclobutoxy) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6 - ((1g, 3d) -3-hydroxycyclobutoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) -3 , 6-diazabicyclo [3.1.1] heptane-6-carboxylate. A mixture of 4- (6-fluoropyridin3-yl) -6 - ((1g, 3g) -3-hydroxycyclobutoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P65; 50 mg, 0.15 mmol), tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (0.046 g, 0.23 mmol) and K ₂ CO ₃ ( _TB ) (0.11 g, 0.77 mmol) in DMSO ( 0.25 ml) was stirred overnight at 85 ° C. The reaction mixture was cooled to ambient temperature, diluted with water (1 ml) and extracted with DCM (3 ml). The organic extracts were purified by silica gel chromatography (using 10% acetone in DCM with 0.05% NH4OH as gradient eluent) to afford the purified title compound (56 mg, 61% yield). MS (apci) m / z = 503.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1R, 3R) -3hydroxycyclobutoxy) pyrazolo [1,5- a] pyrigine-3-carbonitrile. In a solution of tert-butyl-3- (5- (3-cyano-6 ((1g, 3d) -3-hydroxycyclobutoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3 , 6-171 035568 diazabicyclo [3.1.1] heptane-6-carboxylate (step 1; 56 mg, 0.095 mmol) in DCM (0.5 ml) was added TFA (0.11 ml). The resulting mixture was stirred for 4 hours at ambient temperature and then evaporated under reduced pressure. The pH of the residue was adjusted to pH 14 with 1M NaOH. The aqueous mixture was salted out with solid NaCl, then extracted with CHCl ₃ (2x20 ml). The combined organic extracts were dried over anhydrous MgSO ^), filtered and evaporated under reduced pressure to give the pure title compound (55 mg, quantitative yield). MS (apci) m / z = 403.2 (M + H).

Intermediate P79.

tert-butyl 3- (5- (3-cyano-6 - (^) - 2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) 3,6-diazabicyclo [3.1 .1] heptane-6-carboxylate.

A mixture of (R) -4- (6-fluoropyridin-3-yl) -6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P66; 100 mg, 0.320 mmol), tert- butyl 3,6-diazabicyclo [3.1.1] heptane-6karboksilata (95.2 mg, 0.480 mmol) and ₂ Κ ΟΟ ₃ (. _{ι. Β)} (443 mg, 3.20 mmol) in DMSO (1601 l) stirred for 3 days at 80 ° C. The reaction mixture was cooled to ambient temperature, then diluted with water (10 ml) and extracted with DCM (4x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (50-100% EtOAc in hexane isomers as gradient eluent) to afford the purified title compound (97 mg, 62% yield). MS (apci) m / z = 491.2 (M + H).

Intermediate P80.

bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2hydroxypropox ^ pyrazolo ^ ^^ pyridine 3-carbonitrile.

In a solution of tert-butyl 3- (5- (3-cyano-6 - ((R) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate P79; 97 mg, 0.20 mmol) in DCM (2 ml) was added TFA (2 ml). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure to give the title compound (122 mg, quantitative yield). MS (apci) m / z = 391.15 (M + H).

Intermediate P81.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2-hydroxypropoxy) pyrazolo [1,5a] pyridine-3-carbonitrile ...

In a solution of tert-butyl 3- (5- (3-cyano-6 - ((R) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate P79; 131 mg, 0.267 mmol) in DCM (2 ml) was added TFA (2 ml). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (using 0-100% (2% NH4OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to afford the title compound (75 mg, 72% yield). MS (apci) m / z = 391.20 (M + H).

- 172 035568

Intermediate P82.

tert-butyl 3- (5- (3-cyano-6 - ((H) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) 3,6-diazabicyclo [ 3.1.1] heptane-6-carboxylate.

A mixture of ^) - 4- (6-fluoropyridin-3-yl) -6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P67; 100 mg, 0.320 mmol), tert-butyl -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (95.2 mg, 0.480 mmol) and K ₂ CO ₃ ( _TB ) (443 mg, 3.20 mmol) in DMSO (1601 μL) were stirred in within 3 days at 80 ° C. The reaction mixture was cooled to ambient temperature, then diluted with water (10 ml) and extracted with DCM (4x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (50-100% EtOAc in hexane isomers as gradient eluent) to afford the purified title compound (92 mg, 59% yield). MS (apci) m / z = 491.2 (M + H).

Intermediate P83.

bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2hydroxypropoxy ^ irazolo ^ E ^ pyridine 3-carbonitrile.

In a solution of tert-butyl-3- (5- (3-cyano-6 - ((S) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3,6- diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate P82; 92 mg, 0.188 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure to give the title compound (116 mg, quantitative yield). MS (apci) m / z = 391.20 (M + H).

Intermediate P84.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1-hydroxycyclopropyl) methoxy) pyrazolo [1,5-a] pyridine dihydrochloride 3-carbonitrile.

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6 - ((1-hydroxycyclopropyl) methoxy) pyrazolo [1.5a] pyridin-4-yl) pyridin-2-yl) -3,6- diazabicyclo [3.1.1] heptane-6-carboxylate. In a solution of 6 - ((1 - ((tert-butyldimethylsilyl) oxy) cyclopropyl) methoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P68; 292.6 mg, 0.6672 mmol) in DMSO (1.3 ml) was added tert-butyl ester of 3,6-diazabicyclo [3.1.1] heptane-6-carboxylic acid (158.7 mg, 0.8006 mmol) and K2CO ₃ ( _TB .) (922.0 mg, 6.672 mmol) and stirred for 14 days at 90 ° C. The reaction mixture was cooled to ambient temperature, then diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed with water (3x) and saturated aqueous sodium chloride solution (1x), then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 5-95% DCM-acetone as gradient eluent) to afford the purified title compound which was immediately transferred to Step 2. MS (apci) m / z = 503.2 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1hydroxycyclopropyl) methoxy) pyrazolo [1,5-a] dihydrochloride pyridine-3-carbonitrile. A solution of tert-butyl 3- (5- (3cyano-6 - ((1-hydroxycyclopropyl) methoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3.6 diazabicyclo [3.1. 1] heptane-6-carboxylate (step 1; estimated 0.6672 mmol) in 1: 1 DCM: TPA (2 ml) was stirred for 15 min at ambient temperature and then evaporated under reduced pressure. The residue was dissolved in 6M HCl in iso-PrOH (4448 μl, 26.69 mmol), sonicated for several minutes, then evaporated under reduced pressure to afford the purified title compound (121 mg, 38% yield). MS (apci) m / z = 403.2 (M + H).

- 173 035568

Intermediate P85.

bis- (2,2,2-trifluoroacetate) U) -6- (2-hydroxy-2-methylpropoxy) -4- (6- (2-methylpiperazin-1 yl) pyridin-3-yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 1H) -4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5а] pyridin-4-yl) pyridin-2-yl) -3 -methylpiperazine-1-carboxylate. A mixture of 4- (6-fluoropyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 1.70 g, 8.55 mmol), tert-butyl (NI) -3-methylpiperazine-1-carboxylate (123 mg, 0.613 mmol) and K ₂ CO ₃ ( _TB) (212 mg, 1.53 mmol) in DMSO (409 μl) were stirred for 5 days at 80 ° C. After cooling to ambient temperature, the resulting mixture was diluted with water (5 ml) and extracted with DCM (4x5 ml). The combined organic extracts were dried over anhydrous Na ₂ SO _{4 (} TB) _5, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc in a mixture of hexane isomers as gradient eluent) to afford the title compound (10 mg, 6% yield). MS (apci) m / z = 507.3 (M + H).

Stage 2: obtaining bis- (2,2,2-trifluoroacetate) U) -6- (2-hydroxy-2-methylpropoxy) -4- (6- (2methylpiperazin-1-yl) pyridin-3-yl) pyrazolo [ 1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl (N) 4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3methylpiperazine- 1-carboxylate (step 1; 10 mg, 0.020 mmol) in DCM (1 ml) was added TFA (0.5 ml). The resulting mixture was stirred for 2 hours at ambient temperature and then evaporated under reduced pressure to give the title compound (13 mg, quantitative yield). MS (apci) m / z = 407.2 (M + H).

Intermediate P86.

bis- (2,2,2-trifluoroacetate) 4- (6- (4,7-diazaspiro [2,5] octan-7-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 7- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) 4,7- diazaspiro [2.5] octane-4-carboxylate. A mixture of 4- (6-fluoropyridin-3-yl) 6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 50 mg, 0.15 mmol), tert α-butyl 4,7-diazaspiro [2.5] octane-4-carboxylate (65 mg, 0.31 mmol) and K ₂ CO ₃ ( _ra ) (212 mg, 1.5 mmol) in DMSO (766 μl) stirred for 23 h at 80 ° C. After cooling to ambient temperature, the resulting mixture was diluted with water (10 ml) and extracted with DCM (4x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc in hexane isomers as gradient eluent) to afford the title compound (69 mg, 87% yield). MS (apci) m / z = 519.2 (M + H).

Stage 2: preparation of bis- (2,2,2-trifluoroacetate) 4- (6- (4,7-diazaspiro [2.5] octan-7-yl) pyridin-3-yl) 6- (2-hydroxy- 2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl 7- (5- (3cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -4,7diazaspiro [2 , 5] octane-4-carboxylate (step 1; 69 mg, 0.13 mmol) in DCM (2 ml) was added TFA (1 ml). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure to give the title compound (86 mg, quantitative yield). MS (apci) m / z = 419.2 (M + H).

Intermediate P87.

N = \ I \

TPA bis- (2,2,2-trifluoroacetate) 4- (6- (3-oxa-7,9-diazabicyclo [3.3.1] nonan-7-yl) pyridin-3-yl) -6- (2hydroxy- 2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

- 174 035568

Stage 1: preparation of tert-butyl 7- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5а] pyridin-4-yl) pyridin-2-yl) -3-oxa -7,9-diazabicyclo [3.3.1] nonane-9-carboxylate. A mixture of 4- (6fluoropyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 100 mg, 0.306 mmol), tert-butyl 3-oxa-7,9-diazabicyclo [3.3.1] nonane-9-carboxylate (105 mg, 0.460 mmol) and K ₂ CO3 ( _TB ) (127 mg, 0.919 mmol) in DMSO (409 μL) were stirred for 48 h at 90 ° C. After cooling to ambient temperature, the resulting mixture was diluted with water (10 ml). The resulting slurry was filtered and the solid was collected to give the title compound (160 mg, 98% yield). MS (apci) m / z = 535.3 (M + H).

Stage 2: preparation of bis- (2,2,2-trifluoroacetate) 4- (6- (3-oxa-7,9-diazabicyclo [3.3.1] nonan-7yl) pyridin-3-yl) -6- (2 -hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl 7- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3oxa-7 , 9-diazabicyclo [3.3.1] nonane-9-carboxylate (step 1; 160 mg, 0.299 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred for 2 hours at ambient temperature and then evaporated under reduced pressure to give the title compound (198 mg, quantitative yield). MS (apci) m / z = 435.3 (M + H).

Intermediate P88.

bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) -5-fluoropyridin-3-yl) -6- (2hydroxy-2- methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) -3-fluoropyridin-2-yl) - 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate. Via a mixture of 4 bromo-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P41; 15 mg, 0.049 mmol), (6- (6- (tert) -butoxycarbonyl ) -3,6-diazabicyclo [3.1.1] heptan-3-yl) -5-fluoropyridin-3yl) boronic acid (intermediate R; 20 mg, 0.059 mmol), K ^ O ^ (68 mg, 0.49 mmol ) and Pd (PPh ₃ ) ₄ (5.7 mg, 0.005 mmol) in dioxane (250 μl) and water (200 μl), Ar _{(d) was} purged. The resulting mixture was stirred overnight at 85 ° C, then purified directly by silica gel chromatography (using 0-100% EtOAc in a mixture of hexane isomers as eluent gradient) to afford the purified title compound (14 mg, 54% yield). MS (apci) m / z = 467.15 (M + H).

Stage 2: preparation of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) -5fluoropyridin-3-yl) -6- (2- hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) -3-fluoropyridin2-yl) -3 , 6-diazabicyclo [3.1.1] heptane-6-carboxylate (step 1; 14 mg, 0.027 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred for 1 hour at ambient temperature and then evaporated under reduced pressure to give the title compound (17 mg, quantitative yield). MS (apci) m / z = 423.10 (M + H).

Intermediate P89.

bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) -5-methylpyridin-3-yl) -6- (2hydroxy ^ -methylpropox ^ pyrazolo ^ D ^ pyridine-3-carbonitrile.

Stage 1: Preparation of 4- (6-fluoro-5-methylpyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo ^ D ^ pyridine-3-carbonitrile. In a pressure vessel, a solution of 4-bromo-6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P41; 150 mg, 0.484 mmol) in dioxane (200 ml) was successively added 2-fluoro-3-methylpyridine-5-boronic acid (112 mg, 0.725 mmol) and Pd (PPh ₃ ) ₄ (55.9 mg, 0.0484 mmol) and 2 M Na ^ O ^ o ^) (1209 μl , 2.42 mmol). The resulting mixture was purged with Ar _(D ), the vessel was sealed and the mixture was stirred overnight at 90 ° C. After cooling to ambient temperature, the resulting suspension was partitioned between DCM (10 ml) and water (10 ml) and extracted with DCM (3x10 ml). The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-100% EtOAc in hexane isomer as gradient eluent) to afford the purified title compound (60 mg, 36% yield). MS (apci) m / z = 341.1 (M + H).

- 175 035568

Stage 2: preparation of tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) -3-methylpyridin-2-yl) - 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate. A mixture of 4- (6-fluoro5-methylpyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (step 1; 60 mg, 0.18 mmol ), tert-butyl-3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (70 mg, 0.35 mmol) and K ₂ CO ₃ ( _TB ) (244 mg, 1.8 mmol) in DMSO ( 881 μL) was stirred for 23 h at 80 ° C. The resulting suspension was partitioned between DCM (10 ml) and water (10 ml) and extracted with DCM (3x10 ml). The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-100% EtOAc in hexane isomer as gradient eluent) to afford the purified title compound (8.4 mg, 9% yield). MS (apci) m / z = 519.2 (M + H).

Stage 3: obtaining bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) -5methylpyridin-3-yl) -6- (2- hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) -3methylpyridin-2-yl) -3 , 6-diazabicyclo [3.1.1] heptane-6-carboxylate (step 2; 8.4 mg, 0.016 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred for 1 hour at ambient temperature and then evaporated under reduced pressure to give the title compound (10 mg, quantitative yield). MS (apci) m / z = 419.2 (M + H).

Intermediate P90.

bis- (2,2,2-trifluoroacetate) 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2-hydroxy-2methylpropoxy ^ irazolo ^^^ pyridine 3-carbonitrile.

In a solution of tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate P50, step 1; 20 mg, 0.040 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure to give the title compound (25 mg, quantitative yield). MS (apci) m / z = 406.15 (M + H).

Intermediate P91.

4- (2- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrimidin-5-yl) -6- (2-hydroxy-2methylpropoxy-irazolo-^^ pyridine 3-carbonitrile dihydrochloride.

Stage 1: preparation of tert-butyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate. In a pressure vessel through a mixture of 4-bromo-6- (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P41; 68 mg, 0.22 mmol), tert-butyl 3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate R21; 88 mg, 0.22 mmol) and Pd (PPh ₃ ) ₄ (25 mg, 0.022 mmol) in dioxane (730 μl) were purged with Lg _(g) for 30 seconds before adding 2 M K ₂ CO ₃ ( _aq . ) (420 μL, 0.840 mmol). The resulting mixture was purged with Lr _(g) for an additional 2 minutes before sealing the vessel. The reaction mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 15% acetone in DCM as eluent) to give the title compound (53 mg, 44% yield). MS (apci) m / z = 450.2 (M + H); 406.2 (-Boc M).

Stage 2: preparation of dihydrochloride 4- (2- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrimidin-5-yl) -6 (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a ] pyridine-3-carbonitrile. In a solution of tert-butyl 3- (5- (3cyano-6- (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridin-4-yl) pyrimidin-2-yl) -3,6diazabicyclo [3.1 .1] heptane-6-carboxylate (step 1; 53 mg, 0.105 mmol) in DCM (0.5 ml) was added 4 M HCl in dioxane (524 μl, 2.10 mmol). The resulting suspension was diluted with MeOH (250 μl) and the solution was stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure to give the title compound (54 mg, quantitative yield). MS (apci) m / z = 406.2 (M + H).

- 176 035568

Intermediate P92.

2,2,2-trifluoroacetate 1 - ((4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -3chloropyrazolo [1,5-a] pyridine- 6-yl) oxy) -2-methylpropan-2-ol.

Stage 1: preparation of tert-butyl 3- (5- (3-chloro-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1.5а] pyridin-4-yl) pyridin-2-yl) 3,6- diazabicyclo [3.1.1] heptane-6-carboxylate. A mixture of 1 - ((3-chloro-4- (6fluoropyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol (intermediate P69; 258 mg, 0.768 mmol), tert-butyl-3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (229 mg, 1.15 mmol) and K ₂ CO ₃ ( _mw ) (425 mg, 3.07 mmol) in DMSO (1.5 ml) was stirred overnight at 90 ° C in a sealed vessel. Additional tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6 carboxylate (40 mg) and K ^ O ^) (100 mg) were added to the reaction mixture and stirred overnight at 105 ° C. The reaction mixture was cooled to ambient temperature, then diluted with DCM / water. The biphasic mixture was washed with DCM (3x). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc / hexane isomer mixture as eluent gradient) to afford the purified title compound. (330 mg, 84% yield). MS (apci) m / z = 514.2 (M + H).

Stage 2: preparation of 2,2,2-trifluoroacetate 1 - ((4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -3-chloropyrazolo [1,5- a] pyridin-6-yl) oxy) -2-methylpropan-2-ol. In a solution of tert-butyl 3- (5- (3-chloro-6 (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6diazabicyclo [ 3.1.1] heptane-6-carboxylate (step 1; 330 mg, 0.642 mmol) in DCM (5 ml) was added TFA (1.5 ml). The resulting mixture was evaporated under reduced pressure to give the title compound (392 mg, quantitative yield). MS (apci) m / z = 414.1 (M + H).

Intermediate P93.

nh ₂

4- (6- (4-amino-4- (hydroxymethyl) pyneridin-1-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] nyridine-3carbonitrile.

Stage 1: preparation of methyl 4 - ((tert-butoxycarbonyl) amino) -1- (5- (3-cyano-6-ethoxypyrazolo [1,5a] nyridin-4-yl) pyridin-2-yl) piperidin-4- carboxylate. To a solution of 6-ethoxy-4- (6-fluoropyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P6, 303.4 mg, 1.075 mmol) in DMSO (21.50 ml) was added methyl 4-N-Boc-amino-niperidine-4-carboxylic acid ester (416.5 mg, 1.612 mmol) and potassium carbonate (297.1 mg, 2.150 mmol). The reaction mixture was stirred at 110 ° C for 72 hours. The reaction mixture was diluted with water and was extracted with EtOAc. The combined organic extracts were dried over anhydrous MgSO ^) and evaporated under reduced pressure. The crude residue was purified by chromatography on silica gel (0-100% EtOAc in hexane as gradient eluent) to give the title compound (76.7 mg, 13.7% yield) sufficient purity for Step 2. MS (apci) m / z = 521.2 (M + H).

Stage 2: preparation of tert-butyl (1- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -4- (hydroxymethyl) piperidin-4-yl) carbamate. To a solution of lithium borohydride (0.0120 ml, 0.365 mmol) in THF (0.912 ml) was added methyl 4 - ((tert-butoxycarbonyl) amino) -1- (5- (3-cyano-6-ethoxypyrazolo [1.5a ] nyridin-4-yl) pyridin-2-yl) piperidine-4-carboxylate (47.5 mg, 0.0912 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was diluted with EtOAc and washed with saturated aqueous sodium chloride solution. The organic extract was dried over anhydrous MgSO ^) and evaporated under reduced pressure to give the title compound (65.9 mg), which was used in the next step without further purification. MS (apci) m / z = 493.2 (M + H).

Step 3: Preparation of 4- (6- (4-amino-4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile. To a solution of tert-butyl (1- (5- (3-cyano-6ethoxypyrazolo CD ^ pyridine ^ -yl ^ iridin ^ -yl ^ Dhydroxymethyl ^ iperidin ^ -ylCharbamate) (65.9 mg, 0.134 mmol) in DCM (1 ml) was added TPA (0.2 ml, 2.68 mmol) The reaction mixture was stirred at room temperature for 30 min and then evaporated under reduced pressure.

- 177 035568 was dissolved in DCM and washed with saturated aqueous Na2CO _3. The aqueous layer was extracted with DCM, and the combined organic extracts were dried over anhydrous MgSO ^) and evaporated under reduced pressure to give the title compound (35.6 mg, 68% yield). MS (apci) m / z = 393.2 (M + H).

Intermediate P94.

6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile dihydrochloride.

Step 1: Preparation of tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate. In a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 500 mg, 1.19 mmol) in DMF (3.96 ml) were successively added K ^ O ^) (329 mg, 2.38 mmol) and iodoethane (143 μl, 1.78 mmol), then stirred for 18 h at ambient temperature. The reaction mixture was slowly poured into water (32 ml). The resulting suspension was stirred for 15 minutes. The suspension was filtered, washing the solid with water (3x10 ml). After air drying, the solid was collected to give the title compound (530 mg, 99% yield). MS (apci) m / z = 449.2 (M + H).

Step 2: Preparation of 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile dihydrochloride. To a suspension of tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate (stage 1; 530 mg, 1.18 mmol) in MeOH (5.91 ml) was added dropwise 5-6N. HCl in iso-PrOH (4.73 ml, 23.6 mmol). The resulting mixture was stirred for 3 hours at ambient temperature, and then 5-6N. HCl in iso-PrOH (4.73 ml, 23.6 mmol). After stirring for an additional 24 h at ambient temperature, the reaction mixture was filtered under reduced pressure, washing the solid sequentially with MeOH (3x1 ml) and MTBE (3x10 ml). The solid was dried under reduced pressure and collected to give the title compound (445 mg, 89% yield). MS (apci) m / z = 349.2 (M + H).

Intermediate P95.

4- (6-fluoropyridin-3-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Method A.

Step 1: Preparation of 4-bromo-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. To a solution of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1, 1000 mg, 4.201 mmol) in DMA (21.005 L) was added potassium carbonate (1742 mg, 12.60 mmol) and 4- (2-Chloroethyl) morpholine (1.132 ml, 8.402 mmol). The reaction mixture was stirred at 50 ° C for 72 h. After cooling to ambient temperature, the reaction mixture was poured into a saturated NaCl (w) solution. The resulting precipitate was collected by filtration to give the title compound (1475 mg, 4,200 mmol, 99% yield) sufficient purity for Step 2. MS (apci) m / z = 351 (M +).

Step 2: Preparation of 4- (6-fluoropyridin-3-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile. To a solution of 4-bromo-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (0.83 g, 1.394 mmol) in 1,4-dioxane (1000 ml) was added 2-fluoro- 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) pyridine (373.2181 mg, 1.673 mmol), tetrakis- (triphenylphosphine) palladium (0) (32.22577 mg, 0 , 0279 mmol) and aqueous potassium carbonate (2.092 ml, 4.183 mmol). The reaction mixture was purged with argon and stirred at 90 ° C for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with MTBE and washed with 1N HCl. NaOH. The aqueous fractions were extracted with MTBE, then brought to pH 4 with 4N. HCl. Saturated NaCl ( _BOg ) was added and the aqueous mixture was extracted with 4: 1 DCM / IPA. The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (0.341 mg, 0.928 mmol, 66.6% yield). MS (apci) m / z = 368.1 (M + H).

Method B.

To a suspension of 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P63; 1.00 g, 3.93 mmol) in DMA (8 ml) in sequence K ₂ CO ₃ (1.63 g, 11.8 mmol) and 4- (2 chloroethyl) morpholine (883 mg, 5.90 mmol) were added. The resulting mixture was stirred for 19 h at 55 ° C. After cooling to ambient temperature, the resulting mixture was diluted with water (50 ml) and

- 178 035568 was extracted with DCM (3x30 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (3x50 ml), dried over anhydrous MgSO ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 5-100% acetone / hexane isomer mixture as eluent gradient) to afford the purified title compound (870 mg, 60% yield). MS (apci) m / z = 368.1 (M + H).

Intermediate P96.

4- (6- (1,7-diazaspiro [3,5] nonan-7-yl) pyridin-3-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride ...

In a solution of tert-butyl 7- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -1,7-diazaspiro [3.5] nonane -1-carboxylate (example 535; 625 mg, 1.09 mmol) in DCM (3 ml) was added 5-6 M HCl in iso-PrOH (3.05 ml, 15.3 mmol) and stirred for 3 h at ambient temperature. The resulting mixture was diluted with MeOH (3 ml) and stirred for 1 h at ambient temperature. The resulting suspension was filtered, washing the isolated solid with Et ₂ O (5x1 ml). The filtrate was re-filtered and the isolated solids combined and dried under high vacuum to give the title compound (532.3 mg, 89% yield). MS (apci) m / z = 474.2 (M + H).

Intermediate P97.

tert-butyl 4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -1,4-diazepan-1 -carboxylate.

In a pressurized sealed tube, a mixture of 4- (6-fluoropyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile (intermediate P42; 300 mg, 0.919 mmol ), tert-butyl 1,4-diazepan-1-carboxylate (552 mg, 2.76 mmol) and TEA (1.03 ml, 7.35 mmol) in DMSO (1.8 ml) were stirred overnight at 95 ° C ... After cooling to ambient temperature, the reaction mixture was diluted with DCM and quenched with saturated ΝΗ ₄ ^ (^ _η .). After phase separation, the aqueous extracts were washed with additional DCM (3x). The combined organic extracts were then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc / hexane isomer mixture as eluent gradient) to afford the purified title compound (400 mg, 86% yield). MS (apci) m / z = 507.3 (M + H).

Intermediate P98.

N = \

ΤΦΚ

O ⁿ bis- (2,2,2-trifluoroacetate) 4- (6- (1,4-diazepan-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5 -a] pyridine-3-carbonitrule.

To a suspension of tert-butyl 4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridin-4yl) pyridin-2-yl) -1,4-diazepan -1-carboxylate (intermediate P97; 400 mg, 0.790 mmol) in DCM (2.0 ml) was added TFA (1.29 ml, 15.8 mmol) and stirred for 4 h at ambient temperature. The resulting mixture was evaporated under reduced pressure to give the title compound (501 mg, 100% yield). MS (apci) m / z = 407.2 (M + H).

Intermediate P99.

N = \

I / -O-V

6-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

- 179 035568

In a pressure vessel, a mixture of 4-bromo-6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P5; 570 mg, 2.14 mmol), bis- (pinacolato) diborone (5.44 g, 21 , 4 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ (174 mg, 0.214 mmol) and KOAc (1.05 g, 10.7 mmol) in dioxane (21.4 ml), Ar _{(g) was} blown within 10 minutes. The vial was sealed and the mixture was stirred overnight at 90 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and filtered through GF / F paper. The filtrate was evaporated under reduced pressure. The crude residue was purified twice via silica gel chromatography (using 0-10% MeOH in EtOAc, then with 0-100% hexanes in EtOAc as eluent gradient) to give the title compound of sufficient purity for later use (772 mg, ca 63% yield based on purity 55%). MS (apci) m / z = 314.1 (M + H).

Intermediate P100.

tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyrazin-2-yl) piperαzine-1carboxylate.

Via a mixture of 6-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P99; 40 mg, 0 , 13), tert-butyl-4- (5-chloropyrazin-2-yl) piperazine-1 carboxylate (intermediate R23; 38 mg, 0.13 mmol), 2 М К _{3 РО 4} ( _VOD n.) (192 μl, 0.38 mmol) X-phos (mg 12 mg, 0.026 mmol) and Pd ₂ (dba) ₃ (5.8 mg, 0.0064 mmol) in dioxane (639 μL) were purged with Ar ( _r ) for 3 min, and then the vessel was sealed. The reaction mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were sequentially washed with water (2x) and saturated aqueous sodium chloride solution (1x), and then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 10-100% EtOAc in hexane isomers as gradient eluent) to afford the purified title compound (49 mg, 85% yield). MS (apci) m / z = 450.2 (M + H).

Intermediate P101.

bis- (2,2,2-trifluoroacetate) 6-ethoxy-4- (5- (piperazin-1-yl) pyrazin-2-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

To a suspension of tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyrazine-2yl) piperazine-1-carboxylate (intermediate P100; 27 mg, 0.060 mmol ) in DCM (2.0 ml) was added TFA (2 ml, 26.1 mmol) and stirred overnight at ambient temperature. The resulting mixture was evaporated under reduced pressure to give the title compound (35 mg, quantitative yield). MS (apci) m / z = 350.2 (M + H).

Intermediate P102.

tert-butyl 3- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyrazin-2-yl) -3,6 diazabicyclo [3.1.1] heptane-6-carboxylate.

Via a mixture of 6-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrαzolo [1,5-a] pyridine-3carbonitrile (intermediate P99; 150 mg, 0.479 mmol), tert-butyl-3- (5-chloropyrazin-2-yl) -3,6 diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate R15; 149 mg, 0.479 mmol), 2M К _{3 РО 4} ( _VOD n.) (718 μL, 1.44 mmol), X-phos (45.7 mg, 0.0958 mmol) and Pd ₂ (dba) ₃ (21.9 mg, 0.0239 mmol) in dioxane (2, 40 ml) was purged with Ar ( _r ) for 3 min and then the vessel was sealed. The reaction mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% EtOAc in isome

- 180 035568 ditch of hexane as gradient eluent) to afford the purified title compound (95 mg, 43% yield). MS (apci) m / z = 478.2 (M + H).

Intermediate P103.

bis- (2,2,2-trifluoroacetate) 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6ethoxypyrazolo [1,5-a] pyridine- 3-carbonitrile.

To a suspension of tert-butyl-3- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyrazin-2-yl) -3,6diazabicyclo [3.1.1] heptane-6 β-carboxylate (intermediate P102; 95 mg, 0.206 mmol) in DCM (1.0 ml) was added TFA (1 ml, 13.1 mmol) and stirred for 1 h at ambient temperature. The reaction mixture was diluted with Et ₂ O (20 ml). The resulting precipitate was collected and dried under reduced pressure to give the title compound (100 mg, 82.4% yield). MS (apci) m / z = 362.1 (M + H).

Intermediate P104.

(3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4-yl) boronic acid.

In a pressure vessel through a mixture of 4-bromo-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P95; method A, step 1; 200 mg, 0.336 mmol), bis- (pinacolato) diborone (1.446 g, 5.694 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ (46.4 mg, 0.0570 mmol) and KOAc (167.7 mg, 1.709 mmol) in dioxane (3.36 ml) Ar _fr) for 10 min. The vial was sealed and the mixture was stirred overnight at 90 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and filtered through GF / F paper. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (using a stepwise gradient of 0-20% MeOH in DCM with 2% NH ₄ OH, then 98% MeOH with 2% NH ₄ OH as gradient eluent system). The purified residue was dissolved in DCM (2 ml) and triturated with Et ₂ O (5 ml). The resulting slurry was filtered to give the purified title compound (60 mg, 56% yield). MS (apci) m / z = 317.1 (M + H).

Intermediate P105.

tert-butyl 3- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyrazin-2-yl) -3,6 diazabicyclo [3.1.1] heptane -6-carboxylate.

To a mixture of (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4-yl) boronic acid (intermediate P104; 60 mg, 0.190 mmol), tert-butyl 3- (5-chloropyrazine -2-yl) -3,6-diazabicyclo [3.1.1] heptane-6 carboxylate (intermediate R15; 61.9 mg, 0.199 mmol), X-phos (18.1 mg, 0.0380 mmol) and Pd ₂ ( dba) ₃ (8.69 mg, 0.00949 mmol) in dioxane (949 μl), 2 M Κ ₃ ΡΟ ₄ (^ _η .) (285 μl, 0.569 mmol) was added. The resulting mixture was purged with Ar _fr) and then the vessel was sealed. The reaction mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and filtered through GF / F paper. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (using 10% MeOH in DCM with 0.1% NH ₄ OH as gradient eluent) to afford the purified title compound (18 mg, 17% yield). MS (apci) m / z = 547.3 (M + H).

Intermediate P106.

bis- (2,2,2-trifluoroacetate) 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2morpholinoethoxy) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

- 181 035568

To a suspension of tert-butyl-3- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4yl) pyrazin-2-yl) -3,6-diazabicyclo [3.1. 1] heptane-6-carboxylate (intermediate P105; 18 mg, 0.0329 mmol) in DCM (1.0 ml), TPA (1 ml, 13.1 mmol) was added and stirred for 30 min at ambient temperature. The resulting mixture was evaporated under reduced pressure. The resulting residue was evaporated with Et2O (3x5 mL) to give the title compound (22.2 mg, quantitative yield). MS (apci) m / z = 447.2 (M + H).

Intermediate P107.

^) - 2 - (((4-bromo-3-cyanopyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-tert-butyl carboxylate.

To a mixture of ^) - tert-butyl 2- (bromomethyl) morpholine-4-carboxylate (300 mg, 1.07 mmol) and 4-bromo-6hydroxypyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 255 mg, 1.07 mmol) in DMA (2.14 ml) was added Cs ₂ CO ₃ ( _{1. B} ) (1.05 g, 3.21 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the mixture was diluted with DCM and washed sequentially with water (3x) and saturated aqueous sodium chloride solution (1x). The organic extracts were evaporated under reduced pressure to give the title compound (468 mg, quantitative yield%).

1H NMR (CDCl3) δ 8.12 (s, 1H), 7.43 (d, 1H), 7.24 (s, 1H), 7.24, 3.90-4.05 (m, 4H), 3.70-3.89 (m, 2H), 3.42-3.55 (m, 2H), 1.39 (s, 12H).

Intermediate P108.

^) - 2 - (((4-bromo-3-cyanopyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-tert-butyl carboxylate.

The title compound (468 mg, quantitative yield) was prepared in a manner similar to that described for the synthesis of tert-butyl (d) - 2 - (((4-bromo-3-cyanopyrazolo [1,5-a] pyridine) -6yl) oxy ) methyl) morpholine-4-carboxylate (intermediate P107), replacing ^) - tert-butyl-2 (bromomethyl) morpholine-4-carboxylate with tert-butyl ^) - 2- (bromomethyl) morpholine-4-carboxylate.

1H NMR (CDCI3) δ 8.12 (s, 1H), 7.43 (d, 1H), 7.24 (s, 1H), 3.90-4.05 (m, 4H), 3.70- 3.89 (m, 2H), 3.423.55 (m, 2H), 1.39 (s, 12H).

Intermediate P109.

tert-butyl ^) - 2 - (((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5а] pyridine-6- yl) oxy) methyl) morpholine-4-carboxylate.

In a pressure vessel through a mixture of tert-butyl ^) - 2 - (((4-bromo-3-cyanopyrazolo [1,5-a] pyridine-6yl) oxy) methyl) morpholine-4-carboxylate (intermediate P107; 468 mg , 0.749 mmol), bis (pinacolato) diborone (1.90 g, 7.49 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ (61.0 mg, 0.0749 mmol) and KOAc (368 mg, 3 , 75 mmol) in dioxane (7.49 ml), Ar < _d ) was purged for 10 min. The vial was sealed and the mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and filtered through GF / F paper. The filtrate was evaporated under reduced pressure and the residue was triturated with pentane. The pentane slurry was filtered to give the title compound (200 mg, 80% yield).

1H NMR (CDCI3) δ 8.21 (s, 1H), 7.69 (d, 1H), 7.30 (s, 1H), 3.99-4.10 (m, 2H), 3.78- 3.98 (m, 2H), 3.563.65 (m, 2H), 1.49 (s, 9H), 1.43 (s, 12H).

- 182 035568

Intermediate P110.

tert-butyl ^) - 2 - (((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5а] pyridine-6- yl) oxy) methyl) morpholine-4-carboxylate.

The title compound (191 mg, 40% yield) was prepared using a procedure similar to that described for the synthesis of tert-butyl ^) - 2 - (((3-cyano-4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2yl) pyrαzolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P109), replacing tert-butyl (R) -2 - ((( 4-bromo-3-cyanopyrαzolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P107) on tert-butyl (S) -2 - (((4-bromo- 3-cyanopyrαzolo [1,5-a] pyridine-6yl) oxy) methyl) morpholine-4-carboxylate (intermediate P108%).

¹ H NMR (CDCl ₃ ) δ 8.21 (s, 1H), 7.69 (d, 1H), 7.30 (s, 1H), 3.99-4.10 (m, 2H), 3, 78-3.98 (m, 2H), 3.563.65 (m, 2H), 1.49 (s, 9H), 1.43 (s, 12H).

Intermediate P111.

tert-butyl (2R) -2 - (((3-cyano-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3 ) yl) pyrαzin-2-yl) pyrαzolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate.

To a mixture of tert-butyl ^) - 2 - (((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5a] pyridine- 6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P109; 117 mg, 0.169 mmol), 3- (5chloropyrazin-2-yl) -6 - ((6-methoxypyridin-3-yl) methyl) -3 , 6-diazabicyclo [3.1.1] heptane (intermediate R25; 56 mg, 0.17 mmol) in dioxane (844 μl) was added 2 М К _{3 РО4} ( _VOD n.) (253 μl, 0.506 mmol), X-phos (16 mg, 0.34 mmol) and Pd ₂ (dba) ₃ (20 mg, 0.084 mmol). The resulting mixture was purged with Ar _(g) for 10 min and then the vessel was sealed. The reaction mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and washed sequentially with water (3x) and saturated aqueous sodium chloride solution (1x). The organic extracts were evaporated under reduced pressure and the residue was purified by silica gel chromatography (using 0-100% 9: 1 solvent mixture DCM: MeOH with 1% NH4OH in DCM as eluent gradient) to afford the purified title compound (59.8 mg, 54% yield). MS (apci) m / z = 654.3 (M + H).

Intermediate P112.

tert-butyl (2S) -2 - (((3-cyano-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3 ) yl) pyrαzin-2-yl) pyrαzolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate.

The title compound (55.9 mg, 51% yield) was prepared using a procedure similar to that described for the synthesis of tert-butyl (2R) -2 - (((3-cyano-4- (5- (6 - ((6- methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrαzin-2-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4carboxylate (intermediate P111), replacing tert-butyl ^) - 2 - (((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) pyrazolo [1,5- a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P109) on tert-butyl ^) - 2 - (((3-cyano-4) - (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) pyrazolo [1,5a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P110%).

¹ H NMR (CDCl ₃ ) δ 8.21 (s, 1H), 7.69 (d, 1H), 7.30 (s, 1H), 3.99-4.10 (m, 2H), 3, 78-3.98 (m, 2H), 3.563.65 (m, 2H), 1.49 (s, 9H), 1.43 (s, 12H).

- 183 035568

Intermediate P113.

tert-butyl 3 - (((4-bromo-3-cyanopyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -3-fluoroazetidine-1carboxylate.

To a mixture of 4-bromo-6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 591.9 mg, 2.486 mmol) in DMA (12.43 ml) was added K ₂ CO ₃ (t _B ) (1.031 g, 7.459 mmol) and tert-butyl 3- (bromomethyl) -3fluoroazetidine-1-carboxylate (1.0 g, 3.7 mmol), then stirred for 3 h at 60 ° C. After cooling to ambient temperature, the mixture was diluted with saturated aqueous sodium chloride solution and the resulting suspension was filtered. The isolated solids were washed with water (5x). The filtrate was set aside and the isolated solids were dissolved in DCM. The DCM solution was evaporated under reduced pressure to give the title compound (553 mg). The filtrate was extracted with a 4: 1 mixture of DCM: iso-PrOH (4x). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2x), then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to provide additional title compound (500mg). The solids after filtration and treatment of the filtrate were combined and dried under reduced pressure to give the purified title compound (1.033 g, 98% yield). MS (apci) m / z = 423 (M + H).

Intermediate P114.

tert-butyl 3 - (((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5-a] pyridin-6yl) oxy ) methyl) -3-fluoroazetidine-1-carboxylate.

In a tube under pressure, into a solution of tert-butyl-3 - (((4-bromo-3-cyanopyrazolo [1,5-a] pyridine-6yl) oxy) methyl) -3-fluoroazetidine-1-carboxylate (intermediate P113; 200 mg, 0.470 mmol) in dioxane (3.14 ml) was added bis- (pinacolato) diborone (239 mg, 0.941 mmol) and KOAc (138 mg, 1.41 mmol). The resulting mixture was purged with Ar ( _D ) for 5 min, then PdCl ₂ (dppf) -CH ₂ Cl ₂ (38.3 mg, 0.0470 mmol) was added. The resulting mixture was purged with Ar _(g) for an additional 5 min, then the vessel was sealed. The reaction mixture was stirred overnight at 80 ° C, then cooled to ambient temperature and diluted with pentane. The pentane-containing mixture was filtered through GF / F paper, then evaporated under reduced pressure to give the title compound 1: 1 with bis (pinacolato) diborone (400 mg, 90% yield based on 50% purity%).

¹ H NMR (CDCl ₃ ) δ 8.20 (m, 3H), 7.66 (d, 1H), 4.15 (m, 6H), 1.44 (s, 9H), 1.40 (s, 12H).

Intermediate P115.

tert-butyl 3 - (((3-cyano-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyrazine) - 2-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -3-fluoroazetidine-1-carboxylate.

To a mixture of tert-butyl 3 - (((3-cyano-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5a] pyridin-6-yl ) oxy) methyl) -3-fluoroazetidine-1-carboxylate (intermediate P114; 75 mg, 0.16 mmol), 3 (5-chloropyrazin-2-yl) -6 - ((6-methoxypyridin-3-yl) methyl ) -3,6-diazabicyclo [3.1.1] heptane (intermediate R25; 70 mg, 0.11 mmol), X-phos (10 mg, 0.021 mmol) and Pd ₂ (dba) ₃ (4.8 mg, 0 , 0053 mmol) in dioxane (529 μl) was added 2M K ₃ PO ₄ (aq.) (159 μl, 0.320 mmol). The resulting mixture was purged with Ar ( _D ) for 10 min and then the reaction vessel was sealed. The mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and washed sequentially with water and saturated aqueous sodium chloride solution. The organic extracts were dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc in hexane isomers, then 0-10% MeOH with 0.1% NH4OH in EtOAc as gradient eluents) to afford the purified title compound (48 mg, yield 71%), MS (apci) m / z = 642.3 (M + H).

- 184 035568

Intermediate P116.

tert-butyl 3- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyrimidin-2-yl) -3,6 diazabicyclo [3.1.1] heptane -6-carboxylate.

To a mixture of tert-butyl 3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl) -3,6diazabicyclo [3.1.1] heptane- 6-carboxylate (intermediate R21; 360 mg, 0.895 mmol) and K ₂ CO ₃ (t _B ) (618 mg, 4.47 mmol) in a mixture of dioxane (8.95 ml) and water (895 μl) was added 4-bromine -6- (2morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P79, step 1; 314 mg, 0.895 mmol) and Pd (PPh ₃ ) ₄ (103 mg, 0.0895 mmol). The resulting mixture was purged with argon Ar ( _D ) until the reaction vessel was sealed. The mixture was stirred for 16 hours at 80 ° C. After cooling to ambient temperature, the reaction mixture was partitioned between 4: 1 DCM: iso-PrOH and saturated aqueous sodium chloride solution. After phase separation, the organic extracts were additionally washed with saturated aqueous sodium chloride solution (2x) and then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% EtOAc in hexane isomers followed by 0-20% MeOH in EtOAc as gradient eluents) to give the pure title compound (336 mg, 69% yield). MS (apci) m / z = 491.2 (M-tBu).

Intermediate P117.

4- (2- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrimidin-5-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5a] pyridine-3-carbonitrile.

To a suspension of tert-butyl-3- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyrigin-4yl) pyrimidin-2-yl) -3,6-diazabicyclo [3.1. 1] heptane-6-carboxylate (intermediate P116; 336 mg, 0.615 mmol) in DCM (2.05 ml) was added TFA (474 μl, 6.15 mmol) and stirred for 5 h at ambient temperature. Additional TFA (2 ml, 26.1 mmol) was added and the reaction mixture was stirred for an additional 30 min at ambient temperature. The resulting mixture was neutralized with saturated NaHCO ^^.) (30 ml) and the biphasic mixture was extracted with a 4: 1 mixture of DCM: iso-PrOH. The combined organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the title compound (236 mg, 86% yield). MS (apci) m / z = 447.3 (M + H).

Intermediate P118.

3-chloro-6-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5-a] pyrigine.

Via a mixture of 4-bromo-3-chloro-6-methoxypyrazolo [1,5-a] pyridine (intermediate P62, step 1; 152 mg,

0.581 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ (23.7 mg, 0.029 mmol), KOAc (285 mg, 2.91 mmol) and bis (pinacolato) diborone (443 mg, 1.74 mmol) in dioxane (5.8 ml) was purged with Ar (g). The reaction vessel was sealed and the mixture was stirred for 2 h 15 min at 90 ° C. After cooling to ambient temperature, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure to give the title compound (102 mg, 57%). MS (apci) m / z = 309.1 (M + H).

Intermediate P119.

1- (4-bromo-6-methoxypyrazolo [1,5-a] pyrigin-3-yl) ethan-1-ol.

- 185 035568

To a cold (0 ° C) suspension of 4-bromo-6-methoxypyrazolo [1,5-a] pyridine-3-carbaldehyde (intermediate P1, part B, stage 4; 128 mg, 0.502 mmol) in THF (5.02 ml ) was added dropwise a 3 M solution of CH ₃ MgBr in Et ₂ O (201 μl, 0.602 mmol). After adding CH ₃ MgBr, the mixture was allowed to warm to ambient temperature. The resulting mixture was stirred for 1 h at ambient temperature and then saturated IN ₄ Cl ( _aq ) was added quenched. The two-phase mixture was evaporated under reduced pressure to remove organic solvents. The residual aqueous suspension was filtered, washing with water. The solid was collected and dried under reduced pressure to give the title compound (130 mg, 96% yield). MS (apci) m / z = 272.9 (M + H).

Intermediate P120.

N = \

Ν.

2- (4-bromo-6-methoxypyrαzolo [1,5-a] pyridin-3-yl) propanenitrile.

BF ₃ -Et ₂ O (172 μL, 1.36 mmol) and 1- (4-bromo-6 -methoxypyrazolo [1,5-a] pyridin-3-yl) ethan-1-ol (intermediate P119; 123 mg, 0.454 mmol) in DCM (2 ml). The resulting mixture was allowed to slowly warm to ambient temperature. The mixture was stirred for an additional 2 hours at ambient temperature and then saturated NaHCO (^ () was added.). The resulting biphasic mixture was extracted with DCM and the organic extracts were evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-25% EtOAc in hexane as gradient eluent) to afford the title compound (70 mg, 55% yield). MS (apci) m / z = 282.0 (M + H).

Intermediate P121.

(4-bromo-6-methoxypyrαzolo [1,5-a] pyridin-3-yl) methanol.

To a suspension of 4-bromo-6-methoxypyrazolo [1,5-a] pyridine-3-carbaldehyde (intermediate P1, part B, stage 4; 1.10 g, 4.31 mmol) in MeOH (21.6 ml) and THF (21.6 ml) was added NaBH4 (163 mg, 4.31 mmol) followed by stirring for 20 h at ambient temperature. Additional NaBH4 (163 mg, 4.31 mmol) was added and the mixture was stirred for an additional 2 h at ambient temperature. The resulting mixture was evaporated under reduced pressure and the residue was suspended in water (50 ml). The resulting aqueous suspension was filtered by washing with water. The solid was collected and dried under reduced pressure to give the title compound (1.05 g, 95% yield). MS (apci) m / z = 259.1 (M + H).

Intermediate P122.

N = \

2- (4-bromo-6-methoxypyrαzolo [1,5-a] pyridin-3-yl) acetonitrile.

To a cold (0 ° С) solution of TMSCN (323 μl, 2.41 mmol) in DCM (3 ml), BF ₃ -Et ₂ O (229 μl, 1.81 mmol) and (4-bromo-6-methoxypyrazolo [1,5-a] pyridin-3-yl) methanol (intermediate P121; 155 mg, 0.603 mmol). The resulting mixture was allowed to slowly warm to ambient temperature. The mixture was stirred for an additional 2 hours at ambient temperature and then saturated Na1C (To _{aq : v} . The resulting biphasic mixture was extracted with DCM and the organic extracts were evaporated under reduced pressure. The crude residue was purified by chromatography on silica gel (using 0- 30% EtOAc in hexane as gradient eluent) to give the title compound (43 mg, 27% yield) MS (apci) m / z = 268.0 (M + H).

Intermediate R1.

1-benzyl-4- (5- (4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl) pyridin-2-yl) piperazine.

To a solution of 1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2yl) piperazine hydrochloride (1.00 g, 3.07 mmol) in DMF ( 5 ml) was added (bromomethyl) benzene (0.438 ml, 3.69 mmol) and TEA (1.28 ml, 9.21 mmol). After stirring overnight at ambient temperature, water was added to the mixture and sonicated for 10 minutes. The resulting white suspension

- 186,035,568 filtered and the solids washed with water and hexane to give the title compound (0.84 g, 72% yield). MS (apci) m / z = 298.1 (B (OH) ₂ M + H).

Intermediate R2.

BUT

I

(S) - (6- (4- (3-methoxypyrrolidine-1-carbonyl) piperazin-1-yl) pyridin-3-yl) boronic acid.

To a solution of (6- (piperazin-1-yl) pyridin-3-yl) boronic acid (1.5 g, 7.25 mmol) in DMA (36.2 mL, 7.25 mmol) was added DIEA (5.05 ml, 29.0 mmol) and stirred for 20 min at ambient temperature. To the mixture was added 4-nitrophenyl carbonochloridate (2.92 g, 14.5 mmol) and left to stir overnight at ambient temperature. Then, DIEA (5 ml, 29.0 mmol) and N) - 3-methoxypyrrolidine (3.66 g, 36.2 mmol) were added to the mixture and allowed to stir for 3 days at ambient temperature. The reaction mixture was diluted with water and extracted with 20% MeOH / DCM. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (0-40% ACN / H2O). The isolated product was then taken up in MeOH and loaded onto an Isolute® SCX column. The column was washed with MeOH (2 column volumes), and then 4N. NH ₄ OH in MeOH to afford the purified title compound (1.0 g, 41% yield). MS (apci) m / z = 335.1 (M + H).

Intermediate R4.

BUT

I

(6- (6- (tert-butoxycarbonyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid. Method 1.

Step 1: Preparation of tert-butyl 3- (5-bromopyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6 carboxylate. Suspension of tert-butyl ester of 3,6-diazabicyclo [3.1.1] heptane-6-carboxylic acid (1.046 g, 5.27 mmol), 5-bromo-2-fluoropyridine (919 mg, 5.22 mmol) and K ₂ CO ₃ ( _TB ) (3.61 g, 26.1 mmol) in DMSO (5.22 ml) was stirred for 1 day at 90 ° C. After cooling to ambient temperature, the reaction mixture was partitioned between EtOAc and water. The organic extracts were washed with additional water, then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. Purification of the crude compound by chromatography on silica gel (0-50% hexane / EtOAc isomer mixture as eluent gradient) gave the title compound (1.80 g, 97% yield). MS (apci) m / z = 354.0 (M + 1), 356.1 (M + 2).

Stage 2: preparation of (6- (6- (tert-butoxycarbonylU3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridine-3yl) boronic acid Through a mixture of tert-butyl-3- (5-bromopyridine-2- yl) -3,6-diazabicyclo [3.1.1] heptane-6 carboxylate (1.80 g, 5.08 mmol), bis- (pinacolato) diborone (3.87 g, 15.2 mmol), PdCl ₂ (DPPF ) ;; CH ₂ Cl ₂ (414 mg, 0.508 mmol) and KOAc (1.50 g, 15.2 mmol) in dioxane (5.75 ml) were purged with N ₂ ( _r ), then stirred for 3 h at 80 ° C. After cooling to room temperature, the reaction mixture was diluted with DCM and washed with water. The aqueous extracts were washed with DCM. All DCM extracts were combined and dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was sonicated in the mixture hexane (200 ml) and ether (50 ml) for 5 min and the resulting gray slurry was filtered.The collected solid was triturated with MeOH and the resulting slurry was filtered to give the title compound as a white solid (840 mg, 52% yield) . M C (apci) m / z = 320.2 (M + H).

Method 2.

Preparation of (6- (6- (tert-butoxycarbonyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) boronic acid. Suspension of tert-butyl ester of 3,6-diazabicyclo [3.1.1] heptane-6-carboxylic acid (182 mg, 0.918 mmol), 2-fluoro-5- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) pyridine (819 mg, 3.67 mmol) and K ₂ CO ₃ ( _TB ) (634 mg, 4.59 mmol) in DMSO (918 μl) were heated to 90 ° С, then water was added (5 ml). The resulting mixture was stirred for 1 h at 90 ° C, then cooled to ambient temperature and filtered to give the purified title compound (1.0 g, 41% yield). MS (apci) m / z = 320.1 (M + H).

- 187 035568

Intermediate R5.

(^^) - 2 - ((6-methoxypyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane dihydrochloride.

Step 1: Preparation of tert-butyl (^^) - 5- (6-methoxypyridin-3-yl) -2,5-diazabicyclo [2.2.1] heptane2-carboxylate. To a solution of tert-butyl (^^) - (-) - 2,5-diazabicyclo (2.2.1) heptane-2-carboxylate (500 mg, 2.52 mmol) in DCE (12.6 ml), 6- methoxy-nicotinaldehyde (691.7 mg, 5.044 mmol) and NaBH (AcO) ₃ (1.60 g, 7.57 mmol). After stirring overnight at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to afford the purified title compound (725.4 mg, 90% yield). MS (apci) m / z = 320.2 (M + H).

Stage 2: preparation of (^^) - 2- (6-methoxypyridin-3-yl) -2.5 diazabicyclo [2.2.1] heptane dihydrochloride. To a solution of tert-butyl (^^) - 5- (6-methoxypyridin-3-yl) -2.5 diazabicyclo [2.2.1] heptane-2-carboxylate (725.4 mg, 2.271 mmol) in DCM (5 ml) 4N HCl in dioxane (5 ml) was added. The resulting mixture was stirred for 1 h at ambient temperature, then evaporated under reduced pressure, toluene (3x3 ml) was added to the residue and re-evaporated to give the title compound as the dihydrochloride salt (663.6 mg, 90% yield). MS (apci) m / z = 220.2 (M + H).

Intermediate R6.

3 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane dihydrochloride.

Step 1: Preparation of tert-butyl 3 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane 6-carboxylate. To a solution of 3,6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (250 mg, 1.26 mmol) in DCE (6.31 ml), 6-methoxy-nicotinaldehyde (346 mg, 2, 52 mmol) and NaBH (AcO) ₃ (802 mg, 3.78 mmol). The mixture was stirred for 5 hours at ambient temperature. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-100% [4: 1 DCM: MeOH with 2% NH4OH] in DCM as gradient eluent) to give the title compound of sufficient purity for later use (420 mg , quantitative yield). MS (apci) m / z = 320.2 (M + H).

Stage 2: Preparation of 3 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane dihydrochloride. To a solution of tert-butyl 3 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane-6-carboxylate (step 1; 420 mg, 1.31 mmol) in DCM (2 ml ) added 4N. HCl in dioxane (4 ml). The reaction mixture was stirred overnight at ambient temperature. The resulting precipitate was filtered off to give the purified title compound as the dihydrochloride salt (341 mg, 93% yield). MS (apci) m / z = 220.2 (M + H).

Intermediate R7.

HCl I

6iU hydrochloride 3 - ((6-methoxypyridin-3-yl) methyl) -3,8-diazabicyclo [3.2.1] octane.

Step 1: Preparation of tert-butyl 3 - ((6-methoxypyridin-3-yl) methyl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate. To a solution of tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (1.0 g, 4.71 mmol) in DCE (23.6 ml), 6-methoxynicotinaldehyde (711 mg, 5, 18 mmol) and NaBH (AcO) ₃ (1.50 g, 7.07 mmol). The mixture was stirred for 1 day at ambient temperature, then additional 6-methoxy-nicotinaldehyde (711 mg, 5.18 mmol) and NaBH (AcO) ₃ (1.50 g, 7.07 mmol) were added. After stirring for 1 day at ambient temperature, the resulting mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc / mixture of hexane isomers as gradient eluent to give the title compound of sufficient purity for later use (1.50 g, 96% yield) MS (apci) m / z = 334 , 2 (M + H).

Step 2: Preparation of 3 - ((6-methoxypyridin-3-yl) methyl) -3,8 diazabicyclo [3.2.1] octane hydrochloride. A solution of tert-butyl 3 - ((6-methoxypyridin-3-yl) methyl) -3,8 diazabicyclo [3.2.1] octane-8-carboxylate (1.5 g, 4.50 mmol) in 6N. HCl in iso-PrOH (15 ml) was stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure to give the purified title compound as the hydrochloride salt (1.15 g, 95% yield). MS (apci) m / z = 234.1 (M + H).

- 188 035568

Intermediate R9.

1- (pyridin-2-ylmethyl) -4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) piperazine.

In a suspension of 1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) piperazine (1.00 g, 3.46 mmol) in DMF (5 ml) picolinaldehyde (0.556 g, 5.19 mmol), Me ₄ N (AcO) ₃ BH (1.82 g, 6.92 mmol) and TEA (1.45 ml, 10.4 mmol) were added. The resulting mixture was stirred overnight at ambient temperature and then quenched with water. The cooled suspension was filtered and the collected solid was washed with water and hexane to give the title compound (500 mg, 38% yield). MS (apci) m / z = 299.1 (B (OH) ₂ M + H).

Intermediate R10.

1 - ((6-methoxypyridin-3-yl) methyl) -4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 yl) piperazine.

Stage 1: Purification of 97% purity of commercial 6-methoxy-nicotinaldehyde.

A suspension of 97% purity commercial 6-methoxy-nicotinaldehyde (200 g, 1458.4 mmol) in a mixture of hexane isomers (750 ml) was heated with a heat gun to dissolve most of the solid. The resulting hot solution containing orange solids was filtered through a preheated filter funnel into a preheated flask. The hot filtrate was stirred and allowed to cool slowly to ambient temperature. The room temperature solution was left to stand for 2 days at room temperature. The resulting slurry was filtered and the collected solids washed with a mixture of hexane isomers to provide the purified title compound (163.93 g, 82% recovery).

Stage 2: preparation of 1 - ((6-methoxypyridin-3-yl) methyl) -4- (5- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) pyridin 2-yl) piperazine. Into a mixture of 1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridin-2-yl) piperazine (5 g, 17.3 mmol) and 6-methoxynicotinaldehyde 2, 85 g, 20.7 mmol) in DCE (85 ml) was added NaBH (AcO) ₃ (7.3 g, 35 mmol). The resulting mixture was stirred for 2.5 h at ambient temperature, then evaporated under reduced pressure to half the original volume (about 40 ml). The resulting mixture was diluted with EtOAc, then washed with saturated NaHCO _{3 (} in _OD n _N i) and saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (4.86 mg, 69% yield). MS (apci) m / z = 411.2 (M + H).

Intermediate R11.

(6- (8- (tert-butoxycarbonyl) -3,8-diazabicyclo [3.2.1] octan-3-yl) pyridin-3-yl) boric acid.

Suspension of tert-butyl-3,8-diazabicyclo [3.2.1] octane-8-carboxylate hydrochloride (153 mg, 0.616 mmol), 2-fluoro-5- (4,4,5,5-tetramethyl-1,3) 2-dioxaborolan-2-yl) pyridine (125 mg, 0.560 mmol) and

K ^ O ^) (387 mg, 2.80 mmol) in DMSO (5 ml) was stirred for 1 day at 90 ° C, then cooled to ambient temperature. The resulting suspension was filtered and the solids were collected to give the purified title compound (55 mg, 30% yield). MS (apci) m / z = 334.2 (M + H).

Intermediate R12.

(1R, 4R) -2 - ((6-methoxypyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane bis (2,2,2 trifluoroacetate).

Stage 1: obtaining tert-butyl (1R, 4R) -5 - ((6-methoxypyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1]

- 189 035568 heptane-2-carboxylate. To a solution of (1R, 4R) -2,5-diazabicyclo [2.2.1] heptane-2carboxylic acid tert-butyl ester (250 mg, 1.26 mmol) in DCE (6.31 ml) was successively added 6 methoxy nicotinaldehyde (346 mg, 2.52 mmol) and NaBH (AcO) ₃ (802 mg, 3.78 mmol), then stirred overnight at ambient temperature. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to give the purified title compound (20 mg, 5% yield). MS (apci) m / z = 320.2 (M + H).

Step 2: Preparation of (1R, 4R) -2 - ((6-methoxypyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane bis (2,2,2-trifluoroacetate). To a solution of tert-butyl (1R, 4R) -5 - ((6-methoxypyridin-3-yl) methyl) -2.5 diazabicyclo [2.2.1] heptane-2-carboxylate (20 mg, 0.063 mmol) in DCM (1 ml) was added TFA (0.5 ml). The resulting mixture was stirred for 2 hours at ambient temperature, then evaporated under reduced pressure to give the title compound as bis-trifluoroacetate salt (28 mg, quantitative yield). MS (apci) m / z = 220.2 (M + H).

Intermediate R14.

tert-butyl 3- (4-bromophenyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate.

Via a mixture of 1-bromo-4-iodobenzene (0.500 g, 1.77 mmol), tert-butyl-3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (0.491 g, 2.47 mmol), C ^ CO ^ (1.15 g, 3.53 mmol), CuI (16.8 mg, 0.0884 mmol) and 2isobutyrylcyclohexan-1-one (59.5 mg, 0.353 mmol) in DMF (1.5 ml), A _{( d)} for 5 minutes, then stirred for 4 days at ambient temperature. An additional amount of CuI (16.8 mg, 0.0884 mmol) was added to the reaction mixture, then A _{(g) was} purged for 5 min and stirred at 35 ° C for 1 h. The mixture was partitioned between saturated aqueous sodium chloride solution and MTBE ... The organic layer was separated and further washed with saturated aqueous sodium chloride solution and saturated NH4Cl (water). The aqueous extracts were combined and once again extracted with MTBE. The MTBE extracts were combined, then dried over anhydrous MgSO ^), filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM as eluent) to give the purified title compound (190 mg, 30% yield). MS (apci) m / z = 353.0 (M + 1); 355.1 (M + 2), character Br.

Intermediate R15.

tert-butyl 3- (5-chloropyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate.

A mixture of tert-butyl-3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (266 mg, 1.34 mmol), 2.5 dichloropyrazine (260 mg, 1.74 mmol) and ^ CO ^) (927 mg , 6.71 mmol) in DMSO (1.5 ml) was stirred for 2 h at 80 ° C, then overnight at 85 ° C. After cooling to ambient temperature, the mixture was diluted with water and stirred vigorously until the subsequent exothermic effect disappeared. The aqueous mixture was extracted with Et ₂ O and the biphasic mixture was filtered and separated. The aqueous phase was extracted with DCM and the Et ₂ O and DCM extracts were combined. The combined organic extracts were dried over anhydrous MgSO ^), filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in DCM with 0.05% NH4OH as eluent) to afford the purified title compound (286 mg, 69% yield). MS (apci) m / z = 311.0 (M + 1); 313.2 (M + 2), character Cl.

Intermediate R16.

Ν. , ΌΗ ό TFK

2,2,2-trifluoroacetate (3,6-diazabicyclo [3.1.1] heptan-6-yl) (6-hydroxypyridin-3-yl) methanone.

Step 1: Preparation of tert-butyl 6- (6-hydroxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3carboxylate. Suspension of tert-butyl-3,6-diazabicyclo [3.1.1] heptane-3-carboxylate (0.363 g, 1.83 mmol), 6-hydroxynicotinic acid (0.382 g, 2.75 mmol), N-ethyl-I-isopropylpropane -2-amine (1.59 ml, 9.15 mmol) and HATU (0.766 g, 2.01 mmol) in DMF (2 ml) were stirred overnight at ambient temperature. The reaction mixture was diluted with DCM and water. The resulting suspension was filtered to give the title compound as a solid (250 mg, 43% yield).

Stage 2: Preparation of 2,2,2-trifluoroacetate (3,6-diazabicyclo [3.1.1] heptan-6-yl) (6hydroxypyridin-3-yl) methanone. In a solution of tert-butyl 6- (6-hydroxynicotinoyl) -3.6

- 190 035568 diazabicyclo [3.1.1] heptane-3-carboxylate (step 1; 250 mg, 0.783 mmol) in DCM (7.83 ml) was added TFA (1.20 ml). The resulting mixture was stirred for 2 hours at ambient temperature, then evaporated under reduced pressure to give the title compound, assuming quantitative yield.

Intermediate R17.

TPA, bis- (2,2,2-trifluoroacetate) (2R, 6S) -1 - ((6-methoxypyridin-3-yl) methyl) -2,6-dimethylpiperazine.

Step 1: Preparation of tert-butyl (3S, 5R) -3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3S, 5R) -3,5-dimethylpiperazine-1-carboxylate (50 mg, 0.23 mmol) in DCE (1.17 ml), 6-methoxy-nicotinaldehyde (64 mg, 0.47 mmol) was successively added and NaBH (AcO) ₃ (148 mg, 0.70 mmol), then stirred for 1 hour at ambient temperature. The resulting mixture was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (using a gradient of 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as a gradient eluent) to afford the purified title compound (26 mg, 33% yield). MS (apci) m / z = 336.2 (M + H).

Stage 2: Preparation of bis- (2,2,2-trifluoroacetate) (2S, 6R) -1 - ((6-methoxypyridin-3-yl) methyl) -2,6dimethylpiperazine. A solution of tert-butyl (3 S, 5R) -4 - ((6-methoxypyridin-3-yl) methyl) -3.5 dimethylpiperazine-1-carboxylate (26 mg, 0.078 mmol) was dissolved in 1 ml DCM and TPA (1 ml), then stirred for 2 hours at ambient temperature. The resulting mixture was evaporated under reduced pressure to give the purified title compound (36 mg, 33% yield). MS (apci) m / z = 336.2 (M + H).

Intermediate R18.

(1 s, 3 s) -3-hydroxycyclobutyl-4-methylbenzenesulfonate.

A solution of (^^) - 3- (tosyloxy) cyclobutyl pivalate (3.5 g, 10.7 mmol) in DCM (20 ml) was cooled to -78 ° C, then DIBAL-H (25 wt% in toluene, 12.6 ml, 18.8 mmol). The resulting mixture was stirred for 1 hour at -78 ° C. The mixture was quenched by the slow addition of Na ₂ SO ₄ -10H ₂ O at -78 ° C and then allowed to warm to ambient temperature. The resulting suspension was filtered under reduced pressure and the solids were washed with a minimum amount of MTBE. The resulting filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (30% EtOAc in hexane isomer mixture) to give the title compound (1.54 g, 59% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, 2 H), 7.34 (d, 2 H), 4.37-4.44 (m, 1 H), 3.86-3 , 94 (m, 1 H), 2.66-2.73 (m, 2H), 2.45 (s, 3H), 2.08-2.15 (m, 2H), 1.78 (d, 1H).

Intermediate R19.

(1 - ((tert-butyldimethylsilyl) oxy) cyclopropyl) methanol.

Step 1: Preparation of methyl 1 - ((tert-butyldimethylsilyl) oxy) cyclopropane-1-carboxylate. Imidazole (1.19 g, 17.5 mmol) and tert-butyldimethylsilyl chloride (2.77 g , 18.4 mmol). The resulting mixture was stirred for 60 hours at ambient temperature. The reaction mixture was diluted with water and extracted with Et ₂ O (2x). The organic extracts were washed with water (3x) and saturated aqueous sodium chloride solution (1x), then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the title compound (3.45 g, 86% yield %).

1H NMR (400 MHz, CDCl ₃ ) δ 3.71 (s, 3H), 1.33-1.30 (m, 2H), 1.08-1.05 (m, 2H), 0.87 (s , 9H), 0.14 (s, 6H).

Stage 2: preparation of ((1 - ((tert-butyldimethylsilyl) oxy) cyclopropyl) methanol. A solution of methyl 1 ((tert-butyldimethylsilyl) oxy) cyclopropane-1-carboxylate (stage 1; 3.45 g, 15.0 mmol ) in THF (150 ml) was cooled to 0 ° C, then 25 wt% DIBAL-H in toluene (25.2 ml, 37.4 mmol) was slowly added. The resulting mixture was stirred for 1 h at ambient temperature. cooled to 0 ° C and quenched by slowly adding aqueous 0.5 M sodium potassium L (+) - tartrate tetrahydrate (Rochelle salt; 50 ml) The quenched mixture was diluted with Et ₂ O and stirred for 15 min at ambient temperature. The resulting slurry was filtered under reduced pressure and the solids washed with minimal Et ₂ O. The filtrate was washed with water (1x) and brine (1x), then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give

191 035568 title compound (1.71 mg, 56% yield).

1H NMR (400 MHz, CDCl ₃ ) δ 3.55-3.54 (d, 2H), 0.87 (s, 9H), 0.79-0.76 (m, 2H), 0.60-0 , 57 (m, 2H), 0.12 (s, 6H).

Intermediate R20.

(6- (6- (tert-butoxycarbonyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) -5-fluoropyridin-3-yl) boric acid.

A solution of (5,6-difluoropyridin-3-yl) boric acid (20 mg, 0.13 mmol), tert-butyl 3,6 diazabicyclo [3.1.1] heptane-6-carboxylate (50 mg, 0.25 mmol) and K ^ CO ^) (174 mg, 1.3 mmol) in dioxane (629 μl) was stirred for 3 days at 80 ° C. The reaction mixture was evaporated under reduced pressure to give the title compound (20 mg, quantitative yield) of sufficient purity to be used without further purification. MS (apci) m / z = 338.1 (M + H).

Intermediate R21.

tert-butyl 3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl) -3,6diazabicyclo [3.1.1] heptane 6-carboxylic acid.

A mixture of 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (0.311 g, 1.39 mmol), tert-butyl 3,6-diazabicyclo [ 3.1.1] heptane-6-carboxylate (0.303 g, 1.53 mmol) and DIEA (0.484 ml, 2.78 mmol) in DMF (9.25 ml) were stirred overnight at ambient temperature. EtOAc and water were added to the reaction mixture. The organic layer was washed with water and saturated aqueous sodium chloride solution, then dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by silica gel chromatography (10-90% EtOAc in hexane) to give the title compound (68 mg, 12% yield).

Intermediate R22.

6-methoxy nicotinoyl chloride hydrochloride.

A suspension of 6-methoxy-nicotinic acid (18 mg, 0.12 mmol) in SOC12 (1 ml, 0.12 mmol) was stirred for 30 min at 80 ° C. After cooling to ambient temperature, the solution was evaporated under reduced pressure to give the crude title compound, which was used directly in the next step without further purification.

Intermediate R23.

tert-butyl 4- (5-chloropyrazin-2-yl) piperazine-1-carboxylate.

Into a solution of 2,5-dichloropyrazine (1.03 g, 6.91 mmol) in DMSO (10 ml) were successively added ^ CO ^ ra) (2.867 g, 20.74 mmol) and tert-butylpiperazine-1-carboxylate (1.288 ). g, 6.914 mmol), then stirred overnight at 75 ° C. After cooling to ambient temperature, the mixture was partitioned between EtOAc (10 ml) and water (20 ml). After phase separation, the organic extracts were evaporated under reduced pressure to give the title compound (1.928 g, 93% yield). MS (apci) m / z = 199.1 (M-Boc%).

¹ H NMR (CDCl 3) δ 8.07 (m, 1H), 7.86 (m, 1H), 3.56 (s, 8H), 1.48 (s, 9H).

Intermediate R24.

- 192 035568

3- (5-chloropyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane bis (2,2,2-trifluoroacetate).

To a mixture of tert-butyl 3- (5-chloropyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate R15; 300 mg, 0.965 mmol) in DCM (3.0 ml ) was added TFA (3.0 ml, 39 mmol) and stirred for 1 h at ambient temperature. The resulting mixture was diluted with Et ₂ O (20 ml). The resulting slurry was filtered and the isolated solids dried under high vacuum to give the title compound (284 mg, 67% yield). MS (apci) m / z = 211.1 (M + H).

Intermediate R25.

3- (5-chloropyrazin-2-yl) -6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane.

To a solution of 3- (5-chloropyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-bis- (2,2,2-trifluoroacetate) (intermediate R24; 284 mg, 0.647 mmol) in DCM ( 6.47 ml) 6-methoxy-nicotinaldehyde (266 mg, 1.94 mmol) and NaBH (AcO) ₃ (686 mg, 3.24 mmol) were added, followed by stirring for 1 h at ambient temperature. The reaction mixture was diluted with DCM and quenched with saturated II (vodn.). After phase separation on a PS frit with DCM, the organic extracts were evaporated under reduced pressure to give the crude title compound, which was used in the next step without further purification, suggesting quantitative yield. MS (apci) m / z = 298.1 (M-Cl).

Intermediate R26.

3- (5-bromopyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane bis (2,2,2-trifluoroacetate).

Into a mixture of tert-butyl 3- (5-bromopyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate R4, step 1, method 1; 470 mg, 1.3 mmol ), TFA (2.0 ml, 26.1 mmol) was added in DCM (2.0 ml) and stirred for 1 h at ambient temperature. The resulting mixture was evaporated under reduced pressure to give the title compound (478 mg, 75% yield). MS (apci) m / z = 256.0 (M + H).

Intermediate R27.

3- (5-bromopyridin-2-yl) -6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane.

In a mixture of 3- (5-bromopyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-bis- (2,2,2-trifluoroacetate) (intermediate R26; 478 mg, 1.3 mmol) and 6-methoxy-nicotinaldehyde (267 mg, 1.95 mmol) in DCM (10 ml) was added NaBH (AcO) ₃ (551 mg, 2.60 mmol). The resulting mixture was stirred for 30 min at ambient temperature before adding TEA (544 μl, 3.90 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The resulting mixture was quenched with saturated INCO ₃ (aq.) And then the biphasic mixture was extracted with DCM. The organic extracts were evaporated under reduced pressure and the residue was purified by silica gel chromatography (using 0-5% MeOH in DCM as gradient eluent) to afford the purified title compound (163 mg, 33% yield). MS (apci) m / z = 377.1 (M + H).

Intermediate R28.

6 - ((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2yl) -3, 6-diazabicyclo [3.1.1] heptane.

Through a mixture of 3- (5-bromopyridin-2-yl) -6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane (intermediate R27; 150 mg, 0.400), bis- (pinacolato) dibor (305 mg, 1.20 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ (32.6 mg, 0.0400 mmol) and KOAc (118 mg, 1.20 mmol) in dioxane (4 , 00 ml) was purged with Ar ( _g ), then stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, then filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (using 50-100% hexane: EtOAc isomer mixture as eluent gradient) to afford the title compound (118 mg, 70% yield). MS (apci) m / z = 341.2 (corresponding boric acid M + H).

- 193 035568

Obtaining synthetic examples.

Example 1.

N = \ Jf I ^u Od) 4- (6- (benzylpiperazin-1-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile. In a pressure vessel, 4-bromo-6-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P1; 0.25 g, 1.05 mmol), 1-benzyl-4- (5- (4 , 4,5). 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2yl) piperazine (intermediate R1; 0.478 g, 1.26 mmol) and Pd (PPh ₃ ) ₄ (0.121 g, 0.105 mmol) was suspended in 2 M L ₂ CO ₃ ( _BOD n.) (2.63 ml, 5.25 mmol) and 1,4-dioxane (2 ml). N _{2W was} purged through the resulting mixture. The vessel was sealed and the mixture was stirred for 5 h at 100 ° C. The reaction mixture was cooled to room temperature and then water (10 ml) was added. The resulting biphasic mixture was extracted with several portions of DCM in a PS frit. The combined organic extracts were evaporated under reduced pressure and then purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to give the title compound as the TFA salt. The salt was partitioned between 4: 1 DCM: iso-PrOH and saturated Nal ICO) _{3 (I! (UI | I.} The resulting organic extracts were dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the purified compound, specified in title (262.5 mg, yield 61%) MS (apci) m / z = 411.2 (M + H).

Example 2.

N = \ if I

TFK

0X1

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile 2,2,2-trifluoroacetate.

In a solution of 6-methoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile hydrochloride (intermediate P2; 25 mg, 0.075 mmol) in DMA (750 μl) was added TEA (78 μl, 0.45 mmol) and (bromomethyl) benzene (18 μl, 0.15 mmol), and left stirring overnight at ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the title compound (11.9 mg, 37% yield). MS (apci) m / z = 425.2 (M + H).

Example 3.

N = \

Jf Ύ

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3carbonitrile (example 1; 30 mg, 0.0731 mmol) in DMF (500 .mu.l) were added consecutively K ₂ CO _{3 (solid)} (20.2 mg, 0.146 mmol) and bromoethane (10.9 uL, 0.146 mmol) and then stirred for 16 hours at 50 ° C. After cooling to ambient temperature, the reaction mixture was directly purified by C18 reverse phase chromatography (10-100% ACN / H2O as gradient eluent) to afford the title compound (11.0 mg, 34% yield). MS (apci) m / z = 439.2 (M + H).

Compounds in the table. A were prepared using a method similar to that described for the synthesis of example 3, replacing bromoethane with the corresponding alkyl halide. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Each of the named compounds was isolated purified after C18 reverse phase chromatography using an appropriate gradient. In the case marked (*), persistent colored impurities were removed by sequential dissolution in DCM, treatment with activated carbon, filtration through Celite® and evaporation under reduced pressure.

- 194 035568

Table A

No. Example Structure Chemical name MS (apci) m / z 4- (6- (4- 4 N = \ I JLI benzylpiperazine-1 - yl) pyridin-3-yl) -6isoprop oxypyrazolo [1 453.2 (M + H) Ν 3ν ^ Ο , 5-a] pyridine-3carbonitrile 4- (6- (4- Ν = \ benzylpiperazine-1 - five X Ί yl) pyridin-3-yl) -6 - ((3 - methyloxetane-3- 495.2 (M + H) Ο WW QjO yl) methoxy) pyrazolo [1, 5-a] pyridine-3carbonitrile Ν = \ 4- (6- (4- ίι 1 ~ ^ Ν benzylpiperazine-1- 6 '^^ γΛ / γ ^ Ν yl) pyridin-3-yl) -6- (2- 483.2 | Ι Ν = \ ^L CIE ethoxyethoxy) pyrazolo [ 1,5-a] pyridine-3carbonitrile 4- (6- (4- (M + H) NWW Η 1 benzylpiperazine-1- 7 ^ Ν yl) pyridin-3-yl) -6- (2- 497.2 1 < ^Λ οχ isopropoxyethoxy) pyr azolo [1,5-a] pyridine-3carbonitrile 4- (6- (4- (M + H) Ν = \ Ν. χ ~~ benzylpiperazine-1- 8 ₀ ΛΑ F ₃ cr ^ Ν Α + Ο yl) pyridin-3-yl) -6- (2 (trifluoromethoxy) ethox and) pyrazolo [1,5а] pyridine-3carbonitrile 523.2 (M + H) Ν = \ 4- (6- (4- .Ν ^ χfl 1 ~ ^ Ν benzylpiperazine-1- ABOUT II .1 ^ Ν yl) pyridin-3-yl) -6- (3 - 483.2 Have | ^ Λ + Ο methoxypropoxy) pyraz olo [1,5-a] pyridine-3 carbonitrile (M + H)

- 195 035568

Example 12.

4- (6- (4benzylpiperazin-1yl) pyridin-3-yl) -6 ((tetrahydro-2H-pyran4-yl) oxy) pyrazolo [1,5а] pyridine-3carbonitrile

4- (6- (4benzylpiperazin-1yl) pyridin-3-yl) -6 ((tetrahydro-2H-pyran2yl) methoxy) pyrazolo [1,5-a] pyridine-3carbonitrile

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6- (2-methoxyethoxy) pyrazolo [1,5-a] pyridin-3carbonitrile.

Into a solution of 4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3carbonitrile (example 1; 32.3 mg, 0.0787 mmol) in DMF (800 μl), K ₂ CO ₃ ( _TB ) (21.8 mg, 0.157 mmol) and 2-bromoethyl methyl ether (14.8 μl, 0.157 mmol) were added sequentially, followed by stirring for 16 h at 50 ° C.

After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water and saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound as a TFA salt. The salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ₃ ( _VODN .). The resulting organic extracts were dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure to give the title compound (19.3 mg, 52% yield). MS (apci) m / z = 469.2 (M + H).

Example 13.

2,2,2-trifluoroacetate ^) - 4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6- (2hydroxypropoxy) pyrazolo [1,5-a] pyrudin-3-carbonitrile.

Into a solution of hydrochloride (^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyrudine-3-carbonitrile (intermediate P28); 6 mg, 0.0145 mmol) in DCE (145 μl) / MeOH (5 drops) benzaldehyde (3.07 mg, 0.0289 mmol) and NaBH (AcO) ₃ (12.3 mg, 0.0578 mmol ). The resulting mixture was stirred for 1 h at ambient temperature and then purified directly by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound as TPA salts (7.5 mg, 89% yield). MS (apci) m / z = 468.9 (M + H).

Example 14.

6- (azetidin-3 -yloxy) -4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3 carbonitrile.

- 196 035568

Stage 1: preparation of tert-butyl-3 - ((4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -3cyanopyrazolo [1,5-a] pyridin-6-yl) oxy) azetidine -1-carboxylate. Into a solution of 4- (6- (4-benzylpiperazin-1yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (example 1; 27.8 mg, 0.0678 mmol) in DMF (1.4 ml) were added K ₂ CO ₃ ( _TB ) (468 mg, 0.339 mmol) and 1-Boc-3-iodazetidine (38.3 mg, 0.135 mmol), and then stirred for 16 h at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water and saturated sodium chloride solution. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure. Purification by silica gel chromatography (0-30% DCM-MeOH with 2% NH4OH as gradient eluent) gave the title compound which was transferred directly to step 2. MS (apci) m / z = 566.2 (M + H) ...

Step 2: Preparation of 6- (azetidin-3-yloxy) -4- (6- (4-benzylpiperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. A solution of tert-butyl 3 - ((4- (6- (4-benzylpiperazin-1yl) pyridin-3-yl) -3-cyanopyrazolo [1,5-a] pyridin-6-yl) oxy) azetidine-1-carboxylate in 1: 1 DCM: TFA (2 ml) was stirred for 30 min at ambient temperature. The mixture was evaporated under reduced pressure and purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound as a TFA salt. The salt was partitioned between a 4: 1 _DCM:!. I-PrOH and saturated Nal ICC) _{3 (I (UI | I} obtained organic extracts were dried over anhydrous № ^ O4 _(TV), filtered and evaporated under reduced pressure to obtain the title compound (16.9 mg, 54% yield) MS (apci) m / z = 466.2 (M + H).

Example 15.

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6 - ((1-methylazetidin-3-yl) oxy) pyrazolo [1,5а] pyridine-3-carbonitrile.

In a solution of 6- (azetidin-3-yloxy) -4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) pyrazolo [1,5а] pyridine-3-carbonitrile (example 14; 12.4 mg (0.0266 mmol) in formic acid (401.9 μl) formaldehyde (200.1 μl, 2.664 mmol) was added The resulting mixture was stirred for 16 h at 80 ° C, then additional formaldehyde (200.1 μl , 2.664 mmol) and formic acid (200 μl). The mixture was stirred for 60 h at 80 ° C. After cooling to room temperature, the mixture was evaporated under reduced pressure and purified by chromatography on C18 reverse phase (5-95% ACN / water with 0.1% TFA gradient eluent) to give the title compound as a TFA salt The salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ₃ ( _aq .) The resulting organic extracts were separated, dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure to give the title compound (6.7 mg, yield 47%). MS (apci) m / z = 480,2 ( M + H).

Example 16.

6- (azetidin-3-ylmethoxy) -4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

Stage 1: preparation of tert-butyl-3 - (((4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -3cyanopyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) azetidine-1-carboxylate. DIAD (58 μL, 0.29 mmol) was added to a cold (0 ° C) solution of PPh ₃ (77 mg, 0.29 mmol) in 1: 1 DCM: THF (2.0 ml) and stirred for 15 min at 0 ° C. To the resulting mixture at 0 ° C was added a solution of (4- (6- (4-benzylpiperazin-1yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile (example 1; 60 mg , 0.15 mmol) and 1Bos-azetidin-3-yl methanol (55 mg, 0.29 mmol) in 1: 1 DCM: THF (4.0 ml) After stirring overnight at room temperature, the reaction mixture was evaporated at reduced pressure and purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt Salt partitioned between 4: 1 DCM: iso PrOH and saturated №NSO _{3 (aq.).} The resulting organic extracts were separated, dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure to give the title compound (28 mg, 33% yield). MS ( arso m / z = 580.2 (M + H).

Stage 2: Preparation of 6- (azetidin-3-ylmethoxy) -4- (6- (4-benzylpiperazin-1-yl) pyridin-3

- 197 035568 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl 3 - (((4- (6- (4-benzylpiperazin-1yl) pyridin-3-yl) -3-cyanopyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) azetidine -1-carboxylate in DCM (4 ml) was added TFA (2.0 ml). The resulting mixture was stirred for 30 min at ambient temperature and then purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the title compound as a salt TPA. The salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ₃ ( _Bog N). The resulting organic extracts were separated, dried over anhydrous Na ₂ SO ₄ (τ _B ), filtered and evaporated under reduced pressure to give the purified title compound (43 mg, 62% yield). MS (apci) m / z = 480.2 (M + H).

Example 17.

N = \ Jf I Ν- ~ 7 U Λ

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6 - ((1-methylazetidin-3-yl) methoxy) pyrazolo [1,5a] pyridin-3-carbonutrile.

Into a solution of 6- (azetidin-3-ylmethoxy) -4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonutrile (example 16; 22 mg, 0.046 mmol) in formic acid (3.46 μl) formaldehyde (1.28 μl, 45.9 mmol) was added. The resulting mixture was stirred for 5 days at 80 ° C. After cooling to room temperature, the mixture was evaporated under reduced pressure. The residue was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ₃ ( _Bog N). The resulting organic extracts were combined, dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) followed by chromatography on silica gel (10-40% MeOH in EtOAc as eluent gradient) to afford the purified specified in the title compound (3 mg, 13% yield). MS (apci) m / z = 494.2 (M + H).

Example 18.

4- (6- (4-Benzylpiperαzin-1-yl) pyridin-3-yl) -6- (oxetan-3-ylmethoxy) pyrαzolo [1,5-a] pyridine-3carbonitrile.

DIAD (38 μL, 0.19 mmol) was added to a cold (0 ° C) solution of PPh ₃ (51 mg, 0.19 mmol) in 1: 1 DCM: THF (2.0 ml) and stirred for 15 min at 0 ° C. To the resulting mixture at 0 ° C was added a solution of (4- (6- (4-benzylpiperαzin-1-yl) pyridin-3-yl) -6-hydroxypyrαzolo [1,5-a] pyridine-3carbonitrile (example 1; 40 mg , 0.097 mmol) and oxetan-3-ylmethanol (17 mg, 0.19 mmol) in 1: 1 DCM: THF (3.0 ml). The reaction mixture was stirred for 1 h at 0 ° C, then for 1 h at room temperature The mixture was directly purified by C18 reverse phase chromatography (595% ACN / water with 0.1% TFA as gradient eluent) to give the title compound as a TFA salt Salt partitioned between 4: 1 DCM: iso -PgOH and saturated NaHCO ^^.). The resulting organic extracts were combined, dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (28 mg, 60% yield). MS (apci) m / z = 481.2 (M + H).

Example 19.

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6- (2- (1-methylazetidin-3-yl) ethoxy) pyrazolo [1,5a] pyridine-3-carbonitrile.

The title compound was prepared using a procedure similar to that described in Example 18 substituting 2- (1-methylazetidin-3-yl) ethanol for oxetan-3-ylmethanol. After chromatographic purification (10-30% MeOH in DCM as gradient eluent), the title compound was isolated pure (16 mg, 32% yield). MS (apci) m / z = 508.3 (M + H).

- 198 035568

Example 20.

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile.

Into a solution of 4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3carbonitrile (example 1; 28.2 mg, 0.0687 mmol) in DMF (0.8 ml) was added 4- (2chloroethyl) morpholine hydrochloride (25.6 mg, 0.137 mmol) and K ₂ CO ₃ ( _TB ) (47.5 mg, 0.344 mmol), then stirred for 16 h at 50 ° C. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. Purification of the resulting crude product by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA gradient eluent) afforded the purified title compound as a TFA salt. The salt was partitioned between 4: 1 DCM: iso-PrOH and saturated Nal 1C (K _{aq : 1} The resulting organic extracts were combined, dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure to give the title compound ( 19.9 mg, 55% yield) MS (apci) m / z = 524.2 (M + H).

1H NMR (400 MHz, DMSO-06) δ: 8.70-8.69 (d, 1H), 8.57 (s, 1H), 8.32-8.31 (d, 1H), 7.78 -7.75 (dd, 1H), 7.35-7.25 (m, 6H), 6.93-6.91 (d 1H), 4.23-4.20 (t, 2H), 3, 60-3.56 (m, 8H), 3.53 (s, 2H), 2.74-2.71 (t, 2H), 2.502.47 (m, 8H).

Example 21.

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6- (2- (4-methylpiperazin-1-yl) ethoxy) pyrazolo [1,5а] pyridine-3-carbonitrile.

DIAD (24.5 μl, 0.124 mmol) was added to a cold (0 ° С) solution of PPh ₃ (32.6 mg, 0.124 mmol) in 1: 1 DCM: THF (1.0 ml), and stirred for 15 min. at 0 ° C. A solution of (4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6-hydroxypyrazolo [1,5а] pyridine-3-carbonitrile was added to the resulting mixture at 0 ° C (example 1; 34, 0 mg, 0.0828 mmol) and 1- (Nhydroxyethyl) -4-methylpiperazine (14.3 mg, 0.0994 mmol) in 1: 1 DCM: THF (2.0 ml). The reaction mixture was stirred for 16 h at room temperature and then evaporated under reduced pressure. Purification of the crude residue by chromatography on C18 reverse phase (5-95% water-ACN with 0.1% TFA as eluent gradient) gives the purified title compound as a salt TFA Salt was converted to the free base by partitioning between 4: 1 DCM: iso-PrOH and saturated NaHCO ₃ ( _aq .) The resulting organic extracts were combined, dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. to give the title compound (20.1 mg, 45% yield) MS (apci) m / z = 537.2 (M + H).

1H NMR (400 MHz, DMSO-06) δ: 8.70-8.69 (d, 1H), 8.57 (s, 1H), 8.32-8.31 (d, 1H), 7.78 -7.75 (dd, 1H), 7.52 (s, 1H), 7.35-7.25 (m, 5H), 6.93-6.91 (d, 1H), 4.21-4 , 18 (t, 2H), 3.60-3.57 (m, 4H), 3.53 (s, 2H), 3.18-3.13 (q, 2H), 2.73-2.70 (t, 2H), 2.50-2.47 (m, 8H), 2.13 (s, 3H), 1.32-1.28 (t, 2H).

Example 22.

4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6- (2- (dimethylamino) ethoxy) pyrazolo [1,5-a] pyridine3-carbonitrile.

The title compound was prepared using a similar procedure to that described in Example 21 substituting, Ν-dimethylethanolamine for 1- (No. hydroxyethyl) -4-methylpiperazine. After the salt was converted to the free base, further purification was carried out by silica gel chromatography (1-30% DCM-MeOH with 2% NH4OH as gradient eluent) to isolate the purified title compound (12.2 mg, 37% yield ). MS (apci) m / z = 482.2 (M + H).

- 199 035568

Example 23.

4- (6- (4- (3-hydroxy-2-phenylpropanoyl) piperazin-1-yl) pyridin-3-yl) -6-methoxypyrazolo [1,5а] pyridine-3-carbonitrile.

In a solution of 6-methoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile hydrochloride (intermediate P2; 25 mg, 0.0748 mmol) in DCM (1 ml) DIEA (78.1 μl, 0.449 mmol), 3-hydroxy-2-phenylpropanoic acid (24.8 mg, 0.150 mmol) and HATU (33 mg, 0.086 mmol) were added, then stirred overnight at temperature environment. The resulting mixture was extracted with EtOAc and the combined organic extracts were dried over anhydrous Na (O ^), filtered and evaporated under reduced pressure. Purification of the crude residue by C18 reverse phase chromatography (0-75% ACN / water as gradient eluent) afforded the purified title compound (15.7 mg, 41% yield). MS (apci) m / z = 483.2 (M + H).

Example 24.

4- (6- (4- (2- (5-fluoropyridin-2-yl) acetyl) piperazin-1-yl) pyridin-3-yl) -6-methoxypyrazolo [1,5a] pyridine-3-carbonitrile.

The title compound (17 mg, 45% yield) was prepared and purified using a procedure similar to that described in Example 23, substituting 2 (5-fluoropyridin-2-yl) acetic acid for 3-hydroxy-2-phenylpropanoic acid. and using 6 eq. DIEA instead of 5 equiv. MS (apci) m / z = 472.2 (M + H).

Example 25.

about

^) - 6-methoxy-4- (6- (4- (3-methoxypyrrolidine-1-carbonyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a mixed solution of 4-bromo-6-methoxypyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P1, step 6, part B; 20 mg, 0.079 mmol) in dioxane (2.0 ml) was added ^) - (6- (4- (3-methoxypyrrolidine 1-carbonyl) piperazin-1-yl) pyridin-3-yl) boric acid (intermediate R2; 40 mg, 0.12 mmol) and 2 M Κ ₂ ^ ₃ (βο№. ) (79 μL, 0.16 mmol) and then purged with 2 (γ) for 5 min. X-Phos (7.6 mg, 0.016 mmol) and Pd ₂ (dba) ₃ (3.6 mg, 0.0040 mmol) were added to the mixture, then снова _{2 (γ)} was purged again for 5 minutes. The resulting degassed mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2 SO (t0), filtered, and evaporated under reduced pressure. Purification of the crude residue by silica gel chromatography (0-50%, 20% MeOH / DCM in EtOAc as gradient eluent) afforded the purified title compound (22 mg, 58% yield). MS (apci) m / z = 462.2 (M + H).

Example 26.

- 200 035568 tert-butyl 4- (5- (3-cyano-6- (difluoromethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine 1-carboxylate.

In a pressure vessel, a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin4-yl) pyridin-2-yl) piperazine-1-carboxylate (intermediate P3; 150 mg , 0.357 mmol) in ACN (2 ml) and 30 wt% KOH ( _VODN .) (1.78 ml, 0.357 mmol) was cooled to -78 ° C, then 2-chloro-2,2-difluoro- 1 phenylethanone (262.9 μL, 1.784 mmol) before sealing the vessel. The reaction mixture was allowed to warm to ambient temperature over 1 hour and then stirred for 4 hours at 80 ° C. After cooling to room temperature, the resulting mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium chloride solution and the resulting emulsion was filtered through a glass filter. After separation from the emulsion, the organic extracts were dried over anhydrous MgSO ^), filtered, and evaporated under reduced pressure. The crude material was purified by silica gel chromatography (0-75% acetone / hexane isomer mixture as eluent gradient) to afford the purified title compound (58 mg, 35% yield). MS (apci) m / z = 471.1 (M + H).

Example 27.

GJ?

6- (difluoromethoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

Step 1: Preparation of 6- (difluoromethoxy) -4- (6- (piperazin-1-yl) pyridin-3ul) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride. To a solution of tert-butyl 4- (5- (3-cyano-6 (difluoromethox ^ pyrazolo ^^^ pyridinL-yl ^ iridinL-yl ^ iperazineL-carboxylate) (example 27, 57 mg, 0.121 mmol) in DCM (2 ml) 5-6 M HCl in iso-PrOH (4 ml, 20.0 mmol) was added, then stirred at ambient temperature for 2 h. The reaction mixture was evaporated under reduced pressure to give the purified title compound (51.2 mg, yield 95%) MS (apci) m / z = 371.1 (M + H).

Step 2: Preparation of 6- (difluoromethoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3ul) pyrazolo [1,5-a] pyridine-3-carbonitrile. To a solution of 6- (difluoromethoxy) -4- (6 (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride from the previous step (15 mg, 0.034 mmol) in DCE (1.3 ml) was added sequentially picolinaldehyde (6.5 μl, 0.068 mmol) and NaBH (AcO) ₃ (22 mg, 0.10 mmol). The resulting mixture was stirred for 17 h at ambient temperature and then quenched with MeOH (0.5 ml). The quenched mixture was purified directly by silica gel chromatography (using 0-100% acetone / hexane isomer mixture as eluent gradient) to afford the purified title compound (14.0 mg, 90% yield). MS (apci) m / z = 462.1 (M + H).

¹⁹ F NMR (CDCi ₃ ) δ -81.9 (1F), -82.1 (1F).

Example 28.

Ν = \

6- (difluoromethoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3ul) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (12.5 mg, 75% yield) was prepared and purified using a procedure similar to that described in Example 27, substituting 6-methoxy-nicotinaldehyde for picolinaldehyde. MS (apci) m / z = 492.2 (M + H).

¹⁹ F NMR (CDCi ₃ ) δ -81.9 (1F), -82.1 (1F).

Example 29.

tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-ul) piperazine-1

- 201 035568 carboxylate.

To a mixture of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (intermediate P3; 400 mg, 0.951 mmol ) in DMF (10 ml) were successively added to K ₂ CO ₃ ( _TB ) (263 mg, 1.90 mmol) and bromoethane (142 μl, 1.90 mmol), then stirred for 19 h at 50 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to afford the purified title compound (289 mg, 68% yield). MS (apci) m / z = 449.2 (M + H).

Example 30.

6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile dihydrochloride.

In a solution of tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperαzine 1-carboxylate (example 29; 148 mg, 0.330 mmol ) in DCM (2 ml) was added dropwise 5-6 M HCl in isoPrOH (4 ml, 20.0 mmol), and then stirred at ambient temperature for 5 h. The reaction mixture was evaporated under reduced pressure, Et ₂ O was added (3x10 ml) and evaporated again to afford the purified title compound as the dihydrochloride salt (116 mg, quantitative yield). MS (apci) m / z = 349.1 (M + H).

Example 31.

6-ethoxy-4- (6- (4- (2- (5-fluoropyridin-2-yl) acetyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a solution of 6-ethoxy-4- (6- (piperαzin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile dihydrochloride (example 30; 30 mg, 0.086 mmol) in DCM (1 ml) was added DIEA (0.030 ml, 0.17 mmol), 2 (5-fluoropyridin-2-yl) acetic acid (16 mg, 0.10 mmol) and HATU (33 mg, 0.086 mmol). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-100% 20% MeOH / DCM with 2% NH4OH in DCM as gradient eluent). The fractions containing the title compound were combined, evaporated under reduced pressure and then triturated with EtOH (1.5 ml) and water (1.5 ml). The resulting white precipitate was collected by filtration to obtain the purified title compound (3.2 mg, 8% yield). MS (apci) m / z = 486.2 (M + H).

1H NMR (400 MHz, DMSO-dg) δ: 8.38 (t, 1H, J = 1.6 Hz), 8.31 (d, 1H, J = 2.0), 8.17 (s, 1H ), 8.09 (d, 1H, J = 2.3 Hz), 7.71 (dd, 1H, J = 6.3, 2.7 Hz), 7.37 (dd, 2H, J = 4, 3, 1.6 Hz), 7.06 (d, 1H, J = 2.0), 6.73 (d, 1H, J = 8.6 Hz), 4.07 (q, 2H, J = 7 , 0 Hz), 3.95 (s, 2H), 3.78-3.74 (m, 4H), 3.63-3.57 (m, 4H), 1.48 (t, 3H, J = 6.7 Hz).

Example 32.

6-ethoxy-4- (6- (4- (1 - (pyridin-2-yl) cyclopropan-1-carbonyl) piperazin-1-yl) pyridin-3 yl ^ irazolo ^ D ^ pyridine 3-carbonitrile.

The title compound (14.9 mg, 35% yield) was prepared and purified using a procedure similar to Example 31, substituting 1- (pyridin2-yl) cyclopropanecarboxylic acid for 2- (5-fluoropyridin-2-yl) acetic acid. acid. MS (apci) m / z = 494.2 (M + H).

- 202 035568

Example 33.

^) - 6-ethoxy-4- (6- (4- (2- (4-fluorophenyl) -2-hydroxyacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3- carbonitrile.

The title compound was prepared using a procedure similar to that described in Example 31, replacing 2- (5-fluoropyridin-2-yl) acetic acid with d) - 2- (4-fluorophenyl) -2-hydroxyacetic acid. Additional changes in the procedure included an increase in the amount of DIEA used (5 equiv.) And a reduction in the reaction time to 1 h. After chromatography on silica gel (using a stepwise gradient of 0-100% EtOAc in a mixture of hexane isomers, then EtOAc with 10% MeOH as eluents) isolated the purified title compound (17 mg, 62% yield). MS (apci) m / z = 501.2 (M + H).

Example 34.

N = \ jr τ

ABOUT

^) - 6-ethoxy-4- (6- (4- (2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a solution of 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 30; 30 mg, 0.086 mmol) in DCM (1 , 72 ml) was added DIEA (60 μl, 0.344 mmol), ^) - 2-methoxy-2-phenylacetic acid (17.2 mg, 0.103 mmol) and HATU (39.3 mg, 0.103 mmol). The resulting mixture was stirred for 16 hours at ambient temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to afford the purified title compound (19.9 mg, 47% yield). MS (apci) m / z = 497.2 (M + H).

1H NMR (400 MHz, CDCl ₃ ) δ: 8.27 (d, 1H, J = 2.0 Hz), 8.23 (s, 1H), 8.21 (d, 1H, J = 2.0 Hz ), 7.74 (dd, 1H, J = 9.0, 2.7Hz), 7.46-7.34 (m, 5H), 7.14 (d, 1H, J = 2.3Hz) , 6.80 (d, 1H, J = 9.0), 5.12 (s, 1H), 4.10 (q, 2H, J = 7.0 Hz), 3.88-3.52 (m , 6H), 3.50 (s, 3H), 3.48-3.38 (m, 1H), 3.32-3.20 (m, 1H), 1.50 (t, 3H, J = 6 , 65 Hz).

Example 35.

6-ethoxy-4- (6- (4- (1 - (methoxymethyl) cyclopropane-1-carbonyl) piperazin-1-yl) pyridin-3 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A mixture of 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1 ^ -pyridine-3-carbonitrile dihydrochloride (example 30; 10.8 mg, 0.0827 mmol), 1- ( methoxymethyl) cyclopropanecarboxylic acid (10.8 mg, 0.0827 mmol), DIEA (24.0 μl, 0.138 mmol) and HATU (26.2 mg, 0.0689 mmol) in DCM (1 ml) were stirred overnight at ambient temperature and then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the purified title compound as a TFA salt. The salt was partitioned between saturated NaHCO ₃ (aq) (2 ml) and EtOAc (3 ml). The aqueous extracts were washed with additional EtOAc. EtOAc extracts were combined and evaporated under reduced pressure. Purification of the resulting crude product by silica gel chromatography (0-100% acetone in DCM as gradient eluent) afforded the title compound (6.1 mg, 19% yield). MS (apci) m / z = 461.2 (M + H).

- 203 035568

Example 36.

N = \ ί I

Ν '' ^ | OH c _%, A / ο I da-6-ethoxy-4- (6- (4- (2-hydroxy-3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5а] pyridine -3-carbonitrile.

Using a procedure similar to that described in example 35, replacing 1 (methoxymethyl) cyclopropanecarboxylic acid with (H) -2-1ldroxy-3-methylbuta11oic acid and using 4 eq. DIEA, the title compound was isolated (10.8 mg, 28% yield). MS (apci) m / z = 448.9 (M + H).

Example 37.

Ν = λ

JLJL w tfk ο

2,2,2-trifluoroacetate ^) - 6-ethoxy-4- (6- (4- (2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

To a solution of 6-ethoxy-4- (6- (piperαzin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile dihydrochloride (example 30; 30 mg, 0.0861 mmol) in DCM (1.72 ml) was added ^) - 2-methoxy-2-phenylacetic acid (17.2 mg, 0.103 mmol), HATU (39.3 mg, 0.103 mmol) and DIEA (60.0 μl, 0.344 mmol). The resulting mixture was stirred for 16 hours at ambient temperature and then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (595% ACN in water with 0.1% TFA as gradient eluent) to afford the purified title compound (13.9 mg, 32.5% yield). MS (apci) m / z = 497.2 (M + H).

Example 38.

^) - 6-ethoxy-4- (6- (4- (2-hydroxy-3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a solution of 6-ethoxy-4- (6- (piperαzin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile dihydrochloride (example 30; 10.8 mg, 0.0827 mmol) in DCM (1.72 ml) was added ^) - 2-hydroxy-3methylbutanoic acid (12.2 mg, 0.103 mmol), HATU (39.3 mg, 0.103 mmol) and DIEA (60.0 μl, 0.344 mmol) were stirred for 16 hours at ambient temperature and then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the purified title compound as a TFA salt. The salt was neutralized with saturated NaRCO ^^ and extracted with EtOAc (3 ml). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (13.6 mg, 35% yield). MS (apci) m / z = 448.9 (M + H).

Compounds in the table. B was prepared and purified, and the salts were converted to the free base (except as marked with *) using a method similar to that described for the synthesis of Example 38, substituting (^) - 2-hydroxy-3-methylbutanoic acid with the corresponding carboxylic acid. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly.

- 204 035568

TableB

Example 41.

Chemical name (K) -6-ethoxy-4- (6- (4- (2hydroxy-2phenylacetyl) piperazin-1 yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3-carbonitrile (8) -6-ethoxy -4- (6- (4- (2hydroxy-2phenylacetyl) piperazin-1 yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3-carbonitrile

MS (apci) Π1Ζ

* The free base was obtained by dissolving the TPA salt in MeOH and filtering through an Agilent PL-HCO3 PM SPE filter.

4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyrazin-4-yl) pyridin-2-yl) -N-isobutylpiperazine-1carboxylic acid.

In a solution of 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile dihydrochloride (example 30; 10.8 mg, 0.0827 mmol) in anhydrous DMA (1 ml) DIEA (45.1 μl, 0.258 mmol) was added and left stirring for 0.5 h at ambient temperature. To the mixture was added dropwise 1-isocyanato-2-methylpropane (8.54 mg, 0.0861 mmol) and left stirring for 1 h at room temperature and then quenched with water. The resulting white precipitate was collected by filtration, then purified by silica gel chromatography (0-100% acetone in DCM as gradient eluent) to give the purified title compound (14.8 mg, 38% yield). MS (apci) m / z = 447.9 (M + H).

Example 42.

6-ethoxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

To a solution of 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 30; 30 mg, 0.086 mmol) in DCE ( 861 μl) 6-methoxy-nicotinaldehyde (24 mg, 0.17 mmol) and NaBH (AcO) 3 (55 mg, 0.26 mmol) were added sequentially. The resulting mixture was stirred for 2 hours at ambient temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-100% acetone in DCM as gradient eluent) to afford the purified title compound (23 mg, 57% yield). MS (apci) m / z = 469.8 (M + H).

Compounds in the table. C were prepared using a method similar to that described for the synthesis of Example 42, substituting the corresponding aldehyde for 6-methoxy-nicotinaldehyde. The completion of the reactions was monitored by LCMS and the reaction time was adjusted accordingly. Each compound was isolated purified after chromatographic purification using an appropriate gradient eluent. Several chromatographic conditions resulted in the isolation of the TFA salt of the title compound. In the case marked with (*), additional neutralization using an Agilent PL-HCO3 MP SPE filter was required to isolate the free salt of the title compound.

- 205 035568

Table C

No. Example Structure Chemical name MS (apci) m / z 43 N = \ if I TPA ox? 2,2,2-trifluoroacetate 6- ethoxy-4- (6- (4 - ((tetrahydro2H-pyran-4yl) methyl) piperazin-1 yl) pyridine-3- yl) pyrazolo [1,5-a] pyridine 3-carbonitrile 447.2 (M + H) 44 Ν = \ if I XX 6-ethoxy-4- (6- (4- (pyridin2-ylmethyl) piperazine-1 - yl) pyridine-3- yl) pyrazolo [1,5-a] pyridine 3-carbonitrile 440.2 (M + H) 45 N = \ 6-ethoxy-4- (6- (4 (pyrimidin-2-ylmethyl) piperazin-1 yl) pyridine-3- yl) pyrazolo [1,5-a] pyridine 3-carbonitrile 441.2 (M + H)

Example 46.

6-ethoxy-4- (6- (6 - (^) - 2-methoxy-2-phenylacetyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile, 2,2,2-trifluoroacetate.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (intermediate P7; 17 , 2 mg, 0.0477 mmol) in DCM (954 μl) was added (^) - 2-methoxy-2-phenylacetic acid (9.52 mg, 0.0573 mmol), HATU (21.8 mg, 0.0573 mmol ) and DIEA (33.3 μl, 0.191 mmol). After stirring overnight at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (0-20% MeOH in DCM as eluent gradient) followed by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as eluent gradient) to afford the the title compound as a TFA salt. The salt was lyophilized overnight to give the title compound (16.1 mg, 66% yield). MS (apci) m / z = 509.2 (M + H).

Example 47.

2,2,2-trifluoroacetate 6-ethoxy-4- (6- (6 - (^) - 2- (4-fluorophenyl) -2-hydroxyacetyl) -3,6-diazabicyclo [3.1.1] heptane-3- yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (intermediate P7; 17 , 2 mg, 0.0477 mmol) in DCM (954 μl) was added (^) - 2- (4-fluorophenyl) -2-hydroxyacetic acid (9.74 mg, 0.0573 mmol), HATU (21.8 mg, 0.0573 mmol) and DIEA (33.3 μl, 0.191 mmol).

The reaction mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM as eluent gradient) followed by C18 reverse phase chromatography (595% ACN in water with 0.1% TFA as eluent gradient) to afford the title compound in the form of a TPA salt. The salt was lyophilized overnight to give the title compound (8.8 mg, 36% yield). MS (apci) m / z = 513.2 (M + H).

- 206 035568

Example 48.

6-ethoxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (intermediate P7; 34 mg, 0.094 mmol) in DCE (472 μl) was added successively 6-methoxynicotinaldehyde (26 mg, 0.19 mmol) and NaBH (AcO) ₃ (60 mg, 0.28 mmol). After stirring overnight at ambient temperature, the mixture was purified directly by silica gel chromatography (0-10% MeOH in DCM as gradient eluent) to afford the purified title compound (10 mg, 22% yield). MS (apci) m / z = 482.2 (M + H).

Compounds in the table. D was prepared using a method similar to that described for the synthesis of Example 48, replacing 6-methoxy-nicotinaldehyde with the appropriate aldehyde. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Each compound was isolated purified after chromatographic purification using an appropriate gradient eluent. Several chromatographic conditions resulted in the isolation of the TFA salt of the title compound. In the case marked with (*), additional neutralization using an Agilent PL-HCO3 MP SPE filter was required to isolate the free salt of the title compound.

Table D

No. Example Structure Chemical name MS (apci) m / z 49 N = \ ci 4- (6- (6 - ((5-chloropyridin-3yl) methyl) -3.6- diazabicyclo [3.1.1] heptane3-and l) pyridin -3-yl) -6- ethoxypyrazole o [1,5а] pyridine-3-carbonitrile 486.2 (M + H) 50 N = \ I fdb 6-ethoxy-4- (6- (6 - ((5fluoropyridin-3-yl) methyl) 3,6- diazabicyclo [3.1.1] heptan3-yl) pyridine-3- yl) pyrazolo [1,5- a] pyridine-3-carbonitrile 470.2 (M + H) 51 N = \ X Ί + .X ¹ . 6-ethoxy-4- (6- (6- (pyridin3-ylmethyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridine-3- yl) pyrazole o [1,5а] pyridine-3-carbonitrile 452.2 (M + H) 52 Jb 0 i b 6-ethoxy-4- (6- (6 - ((6methylpyridin-3 yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazole o [1,5а] pyridine-3-carbonitrile 466.2 (M + H) 53 about th 0 G / - - Z. ~ z .- ^ 6-ethoxy-4- (6- (6 - ((5methylpyridin-3 yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazole o [1,5а] pyridine-3-carbonitrile 466.2 (M + H) 54 N = \ X Ί 6-ethoxy-4- (6- (6 - ((2methylpyridin-4yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3-carbonitrile 466.2 (M + H)

- 207 035568

55 Qj o G 4- (6- (6 - ((6-chloropyridin-3 yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3-yl) -6ethoxypyrazole o [1,5а] pyridine-3-carbonitrile 486.2 (M + H) 56 Ch d Г dui ¹ . 6-ethoxy-4- (6- (6 - ((5methoxypyridin -3 yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazole o [1,5а] pyridine-3-carbonitrile 482.2 (M + H) 57 Qi o G 6-ethoxy-4- (6- (6- (pyridin2-ylmethyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazole o [1,5- a] pyridine-3-carbonitrile 452.2 (M + H) 58 Q G ddk 4- (6- (6 - ((2,6dimethylpyridin-4yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3-yl) -6- ethoxypyrazole o [1,5а] pyridine-3-carbonitrile 480.2 (M + H) 59 0 / dd / 6-ethoxy-4- (6- (6 - ((5fluoropyridin-2-yl) methyl) - 3.6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazolo [1,5- a] pyridine-3-carbonitrile 470.2 (M + H) 60 Q G 6-ethoxy-4- (6- (6- ((4methoxypyridine -2yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridine-3- yl) pyrazolo [1,5а] pyridine-3-carbonitrile 482.2 (M + H) 61 62 N = \ (I ABOUT N = \ / NA ^ n (I Cd ' ^N C> I djd 6-ethoxy-4- (6- (6 - ((6methylpyridin-2yl) methyl) -3,6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazole o [1,5а] pyridine-3-carbonitrile 6-ethoxy-4- (6- (6 - ((6methoxypyridine-2- yl) methyl) -3.6- diazabicyclo [3.1.1] heptan3-yl) pyridin-3yl) pyrazole o [1,5- a] pyridine-3-carbonitrile 466.2 (M + H) 482.2 (M + H)

Example 63.

4- (6- (6 - ((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) 6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (intermediate P7; 30 mg, 0.0692 mmol) in DCM (692 μl) was added DIEA (30.1 μl, 0.173 mmol). After stirring for 5 min at room temperature, 5-chloro-6-methoxy-nicotinaldehyde (13.1 mg, 0.0762 mmol) and NaBH (AcO) ₃ (29.3 mg, 0.138 mmol) were sequentially added to the reaction mixture. The mixture was stirred overnight at ambient temperature. The resulting suspension was diluted with DCM, and then MeOH was added dropwise until a homogeneous solution was formed. After evaporation of the cooled mixture under reduced pressure

- 208,035,568 residue was purified by silica gel chromatography (first a mixture of hexane isomers followed by 0-10% MeOH in DCM with 2% NH4OH as gradient eluent) to afford the purified title compound (19.8 mg, 55% yield MS (apci) m / z = 516.2 (M + H).

Example 64.

2,2,2-trifluoroacetate 6-ethoxy-4- (6 - ((^^) - 5 - ((6-methoxypyridin-3-yl) methyl) -2,5-diazabicyclo [2.2.1] heptane-2 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A mixture of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 20 mg, 0.071 mmol), dihydrochloride (^^) - 2 - (( 6-methoxypyridin-3-yl) methyl) -2.5 diazabicyclo [2.2.1] heptane (intermediate R5; 62 mg, 0.21 mmol) and ^ CO ^ (49 mg, 0.35 mmol) in DMSO (709 μl ) was stirred for 3 days at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with MeOH, filtered and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as eluent gradient) to afford the title compound as a TFA salt ( 32 mg, yield 76%). MS (apci) m / z = 482.2 (M + H).

Example 65.

6-ethoxy-4- (6- (3 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3yl) pyrαzolo [1,5 -a] pyridine-3-carbonitrile.

A mixture of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 20 mg, 0.071 mmol), dihydrochloride 3 - ((6-methoxypyridine-3 -yl) methyl) -3,6-diazabicyclo [3.1.1] heptane (intermediate R6; 23 mg, 0.078 mmol) and ^ CO ^) (49 mg, 0.35 mmol) in DMSO (709 μL) were stirred for 3 h at 110 ° C Additional 3 - ((6-methoxypyridin-3-yl) methyl) -3.6 diazabicyclo [3.1.1] heptane dihydrochloride (37 mg, 0.127 mmol) was added and the reaction mixture was allowed to stir overnight at 110 ° C. After cooling to ambient temperature, the reaction mixture was filtered and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TFA salt was dissolved in MeOH and filtered through an Agilent PL-HCO ₃ MP SPE column for neutralization, and the filtrate was evaporated under reduced pressure to give the title compound (10 mg, 29% yield). MS (apci) m / z = 482.2 (M + H).

Example 66.

2,2,2-trifluoroacetate 6-ethoxy-4- (6- (3 - ((6-methoxypyridin-3-yl) methyl) -3,8-diazabicyclo [3.2.1] octan-8-yl) pyridine- 3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

A mixture of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 20 mg, 0.071 mmol), 3 - ((6-methoxypyridin-3- yl) methyl) -3,8-diazabicyclo [3.2.1] octane hydrochloride (intermediate R7; 57 mg, 0.21 mmol) and ^ CO ^ (49 mg, 0.35 mmol) in DMSO (709 μL) were stirred at 80 ° C and the completion of the reaction was monitored by LCMS. The reaction mixture was cooled to ambient temperature, then filtered and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as eluent gradient) to give the title compound (1.0 mg, 3 % output). MS (apci) m / z = 496.3 (M + H).

Example 67.

- 209 035568 tert-butyl (3aR, 7aS) -6- (5- (3-cyαno-6-ethoxypyrαzolo [1,5-a] pyridin-4-yl) pyridin-2-yl) octαhydro1Н-pyrrolo [2, 3-c] pyridine-1-carboxylate.

To a suspension of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 60 mg, 0.213 mmol) in DMSO (500 μL) was added (3aR, 7aS) -octahydro-1H-pyrrolo [2,3 ^ pyridine-1-carboxylate (96.2 mg, 0.425 mmol) and K ₂ CO ₃ ( _TB ) (120 mg, 0.85 mmol) and stirred in for 10 hours at 90 ° C. The resulting mixture was cooled to ambient temperature and quenched with 1: 1 NH ₄ OH / water. The quenched mixture was extracted with DCM. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (20-90% ACN / water as gradient eluent) to afford the title compound (77.1 mg, 74% yield). MS (apci) m / z = 489.2 (M + H).

Example 68.

N = \ ^TPK

Η

6-ethoxy-4- (6 - ((3aS, 7aS) -octahydro-6Н-pyrrolo [2,3-c] pyridin-6-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine 3-carbonitrile (TPA salt).

In a solution of tert-butyl (3aR, 7aS) -6- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl-N-ctahydro-III-pyrroloP3- N-pyridine- B carboxylate (example 67; 77.1 mg, 0.158 mmol) in DCM (500 μl) was added TFA (120.8 l, 1.58 mmol) and stirred for 5 h at ambient temperature.The reaction mixture was diluted with MeOH (1 ml) and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.01% TFA as gradient eluent) to give the title compound (51.4 mg, 84% yield) MS (apci) m / z = 389.2 (M + H).

Example 69.

N = \

About ητ | N

6- (2,2-difluoroethoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

To a solution of 6- (2,2-difluoroethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile dihydrochloride (intermediate P8; 23.8) mg (0.0619 mmol) in DCE (619 μl) was added sequentially picolinaldehyde (11.7 μl, 0.124 mmol) and NaBH (AcO) ₃ (39.4 mg, 0.186 mmol). The resulting mixture was stirred for 1 hour at ambient temperature and then evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-100% acetone in DCM as eluent gradient) to afford the purified title compound (15.0 mg, 51% yield). MS (apci) m / z = 476.2 (M + H).

Example 70.

N = \

4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) -6- (2,2,2-trifluoroethoxy) pyrazolo [1,5a] pyridine-3-carbonitrile ...

To a solution of 4- (6- (piperazin-1-yl) pyridin-3-yl) -6- (2,2,2-trifluoroethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (intermediate P9) ; 24 mg, 0.060 mmol) in DCE (619 μl) picolinaldehyde (11.4 μl, 0.119 mmol) and NaBH (AcO) ₃ (37.494 mg, 0.1789 mmol) were added sequentially. After stirring for 1 hour at ambient temperature, the reaction mixture was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-100% acetone in DCM as eluent gradient) to afford the purified title compound (14.6 mg, 50% yield). MS (apci) m / z = 494.2 (M + H).

- 210 035568

Example 71.

6-propoxy-4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3carbonitrile.

To a solution of 4- (6- (piperazin-1-yl) pyridin-3-yl) -6-propoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P10; 26 mg, 0.072 mmol) in DCE (717 μl) picolinaldehyde (6.9 μl, 0.072 mmol) and NaBH (AcO) ₃ (45.6 mg, 0.215 mmol) were added sequentially. After stirring overnight at ambient temperature, the reaction mixture was purified directly by silica gel chromatography (0-5% MeOH in DCM as gradient eluent) to afford the purified title compound (23.5 mg, 72% yield). MS (apci) m / z = 454.2 (M + H).

Compounds in the table. E was prepared using a method similar to that described for the synthesis of example 71, replacing picolinaldehyde with the appropriate aldehyde and / or treating intermediate P10 with the appropriate intermediate from table. AA. The completion of the reactions was monitored by LCMS and the reaction time was adjusted accordingly. Each compound was isolated purified after chromatographic purification using an appropriate gradient eluent. Several chromatographic conditions resulted in the isolation of the TFA salt of the title compound. In the case where marked (*), additional neutralization of the TPA salt was carried out by dissolving the salt in DCM, and then sequentially extracting the solution with saturated NaHCO ^^) and saturated aqueous sodium chloride solution, drying the combined organic extracts over anhydrous NaSO ^), filtering and evaporating under reduced pressure to isolate the free base of the title compound.

Table E

No. Example Structure Chemical name MC (apci) ηι / ζ 72 N = \ Jf t 4- (6- (4 - ((6methoxypyridine -3- yl) methyl) piper zine-1 - yl) pyri din-3 yl) -6propoxypyrazo 484.2 (M + H)

- 211 035568

lo [1,5а] pyridine-3carbonitrile 73 N = \ 6-propoxy-4- (6 (4- (pyrimidine2- ilmethyl) piperaz in-1- yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 455.2 (M + H) 74 N = \ ί I OjQ 6-isobutoxy-4 (6- (4- (pyridine2- ilmethyl) piperaz in-1- yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 468.2 (M + H) 75 N = \ Ji T \ ^ O ^zXz J ^ N O.J3 6-isobutoxy-4 (6- (4- (pyrimidine-2- il- methyl) piperazin -1-yl) pyridine3- yl) pyrazolo [1,5а] pyridine-3carbonitrile 469.2 (M + H) 76 N = \ Jf I ^u oxr 6-isobutoxy-4 (6- (4 - ((6- methoxypyridine -3- yl) methyl) piperazine-1yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 498.2 (M + H)

- 212 035568

77 N = \ 1 11 ^u oxr 4- (6- (4 - ((6methoxypyridine -3yl) methyl) piperazine-1yl) pyridin-3yl) -6- (neopentyloxy) pyrazolo [1,5а] pyridine-3carbonitrile 512.3 (M + H) 78 N = \ XT ⁷ wo 6- (2methylbutoxy) 4- (6- (4 (pyrimidine-2- il- methyl) piperazin -1-yl) pyridine3- yl) pyrazolo [1.5 a] pyridine-3carbonitrile 483.3 (M + H) 79 N = \ XT ⁷ wo 6- (2methylbutoxy) 4- (6- (4 (pyridin-2ylmethyl) piperaz in-1yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 482.3 (M + H) 80 N = \ X Ί ^{J u} oxr 4- (6- (4 - ((6methoxypyridine-3yl) methyl) piperazine-1yl) pyridin-3yl) -6- (2methylbutoxy) p irazolo [1,5а] pyridine-3carbonitrile 512.3 (M + H)

- 213 035568

81 N = \ ⁴ ^ OH! 6- (2ethylbutoxy) -4 (6- (4- (pyridine2- ilmethyl) piperaz in-1- yl) pyridine-3; and l) pyrazole o [1,5а] pyridine-3carbonitrile 496.3 (M + H) 82 / about F / 0 about b 6- (2ethylbutoxy) -4 (6- (4 - ((6methoxypyridine -3- yl) methyl) piperazine-1yl) pyridine-3; and l) pyrazole o [1,5а] pyridine 3- carbonitrile 526.3 (M + H) 83 N = \ ί Ύ 6- (the cycle trains oxy) -4- (6- (4 (pyridin-2ylmethyl) piperaz in-1yl) pyridin-3 and l) pyrazole o [1,5а] pyridine-3carbonitrile 480.2 (M + H) 84 Ν = \ ί I ^ ΟΧΓ 6- (the cycle is loaded with oxy) -4- (6- (4 - ((6methoxypyridin-3yl) methyl) piperazine-1yl) pyridin-3i l) pyrazole o [1,5а] pyridine-3carbonitrile 510.2 (M + H) 85 Ν = \ ί Τ cw 6- (cycle shoots oxy) -4- (6- (4 (pyrimidine-2- il- methyl) piperazine -1-yl) pyridine- 3- and l) pyrazole o [1.5a] pyridine-3carbonitrile 481.2 (M + H).

Example 86.

6 - ((3-methyloxetan-3-yl) methoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine- 3-carbonitrile.

In a suspension of 6-hydroxy-4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P16); 17.3 mg, 0.0420 mmol) in DMF (500 μl) was added sequentially to ₂ CO ₃ ( _TB ) (11.6 mg, 0.0841 mmol) and 3- (bromomethyl) -3-methyloxetane (12 μl, 0.0841 mmol). The resulting mixture was stirred for 16 h at 50 ° C. The mixture was cooled to ambient temperature, then diluted with ACN (0.3 ml), filtered and washed with ACN. Filtrate directly

- 214 035568 was purified by C18 reverse phase chromatography (5-95% ACN / water as gradient eluent) to afford the title compound (2.1 mg, 10% yield). MS (apci) m / z = 496.2 (M + H).

Example 87.

4- (6- (4- (3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5a] pyridine-3-carbonitrile.

To a solution of 6- (2-morpholinoethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P17; 21.7 mg, 0, 0501) mmol) in DCM (1.1 ml) was added sequentially DIEA (34.9 μl, 0.200 mmol) and isovaleryl chloride (7.32 μl, 0.0601 mmol). The resulting mixture was stirred for 16 hours at ambient temperature. The mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (20: 1 DCM / MeOH as eluent) to give the title compound (18 mg, 70% yield). MS (apci) m / z = 518.2 (M + H).

Example 88.

[^) - 4- (6- (4- (2-hydroxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1,5-a] pyridin-3 -carbonitrile.

To a solution of 6- (2-morpholinoethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P17; 22 mg, 0.051) mmol) D - (-) - mandelic acid (11.6 mg, 0.0761 mmol), HATU (33 mg, 0.086 mmol) and DIEA (88.4 μl, 0.507 mmol) were added in DMF (4 ml). After stirring for 16 h at ambient temperature, the mixture was diluted with EtOAc and extracted with water. The combined organic extracts were dried over anhydrous Na ^ O ^, filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The salt was partitioned between a 4: 1 _DCM:!. I-PrOH and saturated Nal 1SO _{3 (1 od1M} resultant organic extracts were combined, dried over anhydrous № ^ O _{4 (solid),} filtered and upa Riva under reduced pressure as a gradient eluent to obtaining the title compound (25 mg, 87% yield) MS (apci) m / z = 568.2 (M + H).

Example 89.

^) - 4- (6- (4- (2-hydroxy-3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile.

The title compound (21 mg, 83% yield) was prepared and purified using a procedure similar to Example 88, replacing D - (-) - mandelic acid with ^) - 2-hydroxy-3methylbutanoic acid (1.2 eq. ), and an increase in the amount of HATU (1.2 equiv.) and DIEA (10 equiv.). MS (apci) m / z = 534.2 (M + H).

Example 90.

6- (2-morpholinoethoxy) -4- (6- (4- (pyrimidin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

- 215 035568

In a solution of 6- (2-morpholinoethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3 carbonitrile (intermediate P17; 16 mg, 0.037) mmol ) in DMF (2 ml) pyrimidine-2-carbaldehyde (14.0 mg, 0.129 mmol), NaBH (AcO) ₃ (15.6 mg, 0.0738 mmol) and acetic acid (22.2 mg, 0.369 mmol). The resulting mixture was stirred for 3 days at ambient temperature. The reaction mixture was extracted with EtOAc and water. The combined organic extracts were then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure.The residue was purified by chromatography on C18 reverse phase (5-95% ACN / water with 0.1% TFA as eluent gradient) followed by chromatography on silica gel (using a stepwise gradient of 20: 1 DCM / MeOH followed by 10: 1 DCM / MeOH as eluent) to give the title compound (9 mg, 46% yield). MS (apci) m / z = 526.2 (M + H).

Example 91.

4- (6- (4- (3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2- (4-methylpiperazin-1yl) ethoxy) pyrazolo [1,5-a] pyridine- 3-carbonitrile.

In a solution of 6- (2- (4-methylpiperazin-1-yl) ethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P18; 24.5 mg, 0.0549 mmol) in DCM (1.1 ml), DIEA (38.2 μl, 0.219 mmol) and isovaleryl chloride (8.03 μl, 0.0658 mmol) were added sequentially. The resulting mixture was stirred for 16 hours at ambient temperature. The residue was evaporated under reduced pressure, then purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ^ (.). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (18.9 mg, 65% yield). MS (apci) m / z = 531.2 (M + H).

Example 92.

U) -4- (6- (4- (2-hydroxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6- (2- (4-methylpiperazin-1 yl) ethoxy) pyrazole [ 1,5-a] pyridine-3-carbonitrile.

In a solution of 6- (2- (4-methylpiperazin-1-yl) ethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P18; 20.2 mg, 0.0452 mmol) in DCM (1 ml) added D - (-) mandelic acid (8.26 mg, 0.0543 mmol), HATU (20.6 mg, 0.0543 mmol) and DIEA (23.6 μl, 0.136 mmol) and stirred for 16 h at ambient temperature. The mixture was evaporated under reduced pressure and then purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ^ (.). The combined organic extracts were dried over anhydrous Na ^ O ^, filtered and evaporated under reduced pressure to give the title compound (19.1 mg, 73% yield). MS (apci) m / z = 581.2 (M + H).

Example 93.

U) -4- (6- (4- (2-hydroxy-3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2- (4-methylpiperazin-1 yl) ethoxy) pyrazole [ 1,5-a] pyridine-3-carbonitrile.

The title compound (17.9 mg, 74% yield) was prepared using a method similar to

- 216 035568 described in example 92, replacing D - (-) - mandelic acid with ^) - 2-hydroxy-3-methylbutanoic acid. C (apci) m / z = 547.2 (M + H).

Example 94.

6- (oxazol-2-ylmethoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a solution of 6- (oxazol-2-ulmethoxy) -4- (6- (piperazin-1-ul) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P19; 15 mg) 0.037 mmol ) in DCE (74.7 μl) picolinaldehyde (4.29 μl, 0.0448 mmol) and NaBH (AcO) ₃ (23.8 mg, 0.112 mmol) were added sequentially. The mixture was stirred overnight at ambient temperature, then purified directly by silica gel chromatography (0-5% MeOH in DCM as gradient eluent) to afford the title compound (10 mg, 54% yield). MS (apci) m / z = 492.8 (M + H).

Example 95.

4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6 - ((3-methyl-1,2,4oxadiazol-5-yl ) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 6 - ((3-methyl-1,2,4-oxadiazol-5-yl) methoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine Β-3-carbonitrile (intermediate P20; 20 mg, 0.048 mmol) in DCE (961 μl) was added sequentially 6-methoxynicotinaldehyde (7.9 mg, 0.058 mmol) and NaBH (AcO) ₃ (30.5 mg, 0.144 mmol). The resulting mixture was stirred overnight at ambient temperature, then purified directly by silica gel chromatography (0-5% MeOH in DCM as gradient eluent) to afford the title compound (16.8 mg, 65% yield). MS (apci) m / z = 537.8 (M + H).

Example 96.

4- (6- (4- (3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) -6- (pyridin-3-ylmethoxy) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a solution of 4- (6- (piperazin-1-yl) pyridin-3-yl) -6- (pyridin-3-ylmethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P21; 43 mg) 0.105 mmol ) and 3-methylbutanoyl chloride (15.4 μl, 0.125 mmol) in DCM (1.05 ml) was added TEA (14.6 μl, 0.105 mmol). The resulting mixture was stirred for 2 hours at ambient temperature. The resulting mixture was purified directly by silica gel chromatography (1-5% MeOH in DCM as eluent gradient) and again by C18 reverse phase chromatography (60:40 ACN: water with 2% TFA as eluent gradient) to give the title compounds in the form of a TPA salt. The TPA salt was partitioned between DCM and saturated NaHCOy (^^). The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO4 ( _mw ), filtered and evaporated under reduced pressure to give the title compound (5 mg, 10% yield). MS (apci) m / z = 496.2 (M + H).

Example 97.

4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (pyridin-3ylmethoxy) pyrazolo [1 ^^ pyridine-3-carbonitrile ...

- 217 035568

To a solution of 4- (6- (piperazin-1-yl) pyridin-3-yl) -6- (pyridin-3-ylmethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P21; 43 mg, 0.105 mmol ) in DCE (1.05 ml), 6methoxynicotinaldehyde (17.2 mg, 0.125 mmol) and NaBH (AcO) ₃ (66.5 mg, 0.314 mmol) were added sequentially. The resulting mixture was stirred for 1 hour at ambient temperature. The resulting mixture was purified directly by chromatography on silica gel (1-5% MeOH in DCM as eluent gradient) followed by C18 reverse phase chromatography (60:40 ACN: water with 2% TFA as eluent gradient) to afford the specified the title compound as a TFA salt. The TPA salt was partitioned between DCM and saturated NaHCO (^^.). The resulting organic extracts were washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the title compound (10.4 mg, 19% yield). MS (apci) m / z = 533.2 (M + H).

Example 98.

6- (2- (1H-imidazol-1-yl) ethoxy) -4- (6- (4- (3-methylbutanoyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine- 3-carbonitrile.

In a solution of 6- (2- (1H-imidazol-1-yl) ethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P22; 20 mg, 0.048 mmol) and 3-methylbutanoyl chloride (5.9 μl, 0.048 mmol) in DCM (483 μl), TEA (6.7 μl, 0.048 mmol) was added. The resulting mixture was stirred for 1.5 hours at ambient temperature. The mixture was evaporated under reduced pressure and the residue was purified by C18 reverse phase chromatography (60:40 ACN: water with 2% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was partitioned between DCM and saturated NaHCO ^ (), and the biphasic mixture was extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na2SC) | ₍ ,, .. “filtered and evaporated under reduced pressure to give the purified title compound (10.4 mg, 43% yield). MS (apci) m / z = 499.3 (M + H).

Example 99.

^) - 6- (2-hydroxyethoxy) -4- (6- (4- (2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3- carbonitrile 2,2,2-trifluoroacetate.

6- (2-hydroxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride solution (intermediate P23; 20 mg, 0.050 mmol), ^) - 2-methoxy-2-phenylacetic acid (9.12 mg, 0.0549 mmol), hAtU (20.9 mg, 0.0549 mmol) and DIEA (34.9 μL, 0.200 mmol) in DCM (249 μl) was stirred for 1 h at ambient temperature. The mixture was evaporated under reduced pressure and then purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt (18 mg, 58 %). MS (apci) m / z = 513.2 (M + H).

1H NMR (400 MHz, DMSO-a6) δ: 8.38 (d, 1H, J = 2.0 Hz), 8.26 (s, 1H), 8.22 (d, 1H, J = 2.3 Hz), 7.68 (dd, 1H, J = 8.6, 2.3 Hz), 7.44-7.32. (m, 5H), 7.20 (d, 1H, J = 2.3 Hz), 6.82 (d, 1H, J = 9.0 Hz), 5.20 (s, 1H), 4.12 (t, 2H, J = 4.3 Hz), 3.89 (t, 2H, J = 4.3 Hz), 3.75-3.46 (m, 7H), 3.41 (s, 5H) , 3.21-3.16 (m, 1H).

Compounds in the table. F was prepared using a method similar to that described for the synthesis of Example 99, substituting () - 2-methoxy-2-phenylacetic acid for the corresponding carboxylic acid. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Each compound was isolated purified after chromatographic purification using an appropriate gradient eluent. Most chromatographic conditions resulted in the isolation of the 2,2,2-trifluoroacetate salt of the title compound.

- 218 035568

TableF

No. Example Structure Chemical name MS (apci) m / z one hundred N = \ TFK HE about 2,2,2-trifluoroacetate (R) -4- (6- (4- (2hydroxy-2- phenylacetyl) piperazi n-1-yl) pyri din-3-yl) 6- (2- hydroxyethoxy) pyrazolo [1,5-а] pyridine-3 carbonitrile 498.8 (M + H) 101 N = \ TFK HE Ο 2,2,2-trifluoroacetate (S) -4- (6- (4- (2hydroxy-2phenylacetyl) piperazi n-1-yl) pyri din-3-yl) 6- (2- hydroxyethoxy) pyrazolo [1,5-а] pyridine-3 carbonitrile 498.8 (M + H) 102 I about about Q / o. tf 2,2,2-trifluoroacetate (S) -6- (2hydroxyethoxy) -4- (6 (4- (2-methoxy-2phenylacetyl) piperazi n-1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 512.8 (M + H) 103 N = \ TPK nA Q ^h f- ^zN v \ ^/ O 1 2,2,2-trifluoroacetate (R) -4- (6- (4- (2hydroxy-3- methylbutanoyl) piper zin-1-yl) pyridin-3 yl) -6- (2- hydroxyethoxy) pyrazolo [1,5-а] pyridine-3 carbonitrile 464.8 (M + H) 104 I О о th 0 / о, o = t> - о __ / I 2,2,2-trifluoroacetate (S) -4- (6- (4- (2hydroxy-3methylbutanoyl) piperazin-1-yl) pyridin-3 yl) -6- (2hydroxyethoxy) pyrazollo [1,5-a ] pyridine-3 carbonitrile 464.9 (M + H)

Example 105.

2,2,2-trifluoroacetate 4- (5- (3-cyano-6- (2-hydroxyethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -Н-isobutylpiperazine-1-carboxamide ...

Into cold (0 ° C) solution of 6- (2-hydroxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P23; 11 mg, 0.027 mmol) and DIEA (24.0 μl, 0.137 mmol) in DMA (549 μl) was added 4-nitrophenyl chloroformate (5.81 mg, 0.0288 mmol). After stirring the mixture for 1 h at 0 ° C, isobutylamine (10.0 mg, 0.137 mmol) was added. The mixture was stirred for 1 day at 80 ° C before additional isobutylamine (10 mg, 0.137 mmol) was added. The mixture was stirred for an additional 4 h at 80 ° C, cooled to ambient temperature, diluted with MeOH and directly purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as eluent gradient) to give of the title compound as a TFA salt (10 mg, 63% yield). MS (apci) m / z = 463.9 (M + H).

- 219 035568

Example 106.

2,2,2-trifluoroacetate 4- (6- (4 - ((5-chloropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (2 hydroxyethoxy) pyrazolo [1, 5-a] pyridine 3-carbonitrile.

A solution of 6- (2-hydroxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride (intermediate P23; 11.6 mg, 0, 0289 mmol), 5-chloropicolinaldehyde (8.19 mg, 0.0579 mmol) and NaBH (AcO) ₃ (18.4 mg, 0.0868 mmol) in DCE (579 μl) were stirred for 1 day at ambient temperature ... The resulting reaction mixture was diluted with MeOH, filtered through a very fine filter and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as 2, 2,2-trifluoroacetate (16.9 mg, 97% yield). MS (apci) m / z = 490.1 (M + H).

Compounds in the table. G was prepared using a method similar to that described for the synthesis of Example 106, substituting the appropriate aldehyde for 5-chloropicolinaldehyde. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Each compound was isolated purified after chromatographic purification using an appropriate gradient eluent. Most chromatographic conditions resulted in the isolation of the 2,2,2 trifluoroacetate salt of the title compound.

Table G

No. Example Structure Chemical name MS (apci) m / z 107 N = \ Ο N TPK ΑΐζΓ 2,2,2 trifluoroacetate 6- (2- hydroxyethoxy) -4- (6- (4 - ((5- methoxypyridine-2yl) methyl) piperazi 486.2 (M + H) n-1-yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 108 Ν = \ TFK OXr ' 2,2,2 trifluoroacetate 4 (6- (4 - ((5- fluoropyridin-2yl) methyl) piperazi i-1-yl) pyridin-3yl) -6- (2hydroxyethoxy) pyrazolo [1,5а] pyridine-3carbonitrile 474.2 (M + H)

Example 109.

2,2,2-trifluoroacetate 6- (2-hydroxyethoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1yl) pyridin-3-yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

Stage 1: preparation of 6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -4- (6- (4 - ((6-methoxypyridin-3yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. A mixture of 2,2,2 trifluoroacetate 6-hydroxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine- 3-carbonitrile (intermediate P24; 9.5 mg, 0.017 mmol), (2-bromoethoxy) (tert-butyl) dimethylsilane (5.1 mg, 0.022 mmol) and ^ CO ^) (8.9 mg, 0.065 mmol) in DMF (108 μl) was stirred for 1 day at 50 ° C. After cooling to ambient temperature, the reaction mixture was directly purified by silica gel chromatography (0-100% EtOAc / hexane isomer mixture as eluent gradient) to afford the title compound (12 mg, 93% yield). MC

- 220 035568 (apci) m / z = 600.8 (M + H).

Stage 2: preparation of 2,2,2-trifluoroacetate 6- (2-hydroxyethoxy) -4- (6- (4 - ((6-methoxypyridin-3yl) methyl) piperαzin-1-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile. To a solution of 6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrαzolo [1, 5-a] pyridine-3-carbonitrile (12 mg, 0.020 mmol) in THF (2 ml) was added TBAF (100 μl, 0.10 mmol), stirred for 3 days at ambient temperature. The resulting suspension was filtered and the solids were washed with MeOH. The filtrate was evaporated and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to give the title compound as 2,2,2-trifluoroacetate (6.8 mg, yield 57%). MS (apci) m / z = 485.8 (M + H).

Example 110.

6- (2-hydroxyethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazole [1, 5-a] pyridine-3-carbonitrile.

In a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxyethoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile hydrochloride (intermediate P27; 17 mg, 0.045 mmol) in DCE (226 μl) was added successively 6-methoxynicotinaldehyde (12 mg, 0.090 mmol) and NaBH (AcO) ₃ (29 mg, 0.14 mmol). After stirring for 3 h at ambient temperature, the reaction mixture was evaporated under reduced pressure and purified by silica gel chromatography (0-20% MeOH in DCM as eluent gradient) to afford the purified title compound (2.7 mg, 12% yield ). MS (apci) m / z = 498.2 (M + H).

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.66 (d, 1H, J = 2.0 Hz), 8.56 (s, 1H), 8.37 (d, 1H, J = 2, 7 Hz), 8.04 (d, 1H, J = 2.0 Hz), 7.81 (dd, 1H, J = 9.0, 2.7 Hz), 7.65 (dd, 1H, J = 8.6, 2.3 Hz), 7.26 (d, 1H, J = 2.3 Hz), 6.76 (d, 1H, J = 9.0 Hz), 6.73 (d, 1H, J = 8.6 Hz), 4.93 (t, 1H, J = 5.5 Hz), 4.11 (t, 2H, J = 4.7 Hz), 3.79 (s, 3H), 3 , 73 (m, 3H), 3.69 (s br, 1H), 3.64 (d, 2H, J = 5.9 Hz), 3.51 (d br, 2H), 3.47 ( s, 2H), 2.47 (m, 1H), 1.55 (d, 1H, J = 8.6 Hz),

Compounds in the table. H was prepared using a method similar to that described for the synthesis of Example 110, substituting the corresponding aldehyde for 6-methoxy-nicotinaldehyde. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Each compound was isolated purified after chromatographic purification using an appropriate gradient eluent.

TableH

No. Example Structure Chemical name MS (apci) m / z 111 Ν ^ \ Ηο ^ _ο ΑΑρ _Ν 4- (6- (6 - ((5- chloropyridin-2yl) methyl) -3,6 diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) -6- (2- hydroxyethoxy) pyrazole [1,5-a] pyridine-3 carbonitrile 502.2 (M + H) 112 Ν = \ HO. JL ο [I Ν 6- (2hydroxyethoxy) -4 (6- (6- (pyridine-2ylmethyl) -3,6- diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) pyrazole o [1,5а] pyridine-3carbonitrile 468.2 (M + H)

Example 113.

- 221 035568

4- (6- (2,7-diazacnuro [3.5] nonan-7-yl) puridin-3-yl) -6- (2-hydroxyethoxy) nurazolo [1,5-a] pyridin-3carbonitrile.

A suspension of 6- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5a] nirigin-3-carbonitrile (intermediate P26; 150 mg, 0.364 mmol) and tert-butyl-2,7-diazaspiro [3,5] nonane-2-carboxylate (247 mg, 1.09 mmol) in DMSO (2.5 ml) in a microwave oven, microwave irradiated at 125 ° C for 1 h The reaction mixture was partitioned between water and DCM and extracted with DCM. The combined organic extracts were dried over anhydrous NaaSO (B), filtered and evaporated under reduced pressure. The residue was dissolved in DCM (2 ml) and 4N. HCl in dioxane (2 ml). After stirring overnight at ambient temperature, the mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-100% [20% MeOH with 2% NH4OH] in DCM as gradient eluent) to afford the purified title compound (115 mg, 78% yield). MS (apci) m / z = 405.2 (M + H).

Example 114.

7- (5- (3-cyano-6- (2-hydroxyethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -X-isopropyl-2,7diazaspiro [3.5] nonane- 2-carboxamide.

In a solution of 4- (6- (2,7-diazaspiro [3.5] nonan-7-yl) pyridin-3-yl) -6- (2-hydroxyethoxy) pyrazolo [1,5а] pyridine-3-carbonitrile (example 113 ; 20 mg, 0.049 mmol) in anhydrous DMSO (246 μl), DIEA (26 μl, 0.15 mmol) and 2-isocyanatopropane (4.2 mg, 0.049 mmol) were added sequentially and stirred overnight at ambient temperature. The reaction mixture was purified directly by chromatography on silica gel (0-20% MeOH in DCM as eluent gradient) followed by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as eluent gradient) to obtain a purified TFA salt of the title compound. The salt was dissolved in MeOH, filtered through an Agilent PL-HCO ₃ MP SPE column for neutralization, and the filtrate was evaporated under reduced pressure to give the purified title compound (9.1 mg, 38% yield). MS (apci) m / z = 490.2 (M + H).

Example 115.

isopropyl 7- (5- (3-cyano-6- (2-hydroxyethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -2.7 diazaspiro [3.5] nonane-2 carboxylate.

In a solution of 4- (6- (2,7-diazaspiro [3.5] nonan-7-yl) pyridin-3-yl) -6- (2-hydroxyethoxy) pyrazolo [1,5а] pyridine-3-carbonitrile (example 113 ; 20 mg, 0.049 mmol) in DCM (247 μl), DIEA (43.2 μl, 0.247 mmol) and isopropylcarbonochloridate (7.70 μl, 0.0544 mmol) were added sequentially and stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-15% MeOH in DCM as gradient eluent) to give the purified title compound (6.7 mg, 28% yield). MS (apci) m / z = 491.2 (M + H).

Example 116.

tert-butyl ^) - 4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate.

- 222 035568

In a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (intermediate P3; 200 mg, 0.476 mmol ) in DMF (5 ml) were sequentially added to K ₂ CO ₃ ( _TB ) (328.7 mg, 2.387 mmol) and H) -2-methyloxirane (166.6 μL, 2.387 mmol). After stirring for 22 h at 40 ° C, additional (R) -2methyloxirane (166.6 μL, 2.387 mmol) was added to the reaction mixture and the reaction temperature was raised to 50 ° C. An additional aliquot of H) -2-methyloxyrane (166.6 μl, 2.387 mmol) was added and the mixture was stirred for 3 days at 50 ° C. The resulting mixture was cooled to ambient temperature, then purified directly by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to afford the purified title compound (121.5 mg, 53% yield). MS (apci) m / z = 479.2 (M + H).

Example 117.

U) -4- (6- (4- (2- (5-fluoropyridin-2-yl) acetyl) piperazin-1-yl) pyridin-3-yl) -6- (2hydroxypropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile 2,2,2-trifluoroacetate.

In a solution of HCl) -6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P28; 7.2 mg, 0.017 mmol), 2- (5-fluoropyridine-2yl) acetic acid (4.04 mg, 0.0260 mmol) and DIEA (15.2 μl, 0.0868 mmol) in DCM (347 μl) was added HATU ( 7.26 mg (0.0191 mmol) then stirred at ambient temperature overnight medium. Education diacylated product (MS (apci) m / z = 652) requiring treatment mixture K ₂ CO _{3 (solid)} (328.7 mg, 2.387 mmol) in MeOH The resulting mixture was stirred overnight at ambient temperature, then filtered and purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to give purified title compound as 2,2,2-trifluoroacetate (10 mg, 92% yield) MS (apci) m / z = 516.8 (M + 2).

Example 118.

4- (6- (4 - ((R) -2-hydroxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6- () -2 hydroxypropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile.

In a solution of HCl) -6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P28; 100 mg, 0.241 mmol), D - (-) - mandelic acid (45.8 mg, 0.301 mmol) and DIEA (210 μl, 1.21 mmol) in DCM (1.21 ml), HATU (110 mg, 0.289 mmol) was added, then stirred overnight at ambient temperature. The reaction mixture was filtered and the filtrate was purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The salt was dissolved in DCM and MeOH and purified by silica gel chromatography (0-20% MeOH in DCM as eluent) to afford the purified title compound (68 mg, 45% yield). MS (apci) m / z = 512.8 (M + H).

1H NMR (400 MHz, CDCI3-) δ: 8.31 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 7.73 (dd, 1H, J = 9, 0, 2.0 Hz), 7.397.32 (m, 5H), 7.10 (s, 1H), 6.71 (d, 1H, J = 9.0 Hz), 5.25 (s, 1H) , 4.38 (br m, 2H), 4.23 (m, 1H), 4.00-3.95 (m, 2H), 3.88-3.78 (m, 2H), 3.65 -3.60 (m, 2H), 3.44-3.39 (m, 2H), 1.31 (d, 3H, J = 6.2Hz).

Compounds in the table. I was prepared using a method similar to that described for the synthesis of example 118, replacing D - (-) - mandelic acid with the appropriate aldehyde, and using different amounts of HATU (1.1-1.25 eq.) And DIEA (3.5-5 eq. .). The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Each compound was isolated purified after one chromatographic purification using an appropriate gradient eluent. After chromatographic purification, the 2,2,2-trifluoroacetate of the title compound was isolated.

- 223 035568

Table I

No. Example Structure Chemical name MS (apci) m / z 119 LL e about about about X 4- (6- (4 - ((R) -2- (4fluorophenyl) -2hydroxyacetyl) pi perazin-1yl) pyridin-3-yl) 6 - ((R) -2hydroxypropoxy) pyrazolo [1,5а] pyridine-3carbonitrile 531.2 (M + H). 120 about · about / about $ - about t 4- (6- (4 - ((R) -2- (4chlorophenyl) -2hydroxyacetyl) pi perazin-1yl) pyridin-3-yl) 6 - ((R) -2hydroxypropoxy) pyrazolo [1,5а] pyridine-3carbonitrile 547.2 (M + H). 121 N = \ BUT.___ About || N about 6 - ((R) -2- hydroxypropoxy) -4- (6- (4 - ((R) -2methoxy-2phenylacetyl) piperazin-1yl) pyridin-3yl) pyrazolo [1,5 a] pyridine-3carbonitrile 527.2 (M + H). 122 % m TPA k.% A,,.,. _{γ γ} ο ^f 2,2,2 trifluoroacetate 4 (6- (4 - ((R) -2hydroxy-3methylbutanoyl) pi perazin-1yl) pyridin-3-yl) 6 - ((R) -2hydroxypropoxy) pyrazolo [1,5 - a] pyridine-3carbonitrile 478.9 (M + H).

Example 123.

^) - 6- (2-hydroxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Into solution ^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile (intermediate P29; 15 mg, 0.040 mmol) and 6-methoxy-nicotinaldehyde (10.9 mg, 0.0793 mmol) in DCE (396 μl), NaBH (AcO) ₃ (33.6 mg, 0.159 mmol) was added and stirred for 1 day at 50 ° C. The resulting mixture was cooled to ambient temperature and purified directly by silica gel chromatography (0-20% DCM / MeOH as gradient eluent). The isolated product was further purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound as a TFA salt. The TPA salt was dissolved in MeOH and sonicated with K ₂ CO ₃ ( _TB ). The resulting suspension was filtered and evaporated in vacuo to give the purified title compound (6.5 mg, 33% yield). MS (apci) m / z = 500.2 (M + H).

1H NMR (400 MHz, DMSO ^) δ: 8.42 (s, 1H), 8.30 (br s, 1H), 8.27 (d, 1H, J = 2.0 Hz), 8.07 (d, 1H, J = 2.3 Hz), 7.74 (dd, 1H, J = 8.3, 2.3 Hz), 7.71 (dd, 1H, J = 8.2, 2.0 Hz), 7.25 (d, 1H, J = 2.0 Hz), 6.91 (d, 1H, J = 9.0 Hz), 6.79 (d, 1H, J = 8.6 Hz) , 4.15-4.11 (m, 1H), 4.00 (dd, 1H, J = 9.0, 5.4Hz), 3.92 (dd, 1H, J = 9.4, 7, 4 Hz), 3.89 (s, 3H), 3.64-3.62 (m, 4H), 3.53 (s, 2H), 2.58-2.56 (m, 4H), 1, 28 (d, 2H, J = 6.3Hz).

- 224 035568

Example 124.

U) -6- (2-hydroxypropoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of H) -6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile (intermediate P29; 15 mg, 0.040 mmol) in DCE (396 μl) and MeOH (5 drops) picolinaldehyde (7.6 μl, 0.079 mmol) and NaBH (AcO) ₃ (33.6 mg, 0.159 mmol) were added. The resulting mixture was stirred overnight at 50 ° C, then additional NaBH (AcO) ₃ (33.6 mg, 0.159 mmol) was added. The resulting mixture was stirred for an additional 2 h at 50 ° C, then cooled to ambient temperature. The reaction mixture was purified directly by silica gel chromatography (0-20% DCM / MeOH as gradient eluent) to afford the purified title compound (12 mg, 64% yield). MS (apci) m / z = 470.2 (M + H).

Example 125.

Щ) -4- (6- (4 - ((5-chloropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (2hygroxypropoxy) pyrazolo [1,5-a] pyridine -3-carbonitrile.

HCl) -6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride solution (intermediate P28; 11 mg, 0.027 mmol), 5 chloropicolinaldehyde (7.5 mg, 0.053 mmol) and NaBH (AcO) ₃ (17 mg, 0.080 mmol) in DCE (530 μl) were stirred for 1 day at ambient temperature. The resulting mixture was purified directly by silica gel chromatography (using a stepwise gradient of 0-100% EtOAc in hexane isomers followed by the addition of 10% MeOH in EtOAc as eluants) to afford the purified title compound (7 mg, 52% yield). MS (apci) m / z = 504.2 (M + H).

Example 126.

Щ) -6- (2-hydroxypropoxy) -4- (6- (4 - ((5-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyrugine -3-carbonitrile.

The title compound (13 mg, 98% yield) was prepared and purified using a procedure similar to Example 125, substituting 5-chloropicolinaldehyde for 5-methoxypicolinaldehyde. MS (apci) m / z = 500.2 (M + H).

Example 127.

(R) -4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -Nisobutylpiperazine-1-carboxamide 2,2 , 2-trifluoroacetate.

Into cold (0 ° C) solution of hydrochloride (HCl) -6- (2-hydroxypropoxy) -4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyrugin-3-carbonitrile ( intermediate P28; 15 mg, 0.0362 mmol) and DIEA (31.6 μl, 0.181 mmol) in DMA (723 μl) was added 4-nitrophenyl chloroformate (8.74 mg, 0.0434 mmol). After stirring the mixture for 1 h at 0 ° C, isobutylamine (13.2 mg, 0.181 mmol) was added. The resulting mixture was stirred for 1 day at 80 ° C before adding additional isobutylamine (13 mg, 0.181 mmol). The mixture was stirred for 4 h at 80 ° C. Received

225,035,568 was diluted with MeOH and directly purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as 2,2,2-trifluoroacetate (15.6 mg, 73% yield). MS (apci) m / z = 477.9 (M + H).

Example 128.

6 - (^) - 2-hydroxypropoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptan-3-yl) pyridine-3 - yl) pyrazolo [1 ^^ pyridine-E-carbonitrile.

Into a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2-hydroxypropoxy) pyrazolo [1,5-a] dihydrochloride pyridine-3-carbonitrile (intermediate P30; 11.8 mg, 0.0276 mmol) in DCE (396 μL), 6-methoxy-nicotinaldehyde (7.58 mg, 0.0553 mmol) and NaBH (AcO) ₃ (17, 6 mg, 0.0829 mmol). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to afford the purified title compound (7 mg, 50% yield). MS (apci) m / z = 512.2 (M + H).

Example 129.

4- (6- (4 - (^) - 2-hydroxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6 - (^) - 2hydroxypropoxy) pyrazolo [1,5-a] pyridine -3 -carbonitrile.

In a solution of hydrochloride (^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P31; 13.8 mg, 0.0333 mmol), ^) - 2-hydroxy-2-phenylacetic acid (5.31 mg, 0.0349 mmol), DIEA (20.3 μL, 0.116 mmol) in DCM (333 μL), HATU was added (13, 9 mg, 0.0366 mmol), then stirred for 1 hour at ambient temperature. The reaction mixture was loaded directly onto a flash column equilibrated with a mixture of hexane isomers and eluted with 0-100% DCM / hexane isomer mixture to 0-20% MeOH in a DCM gradient to afford the purified title compound (8 mg, 47% yield). MS (apci) m / z = 513.2 (M + h).

Example 130.

N = \

Ηο ^ _ο ΑΑρ _Ν ο

6 - (^) - 2-hydroxypropoxy) -4- (6- (4 - (^) - 2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3 -carbonitrile.

The title compound (8 mg, 49% yield) was prepared and purified using a method similar to Example 129, substituting (R) -2methoxy-2-phenylacetic acid for (R) -2-hydroxy-2-phenylacetic acid. MS (apci) m / z = 527.2 (M + H).

Example 131.

N = \

ΗΟγ-θΑΑρ.

= Η I о

(S) -4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -Nisobutylpiperazine-1-carboxylate.

Into cold (0 ° C) hydrochloride solution (^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile ( intermediate P31; 15.6 mg, 0.0376 mmol) and

- 226 035568

DIEA (32.8 μl, 0.188 mmol) in DMA (752 μl) was added 4-nitrophenyl chloroformate (7.96 mg, 0.0395 mmol). After the mixture was stirred for 1 h at 0 ° C, isobutylamine (13.7 mg, 0.188 mmol) was added. The resulting mixture was stirred for 1 day at 80 ° C and then additional isobutylamine (13.7 mg, 0.188 mmol) was added. The mixture was stirred for 4 h at 80 ° C. The resulting mixture was diluted with MeOH and directly purified by C18 reverse phase chromatography. (5-95% ACN / water with 0.1% TFA as gradient eluent). The isolated product was further purified by silica gel chromatography (0-20% MeOH in DCM with 1% NH ₄ OH as gradient eluent) to afford the title compound (4 mg, 22% yield). MS (apci) m / z = 478.2 (M + H).

Example 132.

^) - 6- (2-hydroxypropoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into solution ^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile (intermediate P32; 20 mg, 0.053 mmol) and picolinaldehyde (6.3 μl, 0.066 mmol) in DMF (528.5 μl) was added NaBH (AcO) ₃ (22.4 mg, 0.106 mmol). After stirring for 1 day at ambient temperature, the mixture was filtered through a syringe filter and then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound as a TFA salt. The TFA salt was dissolved in 4: 1 DCM / MeOH (20 ml) and K ₂ CO ₃ (. _Ra ) (10 ml) was added to give the purified title compound (17 mg, 69% yield). MS (apci) m / z = 470.2 (M + H).

Example 133.

^) - 6- (2-hydroxypropoxy) -4- (6- (4 - ((5-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Hydrochloride solution (^) - 6- (2-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P31; 11 mg, 0.027 mmol), 5methoxypicolinaldehyde (7.3 mg, 0.053 mmol) and NaBH (AcO) ₃ (17 mg, 0.080 mmol) in DMF (530 μl) was stirred for 1 day at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using a stepwise gradient of 0-100% EtOAc in hexane isomers followed by 10% MeOH / EtOAc as eluants) to afford the purified title compound (13 mg, 98% yield). MS (apci) m / z = 500.2 (M + H).

Example 134.

^) - 4- (6- (4 - ((5-chloropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxypropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile.

The title compound (8 mg, 60% yield) was prepared and purified using a procedure similar to Example 133, replacing 5-methoxypicolinaldehyde with 5-chloropicolinaldehyde. MS (apci) m / z = 504.2 (M + H).

Example 135.

- 227 035568

^) - 6- (2-hydroxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

In a solution of 2,2,2-trifluoroacetate 6-hydroxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1 yl) pyridin-3-yl) pyrazolo [1,5- a] pyridine-3-carbonitrile (intermediate P24; 10 mg, 0.018 mmol) and K ₂ CO ₃ ( _tB ) (16 mg, 0.11 mmol) in DMF (227 μL) was added ^) - 2-methyloxirane (13 mg , 0.23 mmol). The resulting mixture was stirred for 1 day at 50 ° C. The reaction mixture was loaded directly onto a flash column equilibrated with hexane isomer mixture and eluted with 0-100% DCM / hexane isomer mixture followed by 0-20% MeOH in DCM to give the purified title compound (5.5 mg, 49% yield) ... MS (apci) m / z = 499.8 (M + H).

Example 136.

6 - (^) - 2-hydroxypropoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane3-yl) pyridine-3 - yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In solution, 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2hydroxypropoxy) pyrazolo [1,5-a] pyridine dihydrochloride 3-carbonitrile (intermediate P33; 13.1 mg, 0.0261 mmol) in DCE (130 μl) was added sequentially 6-methoxynicotinaldehyde (7.15 mg, 0.0522 mmol) and NaBH (AcO) ₃ (16.6 mg , 0.0782 mmol). The resulting mixture was stirred for 1 hour at ambient temperature and then evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to afford the purified title compound (7 mg, 53% yield). MS (apci) m / z = 512.2 (M + H).

Example 137.

No. \

BUT. хЖ ^ / ^ χ _k , γ О

ABOUT

6- (W) -2-hydroxybutoxy) -4- (6- (4- (W) -2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

In a solution of HCl) -6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P34; 11.4 mg, 0.0266 mmol), H) -2-methoxy-2-phenylacetic acid (4.64 mg, 0.0279 mmol) and DIEA (16.2 μl, 0.0930 mmol) in DCM (266 μl, 0.0266 mmol) was added HATU (11.1 mg, 0.0292 mmol) and stirred for 1 h at ambient temperature. The reaction mixture was loaded directly onto a flash column equilibrated with hexane isomer mixture and eluted with 0-100% DCM / hexane isomer mixture followed by 0-20% MeOH in DCM to afford the purified title compound (5.6 mg, 39% yield ). MS (apci) m / z = 541.2 (M + H).

Example 138.

(R) -4- (5- (3-cyano-6- (2-hydroxybutoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -Nisobutylpiperazine-1-carboxylate.

Into a cold (0 ° C) solution of hydrochloride (H) -6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile ( intermediate P34; 15.3 mg, 0.0357 mmol) and DIEA (31.2 μl, 0.178 mmol) in DMA (713 μl) was added 4-nitrophenyl chloroformate (7.55 mg, 0.0375 mmol). After stirring the mixture for 1 h at 0 ° C, isobutylamine (13.0 mg, 0.178 mmol) was added. The resulting mixture was stirred for 1 day at 80 ° C and then additional isobutylamine (13 mg, 0.178 mmol) was added. The mixture was stirred for 4 h at 80 ° C, then diluted with MeOH and directly purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent). The isolated product was additionally purified by silica chromatography

228,035,568 gel (0-20% DCM / MeOH / 1% NH4OH as gradient eluent) to give the title compound (2.02 mg, 11% yield). MS (apci) m / z = 492.2 (M + H).

Example 139.

^) - 6- (2-hydroxybutoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridin-3-carbonitrile.

Into a solution of (R) -6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile (intermediate P35; 15.3 mg, 0.0357 mmol) and picolinaldehyde (3.38 μl, 0.0382 mmol) in DCE (764 μl) was added NaBH (AcO) ₃ (8.1 mg, 0.0382 mmol). The resulting mixture was stirred overnight at ambient temperature and then purified directly by silica gel chromatography (0-5% MeOH in DCM as gradient eluent) to afford the purified title compound (4 mg, 22% yield). MS (apci) m / z = 483.9 (M + H).

Example 140.

^) - 4- (6- (4 - ((5-chloropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (2hydroxybutoxy) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Hydrochloride solution ^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P34; 11 mg, 0.026 mmol), 5-chloropicolinaldehyde (7.3 mg, 0.051 mmol) and NaBH (AcO) ₃ (16 mg, 0.077 mmol) in DCE (513 μl) was stirred for 1 day at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using a stepwise gradient of 0-100% EtOAc in hexane isomers followed by the addition of 10% MeOH / EtOAc as eluants) to afford the purified title compound (7 mg, 53% yield). MS (apci) m / z = 518.2 (M + H).

Example 141.

^) - 6- (2-hydroxybutoxy) -4- (6- (4 - ((5-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

The title compound (8 mg, 61% yield) was prepared and purified using a procedure similar to that described in Example 140, substituting 5-methoxypicolinaldehyde for 5-chloropicolinaldehyde. MS (apci) m / z = 514.2 (M + H).

Example 142.

2,2,2-trifluoroacetate ^) - 6- (2-hydroxybutoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin1-yl) pyridin-3-yl) pyrazolo [ 1,5-a] pyridine-3-carbonitrile.

A mixture of 2,2,2-trifluoroacetate 6-hydroxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P24; 10 mg, 0.018 mmol), (R) (+) - 1,2-epoxybutane (1.63 mg, 0.0227 mmol) and K ₂ CO ₃ ( _TB) (9, 39 mg, 0.0680 mmol) in DMF (113 μl) was stirred for 1 day at 50 ° C. The reaction mixture was filtered and purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the purified title compound as 2,2,2-trifluoroacetate salt (14 mg, 99% yield). MS (apci) m / z = 513.8 (M + H).

- 229 035568

Example 143.

4- (6- (4- (W) -2-hydroxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6 - (^) - 2hydroxybutoxy) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Into a solution of hydrochloride (^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P36; 17.2 mg, 0.0401 mmol), H) -2-hydroxy-2-phenylacetic acid (6.41 mg, 0.0421 mmol), DIEA (24.5 μL, 0.140 mmol) in DCM (401 μL), HATU (16, 8 mg, 0.0441 mmol), and then stirred for 1 h at ambient temperature. The reaction mixture was loaded directly onto a flash column equilibrated with a mixture of hexane isomers and eluted with a gradient of 0-100% DCM / mixture of hexane isomers followed by 0-20% MeOH in DCM to give the purified title compound (7.5 mg, yield 3369%). MS (apci) m / z = 527.2 (M + H).

Example 144.

6 - (^) - 2-hydroxybutoxy) -4- (6- (4- (W) -2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (8 mg, 30% yield) was prepared and purified using a procedure similar to Example 143, substituting (R) 2-methoxy-2-phenylacetic acid for (R) 2-hydroxy-2-phenylacetic acid. MS (apci) m / z = 541.2 (M + H).

Example 145.

(S) -4- (5- (3-cyano-6- (2-hydroxybutoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -Nisobutylpiperazine-1-carboxylate.

Into a cold (0 ° C) solution of hydrochloride (^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile ( intermediate P36; 23 mg, 0.0536 mmol) and DIEA (46.8 μl, 0.127 mmol) in DMA (1.072 ml) was added 4-nitrophenyl chloroformate (11.3 mg, 0.0563 mmol). After stirring the mixture for 1 h at 0 ° C, isobutylamine (19.6 mg, 0.268 mmol) was added. The resulting mixture was stirred for 1 day at 80 ° C and then additional isobutylamine (11 mg, 0.06 mmol) was added. The mixture was stirred for an additional 4 h at 80 ° C, then cooled to ambient temperature, diluted with MeOH and directly purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent). The isolated product was further purified by silica gel chromatography (0-20% MeOH in DCM with 0.1% NH ₄ OH as gradient eluent) to afford the title compound (3 mg, 11% yield). MS (apci) m / z = 492.3 (M + H).

Example 146.

^) - 6- (2-hydroxybutoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridin-3-carbonitrile.

- 230 035568

Into a stirred solution ^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1.5 1,5] pyridine-3-carbonitrile (intermediate P37; 14 mg, 0, 0357 mmol) and picolinaldehyde (3.79 μl, 0.0428 mmol) in DCE (713.5 μl) was added NaBH (AcO) ₃ (22.7 mg, 0.107 mmol). The resulting mixture was stirred overnight at ambient temperature and then purified directly by silica gel chromatography (0-5% MeOH in DCM as gradient eluent) to afford the purified title compound (5.4 mg, 31% yield). MS (apci) m / z = 483.8 (M + H).

Example 147.

^) - 4- (6- (4 - ((5-chloropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (2hydroxybutoxy) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Hydrochloride solution (^) - 6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P36; 11 mg, 0.026 mmol), 5-chloropicolinaldehyde (7.3 mg, 0.051 mmol) and NaBH (AcO) ₃ (16 mg, 0.077 mmol) in DCE (513 μl) was stirred for 1 day at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using a stepwise gradient of 0-100% EtOAc in hexane isomers followed by the addition of 10% MeOH / EtOAc as eluants) to afford the purified title compound (9 mg, 68% yield). MS (apci) m / z = 518.2 (M + H).

Example 148.

^) - 6- (2-hydroxybutoxy) -4- (6- (4 - ((5-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5h] pyridin-3 -carbonitrile.

The title compound (6.5 mg, 49% yield) was prepared and purified using a procedure similar to Example 147, substituting 5-methoxypicolinaldehyde for 5-chloropicolinaldehyde. MS (apci) m / z = 514.2 (M + H).

Example 149.

^) - 6- (2-hydroxybutoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5 h] pyridine-3 -carbonitrile.

To a solution of (S) -6- (2-hydroxybutoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P37; 11 mg, 0.026 mmol) in DCE (513 μl) was added sequentially 6 methoxynicotinaldehyde (5.87 mg, 0.0428 mmol) and NaBH (AcO) ₃ (22.7 mg, 0.107 mmol). The resulting mixture was stirred overnight at ambient temperature and then purified directly by silica gel chromatography (0-5% MeOH in DCM as gradient eluent) to afford the purified title compound (8.3 mg, 45% yield). MS (apci) m / z = 513.8 (M + H).

Example 150.

4- (6- (4 - ((R) -2-hydroxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6 - (((2S *, 3R *) - 3hydroxybutane-2- yl) oxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In hydrochloride solution 6 - (((2S *, 3R *) - 3-hydroxybutan-2-yl) oxy) -4- (6- (piperazin-1-yl) pyridine

- 231 035568

3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P38; 25 mg, 0.0583 mmol), ^) - 2-hydroxy-2-phenylacetic acid (9.31 mg, 0.0612 mmol) and DIEA (35.6 μl, 0.204 mmol) in DCM (583 μl), HATU (24.4 mg, 0.0641 mmol) was added and then stirred for 1 h at ambient temperature. The reaction mixture was purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent). The isolated product was further purified by silica gel chromatography (0-20% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the purified title compound (2 mg, 7% yield). MS (apci) m / z = 527.2 (M + H).

Example 151.

6 - (((2S, 3R) -3-rugpoKCu6yTaH-2-ua) oKCu) -4- (6- (4 - ((R) -2-MeTOKCu-2 ^ eHura ^ Tua) nunepa3UH-1yl) pyridine 3 -yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (3 mg, 10% yield) was prepared and purified using a procedure similar to Example 150, substituting (R) -2-methoxy-2-phenylacetic acid for (R) -2-hydroxy-2-phenylacetic acid. MS (apci) m / z = 541.2 (M + H).

Example 152.

tert-butyl 4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate.

In a suspension of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (intermediate P3; 200 mg, 0.476 mmol ) in DMF (5 ml) was successively added to ₂ CO ₃ ( _TB ) (329 mg, 2.38 mmol) and 2,2-dimethyloxirane (171 mg, 2.38 mmol). After stirring overnight at 40 ° C, an additional amount of 2,2-dimethyloxirane (171 mg, 2.38 mmol) was added to the reaction mixture and the reaction temperature was raised to 50 ° C. The mixture was stirred for 24 h at 50 ° C and then another aliquot of 2,2-dimethyloxyrane (171 mg, 2.38 mmol) was added. The resulting mixture was stirred for 3 days at 50 ° C. The reaction mixture was cooled to ambient temperature and purified directly by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to afford the purified title compound (89.6 mg, 38% yield). MS (apci) m / z = 493.3 (M + H).

Example 153.

^) - 4- (6- (4- (2- (4-chlorophenyl) -2-hydroxyacetyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1, 5-a] pyridine-3-carbonitrile.

6- (2-Hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride (intermediate P39; 30 mg, 0 , 0699 mmol), ^) - 2- (4-chlorophenyl) -2 hydroxyacetic acid (13.1 mg, 0.0699 mmol), DIEA (61.1 μL, 0.350 mmol) and HATU (33.2 mg, 0, 0874 mmol) was added sequentially to DCM (0.7 ml). The resulting suspension was stirred for 1 hour at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using a stepwise gradient of 0-100% EtOAc in a mixture of hexane isomers followed by the addition of 10% MeOH / EtOAc as eluants) to afford the purified title compound (28 mg, 71% yield). MS (apci) m / z = 561.2 (M + H).

Compounds in the table. J was obtained using a method similar to that described for the synthesis of example 153, substituting ^) - 2- (4-chlorophenyl) -2-hydroxyacetic acid with the corresponding carboxylic

- 232 035568 acid and using different amounts of HATU (1.1-1.25 eq.) And DIEA (1-3.5 eq.). The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds.

Table J

Example 157.

Chemical name

MS (apci)

Ill / z (K) -6- (2-hydroxy-2methylpropoxy) -4 (6- (4- (2-hydroxy-2phenylacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5а] pyridine- 3carbonitrile (R) -4- (6- (4- (2- (4fluorophenyl) -2hydroxyacetyl) piperazin-1-yl) pyri din- 545.3 3-yl) -6- (2-hydroxy- (M + H) 2-.

methylpropoxy) pyra zolo [1,5-a] pyridine 3-carbonitrile _____ (R) -6- (2-rHflpoKCH-2methylpropoxy) -4 (6- (4- (2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridine-3yl) pyrazole o [1,5а] pyridine-3carbonitrile

527.2 (M + H)

541.2 (M + H)

4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -Nisobutylpiperazine-1-carboxylate.

In a cold (0 ° C) solution of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P39; 15 mg, 0.035 mmol) and DIEA (30.5 μl, 0.175 mmol) in DMA (699 μl) was added 4-nitrophenyl chloroformate (7.40 mg, 0.0367 mmol). After stirring the mixture for 1 h at 0 ° C, isobutylamine (7.40 mg, 0.0367 mmol) was added. The resulting mixture was stirred for 1 day at 80 ° C and then additional isobutylamine (8 mg, 0.04 mmol) was added. The mixture was stirred for 4 h at 80 ° C. The mixture was diluted with MeOH and directly purified with C18 reverse phase (5-95% ACN water with 0.1% TFA as eluent gradient) followed by chromatography on silica gel (0-20% MeOH in DCM with 1% NH ₄ OH in as eluent gradient) to give the title compound (5.6 mg, 33% yield). MS (apci) m / z = 492.3 (M + H).

Example 158.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P40; 15 mg, 0.038 mmol) and 6-methoxy-nicotinaldehyde (10.5 mg, 0.0764 mmol) in DCE (382 μl) was added NaBH (AcO) ₃ (32.4 mg, 0.153 mmol) and stirred for 1 day at 50 ° C. The mixture was cooled to ambient temperature and then purified directly by silica gel chromatography (0-20% DCM / MeOH as gradient eluent). The isolated product was further purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the purified title

- 233 035568 compounds in the form of a TPA salt. The TPA salt was dissolved in MeOH and sonicated with K2CO3 ( _TB ). The resulting suspension was filtered, and the filtrate was evaporated under reduced pressure to give the purified title compound (6.9 mg, 35% yield). MS (apci) m / z = 514.3 (M + H).

Example 159.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile ...

To a solution of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P40; 20 mg, 0.051 mmol) and picolinaldehyde (6.1 μl, 0.064 mmol) in DMF (510 μl), NaBH (AcO) ₃ (21.6 mg, 0.102 mmol) was added and stirred for 1 day at ambient temperature. The mixture was filtered through a syringe filter and then evaporated under reduced pressure. The crude residue was purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was dissolved in 4: 1 DCM / MeOH (10 ml, treated with K ₂ CO ₃ ( _TB ) in an ultrasonic bath. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure to give the purified title compound (11 mg, 45% yield) MS (apci) m / z = 484.2 (M + H).

Example 160.

N = \ I \

4- (6- (4 - ((5-chloropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Solution of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P39; 11 mg, 0.026 mmol), 5 chloropicolinaldehyde (7.3 mg, 0.051 mmol), NaBH (AcO) ₃ (16 mg, 0.077 mmol) in DCE (513 μL) was stirred for 1 day at ambient temperature. The mixture was purified directly by silica gel chromatography (eluting with a stepwise gradient of 0-100% EtOAc in hexane isomer mixture followed by 10% MeOH / EtOAc) to afford the purified title compound (7 mg, 53% yield). MS (apci) m / z = 518.2 (M + H).

Example 161.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4 - ((5-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (8.89 mg, 68% yield) was prepared and purified using a procedure similar to that described in Example 160, substituting 5-methoxypicolinaldehyde for 5-chloropicolinaldehyde. MS (apci) m / z = 514.2 (M + H).

Example 162.

4- (6- (6- (2- (5-fluoropyridin-2-yl) acetyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2 hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine- 3-carbonitrile (intermediate P44; 25 mg, 0.0618 mmol) in DCM (1.24 ml) was successively added 2- (5-fluoropyridin-2-yl) acetic acid (11.5 mg, 0.0742 mmol),

- 234 035568

HATU (28.2 mg (0.0742 mmol) and DIEA (43.1 μl, 0.247 mmol), then stirred overnight at ambient temperature.The reaction mixture was purified directly by chromatography on silica gel (using a stepwise gradient of 0-100% DCM in a mixture of hexane isomers followed by 0-60% [78% DCM / 20% MeOH / 2% NH ₄ OH] in DCM as eluents) to purify the resulting title compound (2.94 mg, 9% yield). MS (apci) m / z = 542.2 (M + H).

Example 163.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3 -yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

Into solution 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 12.2 mg, 0.0277 mmol) in DCE (513 μL), 6-methoxy-nicotinaldehyde (7.59 mg, 0.0553 mmol) and NaBH (AcO) ₃ (17.6 mg, 0.0830 mmol), then stirred overnight at ambient temperature. The mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to give the purified title compound (13.59 mg, 93% yield). MS (apci) m / z = 526.2 (M + H).

1H NMR (400 MHz, DMSO-06) δ: 8.64 (d, 1H, J = 2.3 Hz), 8.55 (s, 1H), 8.38 (d, 1H, J = 2.3 Hz), 8.04 (d, 1H, J = 2.3 Hz), 7.80 (dd, 1H, J = 8.6, 2.3 Hz), 7.64 (dd, 1H, J = 8 , 6, 2.3 Hz), 7.27 (d, 1H, J = 2.0 Hz), 6.76 (d, 1H, J = 8.6 Hz), 6.73 (d, 1H, J = 8.2 Hz), 4.67 (s, 1H), 3.85 (s, 2H), 3.79 (s, 3H), 3.72 (d, 2H, J = 12.5 Hz), 3.64 (d, 2H, J = 5.9 Hz), 3.51 (br d, 2H), 3.47 (s, 2H), 2.47 (m, 1H), 1.55 (d , 1H), 1.20 (s, 6H).

Compounds in the table. K was prepared using a method similar to that described for the synthesis of Example 163, replacing 6-methoxy-nicotinaldehyde with the appropriate aldehyde (1 or 2 equiv.). The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds.

Table K

No. Example Structure Chemical name MC (apci) ηι / ζ 164 hcl. '' Ooh No. \ ¹ JL Cl 4- (6- (6 - ((5chloropyridin-3yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) -6- (2-hydroxy2- methylpropoxy) pyrazol [1,5-a] pyridine-3carbonitrile 530.2 (M + H). 165 nsx. Ν = \ 4- (6- (6 - ((5fluoropyridin-3yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) -6- (2-hydroxy2- methylpropoxy) pyrazol [1,5-a] pyridine-3carbonitrile 514.2 (M + H). 166 not. '' (U Ν = \ ¹ L 6- (2-hydroxy-2methylpropoxy) -4- (6 (6 - ((5- methoxypyridine-2yl) methyl) -3,6 diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) pyrazolo [1,5а] pyridine-3carbonitrile 526.2 (M + H). 167 NSK Ν = \ _ζ νΑ ^ _Ν ¹ JL '''Ο 6- (2-hydroxy-2methylpropoxy) -4- (6 (6 - ((5- methoxypyridin-3yl) methyl) -3,6 diazabicyclo [3.1.1] g eptan-3-yl) pyridin 3-yl) pyrazolo [1,5а] pyridine-3carbonitrile 526.2 (M + H).

- 235 035568

Example 173.

methylpropoxychirazol [1,5-a1pyridine-3carbonitrile

6- (2-hydroxy-2methylpropoxy) -4- (6methylpropoxy) p irazol [1,5-a1pyridine-3carbonitrile methylpropoxychirazol [1,5-a1pyridine-3carbonitrile

4- (6- (6 - ((4-fluoro-2methoxypyridine-3yl) methyl) -3,6 diazabicyclo G 3.1.11 g eptan-3-yl) pyridin3-yl) -6- (2-hydroxy4- (6- (6 - ((6fluoropyridin-3yl) methyl) -3,6 diazabicyclo G 3.1.11 g eptan-3-yl) pyridin3-yl) -6- (2-hydroxymethoxypyridin-2yl) methyl) -3,6 diazabicycloGZ, 1.11g eptane -3-yl) pyridin3-yl shirazolo 11.5а1pyridine-3carbonitrile

6- (2-hydroxy-2methylpropoxy) -4- (6 (6 - ((6-methylpyridin2-yl) methyl) -3,6diazabicycloGZ, 1.11g eptan-3-yl) pyridin3-yl shirazolo 11.5а1pyridin-3carbonitrile

4-6-6-3cyanopyridin-2yl) methyl) -3,6diazabicycloGZ, 1.11g eptan-3-yl) pyridin3-yl) -6- (2-hydroxy4- (6- (6 - ((3-fluoropyridin-2 -yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3- carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 25.3 mg, 0.0530 mmol) in DCM (1 ml), 3-fluoro-2-formylpyridine (19.9 mg, 0.159 mmol), NaBH (AcO) ₃ (33 , 7 mg (0.159 mmol) and AcOH (2 drops) .After stirring for 60 h at ambient temperature, the resulting mixture was evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0 , 1% TFA as gradient eluent) to afford the purified title compound as a TFA salt The TFA salt was partitioned between 4: 1 DCM iso-PrOH and saturated NaHCO ₃ ( _aq ). The combined organic extracts were dried over anhydrous Na ₂ SO _{4 (solid),} filtered and evaporated under reduced pressure to give the title compound (18.2 mg, yield 67%). MS (apci) m / z = 514,2 ( M + H).

Example 174.

4- (6- (6 - ((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl)

- 236 035568

6- (2-hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

Into solution 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride Β-3-carbonitrile (intermediate P43; 30 mg, 0.063 mmol) in DCM (1 ml) was added DIEA (27 μl, 0.16 mmol) and stirred for 5 min at room temperature. To the resulting mixture, 5-chloro-6-methoxy-nicotinaldehyde (11 mg, 0.063 mmol) and NaBH (AcO) ₃ (27 mg, 0.13 mmol) were sequentially added. After stirring for 12 h at ambient temperature, the reaction mixture was diluted with DCM and washed with 10% Na ₂ CO ₃ ( _βod ). The combined organic extracts were dried over anhydrous MgSO ₄ ( _ra ), filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% MeOH / DCM with 1% NH4OH as eluent) to afford the purified title compound (22 mg, 63% yield). MS (apci) m / z = 560.3 (M + H).

Compounds in the table. L was prepared using a method similar to that described for the synthesis of Example 174, substituting the appropriate aldehyde for 5-chloro-6-methoxy-nicotinaldehyde. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds. Where marked (*), no aqueous workup was performed, but direct chromatographic purification of the solubilized reaction mixture was used to isolate the title compound.

TableL

No. Example Structure Chemical name MS (apci) m / z 175 N = \ JAsn her Opr 4- (6- (6 - ((5-fluoro-6methoxypyridin-3 yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyr azole [1,5а] pyridine-3carbonitrile 544.2 (M + H). 176 ZE b oh i b about P 4- (6- (6 - ((6- (difluoromethoxy) pyridin-3-yl) methyl) 3,6- diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyr azole [1,5а] pyridine-3carbonitrile 562.2 (M + H). 177 N = \ Αχ θ || ν 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((2methyloxazol-4yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazole o [1,5а] pyridine -3carbonitrile 500.2 (M + H).

Example 178.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (8 - ((6-methoxypyridin-3-yl) methyl) -3,8diazabicyclo [3.2.1] octan-3-yl) pyridin-3 -yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A mixture of 4- (6- (3,8-diazabicyclo [3.2.1] octan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine hydrochloride 3-carbonitrile (intermediate P45; 24 mg, 0.053 mmol), 6methoxynicotinaldehyde (36.17 mg, 0.2638 mmol) and NaBH (AcO) ₃ (55.9 mg, 0.264 mmol) in DCE (264 μL)

- 237 035568 was stirred overnight at ambient temperature. The mixture was partitioned between DCM saturated with NaHCO ^ o ^) and extracted with DCM. The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-20% DCM / MeOH as gradient eluent) to afford the purified title compound (19.76 mg, 69% yield). MS (apci) m / z = 540.3 (M + H).

Example 179.

2,2,2-trifluoroacetate 6- (2-hydroxy-2-methylpropoxy) -4- (6- (3 - ((6-methoxypyridin-3-yl) methyl) -3,8diazabicyclo [3.2.1] octane- 8-yl) pyridin-3-yl) pyrazolo [1 ^^ pyridinL -carbonitrile.

Mixture of 4- (6-fluoro-pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 20 mg, 0.0613 mmol), hydrochloride 3 - ((6-methoxypyridin-3-yl) methyl) 3,8-diazabicyclo [3.2.1] octane (intermediate R7; 49.6 mg, 0.184 mmol) and ^ CO ^) (42.4 mg, 0.306 mmol) in DMSO (613 μl) was stirred at 80 ° C until the reaction was complete (as determined by LCMS). The reaction mixture was cooled to ambient temperature and then filtered. The residue was directly purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as 2,2,2 trifluoroacetate salt (28.14 mg, 85% yield). %). MS (apci) m / z = 540.3 (M + H).

Compounds in the table. M was obtained using a method similar to that described for the synthesis of example 179, replacing the hydrochloride 3 - ((6-methoxypyridin-3-yl) methyl) -3,8-diazabicyclo [3.2.1] octane (intermediate R7) with the corresponding intermediate bicyclo- piperazine (intermediate R5, R6 or R12) and where marked (*), 15 equiv. ^ CO ^). The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds. After chromatographic purification, the 2,2,2-trifluoroacetate of the title compound was isolated.

Table M

No. Example Structure Chemical name MS (apci) ιη / ζ 180 N = \ Νγ ^ _Ν HO _h / \ _k , \ θ Il 6- (2-hydroxy-2methylpropoxy) -4- (6 ((lR, 4R) -5 - ((6methoxypyridin-3 yl) methyl) -2.5diazabicyclo [2.2.1] heptan -2-yl) pyridine -3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 526.3 (M + H) 181 N = \ HCL z \ ⁰ | l ^{ϊ ΤΦΚ} 2,2,2-trifluoroacetate 6 (2-hydroxy-2methylpropoxy) -4- (6 ((lS, 4S) -5 - ((6methoxypyridin-3 yl) methyl) -2.5- diazabicyclo [2.2.1] heptan-2,2-yl) pyridin3-yl) pyrazolo [1,5а] pyridine-3carbonitrile 526.2 (M + H). 182 N = \ HCL _k , 0 ll ^N 6- (2-hydroxy-2methylpropoxy) -4- (6 (3 - ((6- methoxypyridin-3 yl) methyl) -3,6 diazabicyclo [3.1.1] heptan-6-yl) pyridin-3 yl) pyrazole o [1,5 a] pyridine-3carbonitrile 526.2 (M + H).

- 238 035568

Example 183.

6- (2-hydroxy-2-methylpropoxy) -4- (4- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) phenyl) pyrazole [1,5-a] pyridine-3-carbonitrile.

A mixture of 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine -3-carbonitrile (intermediate P49; 63 mg, 0.16 mmol), 6methoxynicotinaldehyde (27.8 mg, 0.20 mmol) and AcOH (1.8 μL, 0.031 mmol) in DCM (1 ml) were stirred for 10 min at ambient temperature before adding NaBH (AcO) ₃ (49.6 mg, 0.23 mmol). The resulting mixture was stirred overnight at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (20% acetone in DCM with 0.05% NH4OH as eluent) to afford the purified title compound (27 mg, yield

31%). MS (apci) m / z = 525.3 (M + H).

Example 184.

6- (2-hydroxy-2-methylpropoxy) -4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazine -2-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (24 mg, 47% yield) was prepared and purified using a procedure similar to Example 183, substituting 4- (5- (3,6-diazabicyclo [3.1.1] heptane-3yl) pyrazine) -2 -yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P49) on 4- (5- (3,6-diazabicyclo [3.1.1] heptane -3-yl) pyrazin-2-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P50). MS (apci) m / z = 527.2 (M + H).

Example 185.

^) - 6- (3-hydroxypropoxy) -4- (6- (4- (2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3- carbonitrile 2,2,2-trifluoroacetate.

6- (3-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride solution (intermediate P51; 21 mg, 0.051 mmol), DO-2-methoxy-2-phenylacetic acid (10.1 mg, 0.061 mmol), HATU (23.1 mg, 0.061 mmol) and DIEA (26.2 μl, 0.20 mmol) were suspended in DCM (253 μl) ... The resulting suspension was stirred for 1 hour at ambient temperature. The reaction mixture was purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the purified title compound (22.2 mg, 69% yield). MS (apci) m / z = 526.8 (M + H).

Compounds in the table. Q was prepared using a method similar to that described for the synthesis of Example 185, substituting () - 2-methoxy-2-phenylacetic acid with the corresponding carboxylic acid. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds.

- 239 035568

Table Q

Example No. Structure Chemical name MC (apci) ηι / ζ 186 N = \ ί Τ TFK HE ο 2,2,2-trifluoroacetate (К) -4- (6- (4- (2-hydroxy2- phenylacetyl) piperazin -1-yl) pyridin-3-yl) -6 (3- hydroxypropoxy) pyra zolo [1,5-a] pyridine-3carbonitrile 512.8 (M + H) 187 Ν = \ ί Τ ΤΦΚ ΟΗ ο 2,2,2-trifluoroacetate (S) 4- (6- (4- (2-hydroxy-2-phenylacetyl) piperazin -1-yl) pyridin-3-yl) -6 (zhydroxypropoxy) pyrazolo [1,5-a ] pyridine-3carbonitrile 512.8 (M + H) 188 Ν = \ ί Τ ΤΦΚ Ο ^ ο 2,2,2-trifluoroacetate (S) 6- (3- hydroxypropoxy) -4 (6- (4- (2-methoxy-2phenylacetyl) piperazine -1-yl) pyridin-3 yl) pyrazole o [1.5 a] pyridine-3carbonitrile 526.8 (M + H) 189 Ν = \ χ Τ HO ^^^ O ^^^^ Tj ^ N ΤΦΚ ΟΗ ο 1 2,2,2-trifluoroacetate (К) -4- (6- (4- (2-hydroxy3- methylbutanoyl) piperaz in-1-yl) pyridin-3-yl) 6- (3- hydroxypropoxy) pyra zolo [1,5-a] pyridine-3carbonitrile 478.9 (M + H) 190 Ν = \ ί Τ ΗΟ ^^ Νϊ —ΤΦΚ ΟΗ Χ / Ν.Α / Ο 1 2,2,2-trifluoroacetate (S) 4- (6- (4- (2-hydroxy-3methylbutanoyl) piperaz in-1 -yl) pyridin-3-yl) 6- (3- hydroxypropoxy) pyra zolo [1,5-a] pyridine-3carbonitrile 478.9 (M + H)

* 1.1 equiv. HATU and 1.1 equiv. D - (-) - mandelic acid were used in this example.

Example 191.

4- (5- (3-cyano-6- (3-hydroxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -No-isobutylpiperazine-1-carboxamide 2,2,2-trifluoroacetate.

In a cold (0 ° C) solution of 6- (3-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P51; 14 mg, 0.0337 mmol) and DIEA (29.5 μl, 0.169 mmol) in DMA (675 μl) was added 4-nitrophenyl chloroformate (7.14 mg, 0.0354 mmol). After stirring the mixture for 1 h at 0 ° C, isobutylamine (12.3 mg, 0.169 mmol) was added. The resulting mixture was stirred for 1 day at 80 ° C before adding additional isobutylamine (12 mg, 0.17 mmol). The mixture was stirred for 4 h at 80 ° C. The resulting mixture was diluted with MeOH and directly purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the title compound

- 240 035568 (12.8 mg, 64% yield). MS (apci) m / z = 477.9 (M + H).

Example 192.

2,2,2-trifluoroacetate 4- (6- (4 - ((5-chloropyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (3hydroxypropoxy ^ irazolo ^^^ pyridine 3-carbonitrile.

A mixture of 6- (3-hydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile hydrochloride (intermediate P51; 12.1 mg, 0, 0292 mmol), 5-chloropicolinaldehyde (8.26 mg, 0.0583 mmol) and NaBH (AcO) ₃ (18.5 mg, 0.0875 mmol) in DCE (583 μl) were stirred for 1 day at ambient temperature ... The mixture was purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the title compound (17.1 mg, 95% yield). MS (apci) m / z = 504.2 (M + H).

Compounds in the table. R were prepared using a method similar to that described for the synthesis of Example 192, substituting the corresponding aldehyde for 5-chloropicolinaldehyde. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds.

Table R

No. Example Structure Chemical name MC (apci) ηι / ζ 193 N = \ Jf Ύ τφκ 2,2,2-trifluoroacetate 6 (3-hydroxypropoxy) 4- (6- (4 - ((5- methoxypyridine-2yl) methyl) piperazin-1 yl) pyridin-3yl) pyrazole o [1,5а] pyridine-3carbonitrile 500.2 (M + H).

2,2,2-trifluoroacetate 4 (6- (4 - ((5fluoropyridin-2yl) methyl) piperazin-1 yl) pyridin-3-yl) -6 (3hydroxypropoxy) pyr azolo [1,5-a] pyridine 3carbonitrile _________

Example 195.

6- (3-hydroxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3 yl) pyrazolo [1,5-a] pyridine 3- carbonitrile.

Stage 1: preparation of 6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4- (6- (4 - ((6-methoxypyridin-3yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. A mixture of 2,2,2 trifluoroacetate 6-hydroxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine- 3-carbonitrile (intermediate P24: 28 mg, 0.0634 mmol), (3-bromopropoxy) (tert-butyl) dimethylsilane (14.5 μL, 0.0793 mmol) and K ^ O ^ y (26.3 mg, 0.190 mmol ) in DMF (317 μl) was stirred for 1 day at 50 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (0-100% EtOAc / hexane isomer mixture as eluent gradient) to provide the purified title compound (420 mg, 49% yield) MS (apci) m / z = 614.9 (M + H).

Stage 2: preparation of 6- (3-hydroxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of 6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine-3-carbonitrile (35 mg, 0.0570 mmol) in THF (1.14 ml) was added TBAF (114

- 241,035,568 μl, 0.114 mmol), stirred for 1 day at 60 ° C. The resulting mixture was first purified directly by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as eluent gradient), then chromatography on silica gel (0-20% DCM / MeOH as eluent gradient) to give of the title compound (8.8 mg, 31% yield). MS (apci) m / z = 499.8 (M + H).

Example 196.

^) - 6- (2,3-dihydroxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.

Into a mixture of dihydrochloride (^) - 6- (2,3-dihydroxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P52; 20 mg, 0.0507 mmol) in DCE (507 μl) was added sequentially 6-methoxy-3-pyridinecarboxaldehyde (6.95 mg, 0.0507 mmol) and NaBH (AcO) ₃ (32.2 mg, 0.152 mmol), and then stirred overnight at ambient temperature. The mixture was purified directly by silica gel chromatography (0-20% MeOH in DCM as gradient eluent) to afford the title compound (11.4 mg, 44% yield). MS (apci) m / z = 516.2 (M + H).

Example 197.

^) - 6- (2,3-dihydroxypropoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3- carbonitrile.

The title compound (1.2 mg, 5% yield) was prepared and purified using a procedure similar to Example 196, substituting picolinaldehyde (2 eq.) For 6-methoxy-3-pyridinecarboxaldehyde. MS (apci) m / z = 486.2 (M + H).

Example 198.

^) - 6- (2,3-dihydroxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.

The title compound (5.1 mg, 30% yield) was obtained and purified using a procedure similar to that described in Example 196, replacing the dihydrochloride (d) - 6- (2,3-dihydroxypropoxy) -4- (6 (piperazine-1 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P52) dihydrochloride (R) -6- (2,3-dihydroxypropoxy) -4- (6- (piperazine-1 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P53) and using 2 eq. 6-methoxy-3-pyridinecarboxaldehyde. MS (apci) m / z = 516.2 (M + H).

Example 199.

6 - ((3- (hydroxymethyl) oxetan-3-yl) methoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1yl) pyridin-3-yl) pyrazole [ 1,5-a] pyridine-3-carbonitrile.

A mixture of 2,2,2-trifluoroacetate 6-hydroxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P24: 39 mg, 0.088 mmol), [3 (bromomethyl) oxetan-3-yl] methanol (48.0 mg, 0.265 mmol) and K ^ CO ^) (61.0 mg (0.442 mmol) in DMF (883 μL) was stirred for 1 h at 90 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using a stepwise gradient of 0-100% EtOAc in a mixture of hexane isomers, then EtOAc with 10% MeOH as eluents) from to

242 035568 by irradiation of the purified title compound (21 mg, 44% yield). MS (apci) m / z = 542.3 (M + H).

Example 200.

6 - ((^^) - 4-hydroxytetrahydrofuran-3-yl) oxy) -4- (6- (4- (H) -2-methoxy-2phenylacetyl) piperazin-1-yl) pyridin 3-yl) pyrazolo [ 1,5-a] pyridine-3-carbonitrile.

In a hydrochloride solution 6 - ((^^) - 4-hydroxytetrahydrofuran-3-yl) oxy) -4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3- carbonitrile (intermediate P54; 19 mg, 0.043 mmol), (R) -2methoxy-2-phenylacetic acid (7.49 mg, 0.0450 mmol) and DIEA (26.2 μl, 0.150 mmol) in DCM (429 μl) HATU (17.9 mg, 0.0472 mmol) was added. After stirring for 1 h at ambient temperature, the reaction mixture was directly purified by chromatography on C18 reverse phase (5-95% ACN / water with 0.1% TFA as gradient eluent) followed by chromatography on silica gel (0-20% DCM / MeOH / NH ₄ OH as gradient eluent) to afford the purified title compound (3 mg, 13% yield). MS (apci) m / z = 555.2 (M + H).

Example 201.

2,2,2-trifluoroacetate 4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6 (((2S, 5R) -5 -methylmorpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl (2S, 5R) -2 - (((3-cyano-4- (6- (4 - ((6-methoxypyridin-3yl) methyl) piperazin-1-yl) pyridin-3- yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -5-methylmorpholine-4-carboxylate. A mixture of 2,2,2-trifluoroacetate 6-hydroxy-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P24; 15 mg, 0.0340 mmol), tert-butyl (2S, 5R) -2- (hydroxymethyl) -5-methylmorpholine-4-carboxylate (12.6 mg, 0.0408 mmol ) and ^ CO ^ to) (4.70 mg, 0.0340 mmol) in DMF (1 ml) were stirred for 1 day at 50 ° C. After cooling to ambient temperature, the reaction mixture was loaded directly onto a flash column equilibrated with a mixture of hexane isomers and eluted with 0-100% DCM / hexane isomer mixture, followed by 0-20% MeOH in DCM to give the title compound (8 mg, yield 36%). MS (apci) m / z = 656.2 (M + H).

Stage 2: preparation of 2,2,2-trifluoroacetate 4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1yl) pyridin-3-yl) -6 - (((2S, 5R ) -5-methylmorpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. To a solution of tert-butyl (2S, 5R) -2 - (((3-cyano-4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1yl) pyridin-3) -yl ) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -5-methylmorpholine-4-carboxylate (0.012 mmol) in DCM (611 μl) was added TFA (47 μl, 0.61 mmol). The reaction mixture was stirred for 10 minutes at ambient temperature and then evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (5-95% ACN / water with 0.1% TFA as gradient eluent) to afford the purified title compound as 2,2,2-trifluoroacetate salt (3.3 mg , 40% yield). MS (apci) m / z = 554.8 (M + H).

Example 202.

O tert-Butyl 4- (5- (3-cyano-6- (2-methoxyethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate.

In a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (intermediate P3; 400 mg, 0.951 mmol ) in DMF (8 ml) were sequentially added ((CO ^ ta) (4.70 mg, 0.0340 mmol) and a solution of 1-bromo-2-methoxyethane (264 mg, 1.90 mmol) in DMF (2 ml). The resulting mixture was stirred for 19 h at 50 ° C. After cooling down to temp

243 035568 At ambient conditions, the reaction mixture was purified directly by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to afford the title compound (345 mg, 76% yield). MS (apci) m / z = 479.2 (M + H).

Example 203.

6- (2-Methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile dihydrochloride.

In a solution of tert-butyl 4- (5- (3-cyano-6- (2-methoxyethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (example 202; 343 mg, 0.717 mmol) in DCM (2 ml) was added 5-6 M HCl in iso-PrOH (4 ml, 20.0 mmol) and stirred for 1 h at ambient temperature. The mixture was diluted with DCM and MeOH and evaporated under reduced pressure to give the title compound as the dihydrochloride salt (322 mg, quantitative). MS (apci) m / z = 379.2 (M + H).

Example 204.

6- (2-methoxyethoxy) -4- (6- (4- (3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

To a solution of 6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P55; 20.1 mg, 0, 0531) mmol) in DCM (1.0 ml), DIEA (37.0 μl, 0.212 mmol) and isovaleryl chloride (7.77 μl, 0.0637 mmol) were added sequentially. The resulting mixture was stirred for 16 hours at ambient temperature. The mixture was evaporated under reduced pressure and the residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. TFA salt was partitioned between a 4: 1 _DCM:!. I-PrOH and saturated Nal ICO _{3 (I iui | i} The combined organic extracts were dried over anhydrous K ^ O _{4 (solid),} filtered and evaporated under reduced pressure to obtain the title compound (22.0 mg, 90% yield) MS (apci) m / z = 463.2 (M + H).

Example 205.

^) - 4- (6- (4- (2-hydroxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6- (2methoxyethoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile.

To a solution of 6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P54; 20.8 mg, 0, 0550) mmol) in DCM (429 μL) was added sequentially with D (-) - mandelic acid (10 mg, 0.0660 mmol), HATU (25.1 mg, 0.0660 mmol) and DIEA (38.3 μL, 0.220 mmol). After stirring for 16 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ^ (.). The combined organic extracts were dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure to give the title compound (18.6 mg, yield 66%). MS (apci) m / z = 513.2 (M + H).

1H NMR (400 MHz, DMSOL6) δ: 8.69-8.68 (d, 1H), 8.56 (s, 1H), 8.32-8.31 (d, 1H), 7.78-7 , 76 (dd, 1H), 7.41-7.27 (m, 6H), 6.92-6.90 (d, 1H), 5.74-5.72 (d, 1H), 5.48 -5.46 (d, 1H), 4.42-4.22 (m, 2H), 3.70-3.68 (m, 2H), 3.65-3.20 (m, 11H).

- 244 035568

Example 206.

^) - 4- (6- (4- (2-hydroxy-3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2methoxyethoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile.

The title compound (21.1 mg, 81% yield) was prepared and purified using a procedure similar to Example 205, replacing D - (-) - mandelic acid with ^) - 2-hydroxy-3methylbutanoic acid. MS (apci) m / z = 479.2 (M + H).

Example 207.

No. \

II / ° ^ ο ^ζ Αγ + _N

AxAds about

^) - 4- (6- (4- (2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6- (2methoxyethoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile.

To a solution of 6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile dihydrochloride (example 203; 9.7 mg, 0.021 mmol) in DCM (300 μL) was sequentially added with ^) - 2-methoxy-2-phenylacetic acid (5.4 mg, 0.032 mmol), DIEA (15 μL, 0.086 mmol) and HATU (12 mg, 0.032 mmol). After stirring for 17 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (10-100% acetone / hexane isomer mixture as eluent gradient) to give the crude title compound (15 mg). This compound was purified by C18 reverse phase chromatography (5-95% water-ACN as gradient eluent) to afford the purified title compound (7.0 mg, 62% yield). MS (apci) m / z = 527.2 (M + H).

Example 208.

4- (5- (3-cyano-6- (2-methoxyethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -Nisobutylpiperazine-1-carboxylate.

Into a solution of 6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P54; 24.7 mg, 0, 0653) mmol) in DMA (1.3 ml) were added sequentially DIEA (114 μl, 0.653 mmol) and 4-nitrophenyl chloroformate (15.8 mg, 0.0783 mmol). After stirring the mixture for 1 h at ambient temperature, isobutylamine (32.4 μl, 0.326 mmol) was added. The resulting mixture was stirred for 16 h at 80 ° C. After cooling to ambient temperature, the resulting mixture was diluted with EtOAc and washed sequentially with water and saturated aqueous sodium chloride solution. The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was partitioned between 4: 1 DCM: iso-PrOH and saturated Nal 1CX) _{3 (1! Od1M} . The resulting organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (10, 2 mg, 33% yield). MS (apci) m / z = 478.3 (M + H).

Example 209.

- 245 035568

2,2,2-trifluoroacetate 4- (6- (4- (2-isopropoxyethyl) piperazin-1-yl) pyridin-3-yl) -6- (2methoxyethoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile.

In a solution of 6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P54; 15 mg, 0.0396) mmol) in DMF (400 μl) was added sequentially DIEA (27.7 μl, 0.159 mmol) and 2- (2-bromoethoxy) propane (20 μl, 0.119 mmol), and stirred for 3 days at 50 ° C. After cooling to ambient temperature, the reaction mixture was filtered, washed with ACN (0.6 ml) before purification by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent) to give the title compounds as a TFA salt (16.4 mg, 89% yield). MS (apci) m / z = 465.2 (M + H).

Example 210.

6- (2-methoxyethoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine 3-carbonitrile ...

In a solution of (6- (2-methoxyethoxy) -4- (6- (piperαzin-1-yl) pyridin-3-yl) pyrαzolo [1,5-α] pyridine-3carbonitrile (intermediate P54; 14.3 mg, 0 , 0378 mmol) in DCE (400 μl), 6methoxynicotinaldehyde (10.4 mg, 0.0756 mmol) and NaBH (AcO) ₃ (24 mg, 0.113 mmol) were added sequentially and then stirred overnight at ambient temperature. diluted with water (5 ml) and extracted with DCM The combined organic extracts were dried over anhydrous MgSO ^), filtered and evaporated under reduced pressure. The crude product was purified directly by silica gel chromatography (0-100% acetone / hexane isomer mixture as gradient eluent) to afford the purified title compound (15.6 mg, 83% yield). MS (apci) m / z = 500.2 (M + H).

¹ H NMR (400 MHz, CDCl3) δ: 8.31 (d, 1H), 8.19 (s, 1H), 8.15 (d, 1H), 8.08 (d, 1H), 7.70 (dd, 1H), 7.62 (br d, 1H), 7.15 (d, 1H), 6.75 (m, 2H), 4.18 (m, 2H), 3.95 (s, 3H), 3.80 (m, 2H), 3.65 (m, 4H), 3.50 (br s, 2H), 3.47 (s, 3H), 2.56 (m, 4H).

Example 211.

6- (2-methoxyethoxy) -4- (6- (4- (pyrimidin-2-yl-methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

The title compound was prepared and purified using a procedure similar to that described in Example 210, substituting pyrimidine-2-carbaldehyde for 6-methoxy-nicotinaldehyde using saturated NaHCOyj ^.) Instead of water during work-up and 25-100% acetone / hexane isomer mixture as a gradient eluent for purification to provide the purified title compound (16.6 mg, 89% yield). MS (apci) m / z = 471.2 (M + H).

Example 212.

2,2,2-trifluoroacetate 6- (2-methoxyethoxy) -4- (6- (4 - ((tetrahydro-2H-pyran-4-yl) methyl) piperazin-1yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile The title compound was prepared and purified using a procedure similar to Example 210, substituting tetrahydro-2H-pyran-4-carbaldehyde for 6methoxynicotinaldehyde using 1M Na (Oy (^^) instead of water during work-up and purified by C18 reverse phase chromatography with 5-95% ACN / water with 0.1% TFA gradient eluent to afford the purified title compound as 2,2,2-trifluoroacetate salt (17 , 9 mg, yield 89%). MS (apci) m / z = 477.2 (M + H).

- 246 035568

Example 213.

6- (2-methoxyethoxy) -4- (6- (4 - ((6-methoxypyridin-2-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine 3-carbonitrile ...

To a solution of (6- (2-methoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5а] pyridine-3-carbonitrile dihydrochloride (example 203; 9.8 mg) 0.0217 mmol) in DCE (300 μl) was added sequentially 6-methoxypicolinaldehyde (5.22 μl, 0.434 mmol) and NaBH (AcO) ₃ (13.8 mg, 0.0651 mmol), and then stirred for 16 h at ambient temperature. The mixture was quenched with MeOH (0.5 ml) and purified directly by silica gel chromatography (10-100% acetone / hexane isomer mixture as eluent gradient) to afford the purified title compound (10.2 mg, 94% yield). MS (apci) m / z = 500.3 (M + H).

Compounds in the table. S was prepared using a method similar to that described for the synthesis of Example 213, replacing 6-methoxypicolinaldehyde with the appropriate aldehyde. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds.

Table S

No. Prime Ra Structure Chemical name MS (apci) Ill / z 214 N = \, νΑ ^ ν η ί I 6- (2-methoxyethoxy) -4 (6- (4- (pyridin-2ylmethyl) piperazin-1 yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 470.2 (M + H)

- 247 035568

215 N = \ Ω I xX XX 6- (2-methoxyethoxy) -4 (6- (4- (pyridin-3ylmethyl) piperazin-1 yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 470.2 (M + H) 216 N = \ n 1 J οχ + 4- (6- (4 - ((5- fluoropyridin-2yl) methyl) piperazin1 -yl) pyridin-3 -yl) -6 (2- methoxyethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile 488.2 (M + H). 217 N = \ χΝ ^ Λ ~ ^ Ν ^ν ΌΧΓ 4- (6- (4 - ((5chloropyridin-2yl) methyl) piperazine- 1 -yl) pyridin-3-yl) -6 (2- methoxyethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile 504.2 (M + H). 218 Ν = \, ΝχΑχ _Ν Ο f I χχ Γ ^γα </ Νγ> χ ^ Ν 4- (6- (4 - ((6chloropyridin-3yl) methyl) piperazine- 1 -yl) pyridin-3-yl) -6 (2- methoxyethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile 504.2 (M + H). 219 Ν = \ χΝ ^ Α ^ Ν Ο ί X ^ Ό-ΧΤ 6- (2-methoxyethoxy) -4 (6- (4 - ((6- methylpyridin-3yl) methyl) piperazine- 1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 484.2 (M + H)

- 248 035568

220 N = \ n 1I r ^ N 6- (2-methoxyethoxy) -4 (6- (4 - ((2- methylpyridin-4yl) methyl) piperazine- 1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 484.3 (M + H). 221 N = \ n / - $ _n n 1 X + Ж 6- (2-methoxyethoxy) -4 (6- (4 - ((5- methoxypyridin-2yl) methyl) piperazin1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 500.2 (M + H). 222 \ about about 3¾ Q / ABOUT 6- (2-methoxyethoxy) -4 (6- (4 - ((5- methylpyridin-2yl) methyl) piperazine- 1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 484.3 (M + H). 223 \ about five 0 ί 0ns / 6- (2-methoxyethoxy) -4 (6- (4 - ((4- methoxypyridin-2yl) methyl) piperazin1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 500.2 (M + H). 224 3/0 £ 0 b o \ 6- (2-methoxyethoxy) -4 (6- (4 - ((5- methoxypyridin-3yl) methyl) piperazin1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 500.2 (M + H).

- 249 035568

225 " / 0 b about \ 4- (6- (4 - ((5- fluoropyridine-3yl) methyl) piperazine- 1 -yl) pyridin-3-yl) -6 (2- methoxyethoxy) pyrazol o [1,5-a] pyridine-3 carbonitrile 488.2 (M + H). 226 No. \ About 1I Cl AND 4- (6- (4 - ((5- chloropyridin-3yl) methyl) piperazine- 1 -yl) pyridin-3-yl) -6 (2- methoxyethoxy) pyrazol o [1,5-a] pyridine-3 carbonitrile 504.2 (M + H). 227 4 about j a about about \ 6- (2-methoxyethoxy) -4 (6- (4 - ((6methylpyridin-2yl) methyl) piperazin1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 484.3 (M + H). 228 r = Z. ABOUT / 0 b about \ 6- (2-methoxyethoxy) -4 (6- (4 - ((5- methylpyridin-3yl) methyl) piperazin1-yl) pyridin-3 yl) pyrazolo [1,5а] pyridine-3carbonitrile 484.2 (M + H) 229 A o t A 44 o o \ 4- (6- (4 - ((2,6dimethylpyridin-4yl) methyl) piperazine- 1 -yl) pyridin-3-yl) -6 (2- methoxyethoxy) pyrazol o [1,5-a] pyridine-3 carbonitrile 498.3 (M + H).

Example 230.

.. η -, Y -1 -. TFK

Y '°' ΊΓ1 'γ'Ί _: к ν ... .ο.;., J Τ

2,2,2-trifluoroacetate tert-butyl 4- (5- (3-cyano-6- (2-isopropoxyethoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ...

In a solution of tert-butyl 4- (5- (3-cyano-6-hydroxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (intermediate P3; 200 mg, 0.476 mmol) in DMF (5 ml), K ^ Oz ^ c) (131 mg, 0.951 mmol) and 2- (2-bromoethoxy) propane (16 μL, 0.951 mmol) were added successively. The resulting mixture was stirred for 17 h at 50 ° C. After cooling to ambient temperature, the reaction mixture was filtered through an Acrodisc® syringe filter, rinsing with ACN. The filtrate was purified directly by C18 reverse phase chromatography (5-95 ACN / water with 0.1% TFA as gradient eluent) to afford the title compound as 2,2,2 trifluoroacetate salt (75.5 mg, 26% yield ). MS (apci) m / z = 507.2 (M + H).

Example 231.

6- (2-isopropoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile dihydrochloride.

In a solution of 2, 2,2-trifluoroacetate tert-butyl-4- (5- (3-cyano-6- (2-isopropoxyethoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine- 1-carboxylate (example 230; 74 mg, 0.119 mmol) in DCM (2 ml)

- 250 035568 was added 5-6 M HCl in iso-PrOH (4 ml, 20.0 mmol) and stirred for 1 h at ambient temperature. The mixture was evaporated under reduced pressure with Et ₂ O (3x5 ml) to give the purified title compound as the dihydrochloride salt (54.7 mg, 96% yield). MS (apci) m / z = 407.2 (M + H).

Example 232.

6- (2-isopropoxyethoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1 _5-a] i pyridine 3-carbonitrile.

To a solution of 6- (2-isopropoxyethoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 231; 11.5 mg, 0 , 0240 mmol) in DCE (400 μl) was added sequentially 6-methoxy-nicotinaldehyde (6.58 mg, 0.0480 mmol) and NaBH (AcO) ₃ (15.3 mg, 0.0720 mmol). After stirring for 24 h at ambient temperature, 6-methoxy-nicotinaldehyde (5 mg) and NaBH (AcO) ₃ (10 mg) were added. The mixture was stirred for 39 hours at ambient temperature, then diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous MgSO ^), filtered and evaporated under reduced pressure. The crude product was purified directly by silica gel chromatography (25-100% acetone / hexane isomer mixture as eluent gradient) to afford the purified title compound (9.6 mg, 76% yield). MS (apci) m / z = 528.2 (M + H).

Example 233.

6- (2-isopropoxyethoxy) -4- (6- (4- (pyrimidin-2-yl-methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound was prepared and purified using a procedure similar to that described in Example 232 substituting pyrimidine-2-carbaldehyde for 6-methoxy-nicotinaldehyde, using saturated NaHCO ₃ ( _aq ) instead of water during work-up, and 25-100% acetone. a mixture of hexane isomers as eluent gradient for purification to provide the purified title compound (11.8 mg, 76% yield). MS (apci) m / z = 499.2 (M + H).

Example 234.

6- (2-isopropoxyethoxy) -4- (6- (4 - ((tetrahydro-2H-pyran-4-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine- 3-carbonitrile.

The title compound was prepared and purified using a procedure similar to that described in Example 232, substituting tetrahydro-2H-pyran-4-carbaldehyde for 6-methoxy-nicotinaldehyde using saturated NaHCO (^ () instead of water during work-up and 25-100% acetone / a mixture of hexane isomers as eluent gradient for purification to give the purified title compound (11.8 mg, 75% yield). MS (apci) m / z = 505.2 (M + H).

Example 235.

tert-Butyl (R) -4- (5- (3-cyano-6- (2-methoxypropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate.

Into a cold (0 ° C) solution of tert-butyl ^) - 4- (5- (3-cyano-6- (2-hydroxypropoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) piperazine -1-carboxylate (example 116; 120 mg, 0.251 mmol) in DMF (2.5 ml) was added NaH ( _ra ) (18.1 mg, 0.752 mmol) and stirred for 25 min at 0 ° C before addition

- 251 035568 em iodomethane (47.04 μl, 0.752 mmol). The reaction mixture was stirred for 90 minutes at ambient temperature. The resulting mixture was quenched by the addition of MeOH (0.5 ml) and then purified directly by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to afford the purified title compound (102.2 mg, yield 83 %). MS (apci) m / z = 493.3 (M + H).

Example 236.

^) - 6- (2-methoxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridin-3-carbonitrile dihydrochloride.

In a solution of tert-butyl (R) -4- (5- (3-cyano-6- (2-methoxypropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ( example 235; 74 mg, 0.119 mmol) in DCM (2 ml) was added 56 M HCl in iso-PrOH (4 ml, 20.0 mmol) and stirred for 2 h at ambient temperature. The suspension was evaporated under reduced pressure to give the purified title compound as the dihydrochloride salt (86.7 mg, 91% yield). MS (apci) m / z = 393.2 (M + H).

Example 237.

N = \ ο

4- (6- (4 - ((R) -2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6 - (^) - 2 methoxypropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile.

In a solution of dihydrochloride ^) - 6- (2-methoxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 236); 10.0 mg, 0.0215 mmol) in DCM (300 μl) were sequentially added (^) - 2-methoxy-2-phenylacetic acid (5.36 mg, 0.0322 mmol), DIEA (15 μl, 0.086 mmol) and HATU (12.3 mg, 0.0322 mmol). After stirring for 17 h at ambient temperature, the reaction mixture was purified directly by silica gel chromatography (10-100% acetone / hexane isomer mixture as eluent gradient) to give the purified title compound (10.4 mg, 90% yield) ... MS (apci) m / z = 541.2 (M + H).

Example 238.

^) - 6- (2-methoxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

In a solution of dihydrochloride (^) - 6- (2-methoxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 236; 9.4 mg, 0.020 mmol) in DCE (300 μl) was added sequentially 6-methoxynicotinaldehyde (5.5 mg, 0.040 mmol) and NaBH (AcO) ₃ (13 mg, 0.061 mmol), and then stirred for 16 h at ambient temperature ... MeOH (500 μl) was added to the mixture and purified directly by silica gel chromatography (10-100% acetone / hexane isomer mixture as eluent gradient) to afford the purified title compound (9.3 mg, 90% yield). MS (apci) m / z = 514.3 (M + H).

Compounds in the table. T was obtained using a method similar to that described for the synthesis of Example 238, replacing 6-methoxy-nicotinaldehyde with the appropriate aldehyde. The completion of the reactions was monitored by LCMS and the reaction times were adjusted accordingly. Chromatographic purification using an appropriate gradient eluent provided the title compounds.

- 252 035568

Table T

No. Prime Ra Structure Chemical name MS (apci) ιη / ζ 239 / Pts, Ν = \ Ax / lX I ~ ^ N W (R) -4- (6- (4 - ((5chloropyridin-2yl) methyl) piperaz in -1-yl) pyridin3-yl) -6- (2methoxypropoxy) pyrazolo [1,5а] pyridine-3carbonitrile 518.2 (M + H) 240 Ν = \ Sc 1 (R) -6- (2methoxypropoxy) -4- (6- (4 - ((5- methoxypyridine 2- yl) methyl) piperaz in-1 -yl) pyridine3- yl) pyrazolo [1,5а] pyridine-3carbonitrile 514.2 (M + H) 241 '(U Ν = \ Q ι Yulu (R) -6- (2methoxypropoxy) -4- (6- (4 - ((5methylpyridin-2yl) methyl) piperaz in-1-yl) pyridin3yl) pyrazolo [1,5а] pyridine-3carbonitrile 498.2 (M + H)

Example 242.

4- (6- (4 - (^) - 2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3-yl) -6 - (^) - 2methoxypropoxy) pyrazolo [1,5-a] pyridine -3-carbonitrile.

In a solution of dihydrochloride (^) - 6- (2-methoxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P56; 10.4 mg, 0.0223 mmol) in DCM (300 μl) was successively added (^) - 2-methoxy-2-phenylacetic acid (5.57 mg, 0.0335 mmol), DIEA (15.6 μl, 0.0894 mmol) and HATU (12.7 mg 0.0335 mmol). After stirring for 17 hours at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (10-100% acetone / hexane isomer mixture as eluent gradient) to give the crude title compound. The crude compound was subjected to repeated C18 reverse phase chromatography (5-95% ACN / water as gradient eluent) to afford the purified title compound (1.6 mg, 13% yield). MS (apci) m / z = 541.3 (M + H).

Example 243.

^) - 6- (2-methoxypropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine -3-carbonitrile.

Into a solution of dihydrochloride (^) - 6- (2-methoxypropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P56; 21 mg, 0.036 mmol) in DCE (400 μl) was added sequentially 6-methoxy-nicotinaldehyde (9.9 mg, 0.072 mmol) and NaBH (AcO) ₃ (23 mg, 0.11 mmol), and then stirred for 18 h at ambient temperature ... The mixture was purified directly by chromatography on silica gel (0-100% acetone / mixture of hexane isomers in ca

- 253 035568 as gradient eluent) to afford the purified title compound (8.5 mg, 46% yield). MS (apci) m / z = 514.2 (M + h).

Example 244.

^) - 6- (2-methoxypropoxy) -4- (6- (4- (pyridin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

The title compound was prepared and purified using a procedure similar to that described in Example 243 substituting picolinaldehyde for 6-methoxy-nicotinaldehyde to give the purified title compound (8.2 mg, 47% yield). MS (apci) m / z = 484.2 (M + H).

Example 245.

tert-butyl 4- (5- (3-cyano-6- (2-methoxy-2-methylpropoxy) pyrαzolo [1.5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate.

Into a cold (0 ° C) solution of tert-butyl-4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl ) piperazine-1-carboxylate (example 152; 68 mg, 0.138 mmol) in DMF (1.4 ml) was added NaH ^) (9.94 mg, 0.414 mmol) and stirred for 25 min at 0 ° C before adding iodomethane (25.9 μl, 0.414 mmol). The reaction mixture was stirred for 90 minutes at ambient temperature. The resulting mixture was added with MeOH (500 μL) and then purified directly by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to afford the purified title compound (52.5 mg, 75% yield) ... MS (apci) m / z = 507.3 (M + H).

Example 246.

6- (2-Methoxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile dihydrochloride.

In a solution of tert-butyl 4- (5- (3-cyano-6- (2-methoxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazine-1-carboxylate ( example 245; 67 mg, 0.132 mmol) in DCM (2 ml) was added 56 M HCl in iso-PrOH (4 ml, 20.0 mmol) and stirred for 2 h at ambient temperature. The solution was evaporated under reduced pressure to give the purified title compound as the dihydrochloride salt (63.5 mg, quantitative yield). MS (apci) m / z = 407.2 (M + H).

Example 247.

^) - 6- (2-methoxy-2-methylpropoxy) -4- (6- (4- (2-methoxy-2-phenylacetyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a suspension of 6- (2-methoxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 246; 10, 4 mg, 0.0217 mmol) in DCM (300 μl) was sequentially added (^) - 2-methoxy-2-phenylacetic acid (5.41 mg, 0.0325 mmol), DIEA (15.1 μl, 0.0868 mmol ) and HATU (12.4 mg, 0.0325 mmol). After stirring for 17 h at ambient temperature, the reaction mixture was purified directly by chromatography on sily

254,035,568 cagel (0-100% acetone / hexane isomer mixture as gradient eluent) to afford the purified title compound (11.9 mg, 99% yield). MS (apci) m / z = 555.3 (M + H).

Example 248.

2,2,2-trifluoroacetate 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -No phenyl- 3,6-diazabicyclo [3.1.1] heptane-6-carboxamide.

To a suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride Β-3-carbonitrile (intermediate P43, 0.030 g, 0.063 mmol) in DMA (0.75 ml) was added triethylamine (0.044 ml, 0.31 mmol) followed by isocyanatobenzene (9 mg, 0.075 mmol) at ambient temperature. After stirring overnight, the reaction mixture was partitioned between DCM and water. After phase separation, the aqueous layer was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The crude compound was purified using Gilson Prep HPLC (5-95% ACN / water with 0.1% TFA) to afford the title compound as a white solid (0.019 g, 48.0% yield).

¹ H NMR (CDCl ₃ ) δ 8.41 (m, 1H), 8.20-8.22 (m, 2H), 8.00-8.03 (m, 1H), 7.39-7.43 (m, 2H), 7.18-7.22 (m, 3H) 6.99-7.03 (m, 2H), 4.56 (m, 2H), 4.39-4.42 (m, 2H), 3.86 (s, 2H), 3.69-3.75 (m, 2H), 2.80-2.84 (m, 1H), 1.601.62 (m, 1H), 1.38 (s, 6H). MS (apci) m / z = 524.2 (M + H).

Example 249.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (quinolin-6-ylmethyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazole [ 1,5-a] pyridine-3-carbonitrile.

To a suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43, 25 mg, 0.0524 mmol) in 1,2-dichloroethane (0.3 ml) was added quinoline-6-carbaldehyde (8.23 mg, 0.0524 mmol), followed by sodium triacetoxyhydroborate (33.3 mg, 0.157 mmol) at ambient temperature. After 4 h stirring, the reaction mixture was purified by silica gel chromatography (using 0-100% DCM in hexane isomers followed by 0-100% [20% MeOH with 2% NH4OH] in DCM as gradient eluent) to give the title compound (14.8 mg, 51.8% yield).

1H NMR (CD3OD) δ 8.76 (m, 1H), 8.33 (m, 1H), 8.27 (d, 1H), 8.22-8.25 (m, 2H), 7.96- 7.99 (d, 1H), 7.82 (m, 1H), 7.75-7.80 (m, 2H), 7.43-7.47 (m, 4H), 7.24 (d, 1H), 6.77-6.80 (d, 1H), 3.83-3.92 (m, 8H), 3.59-3.64 (d, 2H), 2.71-2.78 ( m, 1H), 1.69-1.72 (d, 1H), 1.33 (s, 6H). MS (apci) m / z = 546.3 (M + H).

Example 250.

4- (6- (6- (5-fluoro-6-methoxy-nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43, 25 mg, 0.05237 mmol) in DCM (1 ml) was added 5-fluoro-6-methoxy-nicotinic acid (11.7 mg, 0.069 mmol), HATU (23.9 mg, 0.063 mmol ) and DIEA (36 μL, 0.21 mmol) at ambient temperature. After stirring for two hours, the reaction mixture was evaporated under reduced pressure and purified using silica gel chromatography (0-20% EtOAc / MeOH as gradient eluent) to give the title compound (15.4 mg, 52.8% yield).

1H NMR (CD3OD) δ 8.39-8.41 (d, 1H), 8.28-8.30 (m, 2H), 8.25-8.27 (d, 1H), 7.71-7 , 77 (m, 2H), 7.25-7.27 (d, 1H), 6.73-6.76 (d, 1H), 4.86-4.95 (m br, 1H), 4 , 66-4.75 (m br, 1H), 4.18-4.29 (m br, 1H), 3.60-3.77 (m, 3H), 2.91-2.99 ( m, 1H), 1.73-1.79 (d, 1H), 1.32 (s, 6H). MS (apci) m / z = 558.2 (M + H).

- 255 035568

Example 251.

4- (6- (6- (sec-butylsulfonyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1, 5-a] pyridine-3-carbonitrile.

To a suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43, 0.0278 g, 0.0582 mmol) in DCM (1.0 ml), triethylamine (0.032 ml, 0.233 mmol) was added, followed by sec-butylsulfonyl chloride (10.0 mg, 0.064 mmol) at a temperature environment. After stirring for 1 hour, additional triethylamine (15.8 μl, 0.116 mmol) and sec-butylsulfonyl chloride (20.0 mg, 0.128 mmol) were added to the reaction mixture and stirred at ambient temperature for an additional 17 hours. stirring overnight, the reaction mixture was evaporated under reduced pressure and purified using Gilson preparative HPLC (5-95% water / ACN with 0.1% TFA as gradient eluent). The desired fractions were then pooled and partitioned between 4: 1 DCM: 1PA and saturated aqueous NaHCO ₃ . The organic extracts were combined and dried over sodium sulfate, filtered and evaporated to give the title compound as a white solid (7.5 mg, 23.3% yield). MS (apci) m / z = 525.2 (M + H).

Example 252.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (6-methoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3 -car bonitrile.

To a suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43, 0.6 g, 1.26 mmol) in DCM (25 ml) was added 2-methoxy-5-pyridinecarboxylic acid (0.231 g, 1.51 mmol), HATU (0.573 g, 1, 51 mmol) and DIEA (0.876 ml, 5.03 mmol). The reaction mixture was stirred at ambient temperature overnight and then additional DIEA (0.220 ml, 1.26 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between DCM (40 ml) and saturated aqueous ammonium chloride (40 ml). The aqueous layer was extracted with DCM (3x25 ml). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The crude compound was purified using silica gel chromatography (using 0-10% EtOAc / MeOH as eluent gradient). The isolated product was dissolved in DCM (10 ml), added with activated carbon, filtered through Celite® and washed with DCM. The filtrate was evaporated under reduced pressure to give the title product. (470 mg, 69.3% yield).

1H NMR (DMSOH) δ 8.60-8.65 (d, 1H), 8.53 (s, 1H), 8.49-8.51 (m, 1H), 8.28-8.31 (d , 1H), 7.91-7.95 (m, 1H), 7.73-7.78 (m, 1H), 7.23-7.25 (m, 1H), 6.81-6.85 (m, 1H), 6.65-6.69 (d, 1H), 4.84-4.94. (m br, 1H), 4.66 (s, 1H), 4.51-4.63 (m br, 1H), 4.04-4.20 (m br, 1H), 3.88 (s, 3H), 3.83 (s, 2H) 3.60-3.63 (m, 2H), 3.42-3.53 (m br, 1H), 2.75-2.85 ( m, 1H), 1.63-1.69 (m, 1H), 1.18 (s, 6H). MS (apci) m / z = 540.2 (M + H). Example 253.

4- (6- (4 - ^ - leucyl) piperazin-1-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl (R) - (1- (4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) piperazin-1-yl ) -4-methyl-1-oxopentan-2-yl) carbamate. In a solution of bis- (2,2,2trifluoroacetate) 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile

- 256 035568 (intermediate P74; 64 mg, 0.184 mmol) in DMF (4 ml) was successively added HATU (138 mg, 0.36 mmol), (tert-butoxycarbonyl) -O-leucine (42.5 mg, 0.184 mmol) and DIEA (192 μL, 1.10 mmol), The reaction mixture was stirred overnight at ambient temperature and then directly purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO _{3 was} added and extracted with 20% IPA in DCM. The organics were dried over MgSO ₄ , filtered and evaporated to give the purified title compound (39 mg, 38% yield). MS (apci) m / z = 562.3 (M + H).

Stage 2: Preparation of 4- (6- (4 - ^ - leucyl) piperazin-1-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5a] pyridine-3-carbonitrile. In a solution of tert-butyl (R) - (1- (4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin4-yl) pyridin-2-yl) piperazin-1-yl) - 4-methyl-1-oxopentan-2-yl) carbamate (step 1; 39 mg, 0.069 mmol) in DCM (4 ml), TPA (2 ml) was added and stirred for 30 min at ambient temperature, then evaporated at reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO _{3 was} added and extracted with 20% IPA in DCM. The organic layer was dried over MgSO ₄ , filtered and evaporated to give the purified title compound. (25 mg, 78% yield). MS (apci) m / z = 462.3 (M + H).

Example 254.

^) - 4- (6- (4- (2-amino-2- (3-chlorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5a] pyridin-3- carbonitrile.

Stage 1: preparation of tert-butyl ^) - (1- (3-chlorophenyl) -2- (4- (5- (3-cyano-6-ethoxypyrazolo [1,5a] pyridin-4-yl)) pyridin-2 -yl) piperazin-1-yl) -2-oxoethyl) carbamate. Into a solution of 6-ethoxy-4- (6 (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P73; 261.9 mg, 0.7517 mmol) in DMF (7.5 ml) was added 2 ^) - 2 - ((tert-butoxycarbonyl) amino) -2- (3chlorophenyl) acetic acid (429.6 mg, 1.503 mmol) and HATU (571.6 mg, 1.503 mmol ), then stirred for 2 h at ambient temperature. The resulting mixture was diluted with EtOAc, then extracted with water (3x) and saturated aqueous sodium chloride solution (1x). The organic extracts were dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure to give the title compound, which was used directly in Step 2 without further purification (estimated quantitative yield). MS (apci) m / z = 616.3 (M + H).

Stage 2: preparation of ^) - 4- (6- (4- (2-amino-2- (3-chlorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile. Crude tert-butyl ^) - (1- (3-chlorophenyl) -2- (4- (5- (3cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) piperazine -1-yl) -2-oxoethyl) carbamate (step 1; 0.7517 mmol) was dissolved in 1: 1 DCM: TPA (7.5 ml), stirred for 30 min at ambient temperature, and then evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-90% water-ACN with 0.1% TFA as gradient eluent). The fractions containing the desired compound was diluted with 4: 1 DCM: i-PrOH and extracted with saturated NaHCO ^^ y Organic extracts were dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure.. The residue required further purification by silica gel chromatography (using 1-30% DCM-MeOH with 2% NH4OH as gradient eluent) to afford the purified title compound (110.4 mg, 28% yield). MS (apci) m / z = 516.2 (M + H).

Example 255.

4- (6- (4- (2-amino-2- (4-fluorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl (2- (4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazin-1-yl) -1- (4-fluorophenyl) -2-oxoethyl) carbamate. Into a mixture of 6-ethoxy-4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P73; 53 mg, 0.15 mmol), (R ) -N

- 257 035568

H) -2 - ((tert-butoxycarbonyl) amino) -2- (4-fluorophenyl) acetic acid (41 mg, 0.15 mmol) and HATU (174 mg, 0.46 mmol) in DCM (761 μL) were added DIEA (106 μl, 0.61 mmol). The reaction mixture was stirred overnight at ambient temperature and then filtered. The filtrate was evaporated under reduced pressure and purified by silica gel chromatography (using 0-10% DCM / MeOH as gradient eluent) to give the title compound (racemization occurred under these conditions) (87 mg, 95% yield). MS (apci) m / z = 500.2 (M + H).

Stage 2: preparation of 4- (6- (4- (2-amino-2- (4-fluorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridin-3 -carbonitrile. In a solution of tert-butyl (2- (4- (5- (3-cyano-6ethoxypyrazolo [1,5-a] pyridin-4-yl) pyrigin-2-yl) piperazin-1-yl) -1- (4 -fluorophenyl) -2oxoethyl) carbamate (step 1; 87 mg, 0.15 mmol) in DCM (1.45 ml) was added TFA (112 μl). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-10% CHCl ₃ / MeOH as eluent gradient). Fractions containing the desired compound were combined and evaporated under reduced pressure. The residue was triturated in dichloromethane / hexane isomer mixture, then evaporated under reduced pressure to afford the purified title compound, assuming quantitative yield. MS (apci) m / z = 500.2 (M + H).

Example 256.

4- (6- (4- (3-amino-2- (4-fluorophenyl) propanoyl) piperazin-1-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl (3- (4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazin-1-yl) -2- (4-fluorophenyl) -3-oxopropyl) carbamate. Into a mixture of 6-ethoxy-4- (6- (piperazin-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P73; 42 mg, 0.12 mmol), 3 { [(tert-butoxy) carbonyl] amino} -2- (4-fluorophenyl) propanoic acid (34 mg, 0.12 mmol) and HATU (138 mg, 0.36 mmol) in DCM (603 μl) was added DIEA (42 μL, 0.24 mmol). The reaction mixture was stirred for 1 h at ambient temperature and then directly purified by silica gel chromatography (using 0-10% CHCl ₃ / MeOH with 0-1% NH ₄ OH as gradient eluent). Fractions containing the desired compound were combined, evaporated under reduced pressure, and then triturated with a mixture of hexane isomers to provide the purified title compound (42 mg, 57% yield). MS (apci) m / z = 514.3 (M-Boc).

Stage 2: preparation of 4- (6- (4- (3-amino-2- (4-fluorophenyl) propanoyl) piperazin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridin-3 -carbonitrile. In a solution of tert-butyl (3- (4- (5- (3-cyano-6ethoxypyrazolo [1,5-a] pyridin-4-yl) pyrigin-2-yl) piperazin-1-yl) -2- (4 α-fluorophenyl) -3oxopropyl) carbamate (step 1; 42 mg, 0.068 mmol) in DCM (684 μl) was added TFA (53 μl) and stirred overnight at ambient temperature. The resulting mixture was purified directly by silica gel chromatography (using 0-10% CHCl3 / MeOH with 0-1% NH4OH as gradient eluent). Fractions containing the desired compound were combined, evaporated under reduced pressure, then triturated with a mixture of hexane isomers to provide the purified title compound (35, quantitative yield). MS (apci) m / z = 514.2 (M + H).

Example 257.

tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyrigin-4-yl) pyridin-2yl) -3,6-diazabicyclo [3.1 .1] heptane-6-carboxylate.

A mixture of 4- (6-fluoropyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P42; 1.70 g, 8.55 mmol), 3.6 diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (1.70 g, 8.55 mmol) and K ₂ CO ₃ ( _ra ) (7.88 g, 57.0 mmol) in DMSO (7 ml) was stirred for 12 h at 90 ° C. The resulting thick suspension was diluted with additional DMSO (2 ml) and stirred for 12 h at 90 ° C. The mixture was cooled to ambient temperature and diluted with water (100 ml). The aqueous mixture was washed with DCM.

258,035,568, the extracts were dried over anhydrous MgSO4 ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (30-80% EtOAc / hexane isomer gradient eluent system) to afford the purified title compound (2.87 g, 100% yield). MS (apci) m / z = 505.2 (M + H).

Example 258.

4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy-pyrazolo ^^^ pyridine 3-carbonitrile dihydrochloride.

In a solution of tert-butyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3, 6- diazabicyclo [3.1.1] heptane-6-carboxylate (example 257; 3.05 g, 6.04 mmol) in DCM (20 ml) was added 4N HCl in dioxane (15.1 ml, 60.4 mmol). The resulting mixture was stirred for 12 hours at ambient temperature and then evaporated under reduced pressure. The residue was diluted with DCM and toluene and then sonicated before evaporation under reduced pressure to afford the title compound as the dihydrochloride salt (2.44 g, quantitative yield). MS (apci) m / z = 405.2 (M + H).

Example 259.

4- (6- (6- (2-amino-2- (4-fluorophenyl) acetyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1, 5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl (2- (3- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -3,6-diazabicyclo [3.1. 1] heptan-6-yl) -1- (4-fluorophenyl) -2-oxoethyl) carbamate.

In a mixture of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine3-carbonitrile (intermediate P75; 30 mg , 0.083 mmol), ^) - 2 - ((tert-butoxycarbonyl) amino) -2- (4fluorophenyl) acetic acid (22 mg, 0.083 mmol) and HATU (95 mg, 0.25 mmol) in DCM (416 μl) DIEA (58 μl, 0.33 mmol) was added and stirred for 1 h at ambient temperature. The reaction mixture was evaporated under reduced pressure, diluted with water and filtered under vacuum. The collected solids were dissolved in DCM, dried over anhydrous Na ^ Oy ^, filtered and evaporated under reduced pressure to give the purified title compound (racemization occurred under these conditions) (15 mg, 29% yield). MS (apci) m / z = 512.2 (M + H).

Stage 2: preparation of 4- (6- (6- (2-amino-2- (4-fluorophenyl) acetyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6- ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl (2- (3- (5- (3cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1] .1 ] heptan-6-yl) -1- (4fluorophenyl) -2-oxoethyl) carbamate (step 1; 15 mg, 0.025 mmol) in DCM (245 μl) TPA (19 μl) was added and stirred overnight at ambient temperature ... The resulting mixture was purified directly by silica gel chromatography (using 0-10% CHCl ₃ / MeOH with 0-1% NH ₄ OH as gradient eluent). Fractions containing the desired compound were combined and evaporated under reduced pressure. The residue was triturated with DCM / hexane isomer mixture then evaporated under reduced pressure to give the purified title compound (2 mg, 16% yield). MS (apci) m / z = 512.2 (M + H).

Example 260.

4- (6- (6- (3-amino-2- (4-fluorophenyl) propanoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6ethoxypyrazolo [1, 5-a] pyridine-3-carbonitrile.

The title compound was prepared and purified using an analogous two step procedure as described in Example 259, replacing ^) - 2 - ((tert-butoxycarbonyl) amino) -2- (4

- 259 035568 fluorophenyl) acetic acid for 3 - ((tert-butoxycarbonyl) amino) -2- (4-fluorophenyl) propanoic acid and using a smaller amount of DIEA (2 equiv.) In stage 1. Trituration with a mixture of hexane isomers at the final this step gave the title compound (34 mg, 69% overall yield). MS (apci) m / z = 526.2 (M + H).

Example 261.

^) - 4- (6- (4- (2- (3-chlorophenyl) -2- (dimethylamino) acetyl) piperazin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine- 3-carbonitrile.

Into a mixture ^) - 4- (6- (4- (2-amino-2- (3-chlorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine- 3-carbonitrile (example 254; 56.8 mg, 0.110 mmol) in 1: 1 DCM: MeOH (1.1 ml) formaldehyde (82.7 μl, 1.10 mmol) and NaBH (AcO) ₃ (117 mg, 0.550 mmol). After stirring overnight at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent). The fractions containing the desired compound were combined and extracted with 4: 1 DCM:. I-PrOH and saturated NaHCO ^ B ^) · The organic extracts were dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure to afford purified compound indicated in the title (47.8 mg, yield 80%). MS (apci) m / z = 544.3 (M + H).

Compounds in the table. U was obtained using a method similar to that described for the synthesis of example 261, with the substitution of ^) - 4- (6- (4- (2-amino-2- (3-chlorophenyl) acetyl) piperazin-1-yl) pyridin-3- yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile with the corresponding amine of the example given in the table. Completion of reactions was monitored by LCMS and reaction times (and the need for additional reagents) were adjusted accordingly. The title compounds were isolated after chromatographic purification using an appropriate gradient eluent. Where marked (*) - and in the event that the TPA salt of the title compound was not isolated by chromatographic purification, no secondary main treatment after the chromatographic purification used in Example 261 was performed.

Table U

No. Example Amine used Structure Chemical name MS (apci) m / z 262 Etc. 255 LL + about what about ( 4- (6- (4- (2 (dimethylamine 0) -2- (4fluorophenyl) acetyl) piperazin-1 yl) pyridin-3yl) -6ethoxypyrazole o [1,5а] pyridine-3 carbonitrile 528.30 (M + H)

- 260 035568

ethoxypyrazole ethoxypyrazole ethoxypyrazole ethoxypyrazole

542.30

M + H a | pyridine-3carbonitrile

490.30 (M + H) a1pyridine-3carbonitrile

4- (6- (6- (3 (dimethylamine

0-2-4fluorophenyl) propanoyl) a1pyridine-3carbonitrile

4- (6- (6- (2 (dimethylamine

0-2-4 fluorophenyl) acetyl) -3.6 diazabicyclo

3.1.11heptane-3yl) pyridine-34- (6- (4- (3 (dimethylamine

0-2-4 fluorophenyl) propanoyl-perazin-1yl) pyridine-3a] pyridine-3carbonitrile

4- (6- (4 (dimethyl-Dleicil) pipera zine-1yl) πyridine-3diazabicyclo [

3.1.1 | heptane-3ylcyridine-3 * Purification was performed using C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA) followed by secondary chromatography on silica gel (2-5% MeOH in DCM).

Example 267.

about

6-ethoxy-4- (6- (6- (6-hydroxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3- carbonitrile.

In a pressure vessel, a mixture of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P6; 0.266 g, 0.941 mmol), bis- (2.2.2 -trifluoroacetate) (3.6 diazabicyclo [3.1.1] heptan-6-yl) (6-hydroxypyridin-3-yl) methanone (intermediate R; 0.172 g) 0.385 mmol) and TEA (2.19 ml, 15.7 mmol ) was suspended in DMSO (5 ml). The vessel was sealed, and then the reaction mixture was stirred for 2 h at 90 ° C. Added additional amount of TEA (2 ml) and the reaction mixture was stirred at 100 ° C for 5 days in a sealed vessel. After cooling to ambient temperature, the resulting mixture was diluted with DCM and quenched with saturated ΝΗ ₄ ^ (^ _η ,). The quenched mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% ACN in

261 035568 water with 0.1% TFA as gradient eluent) and chromatography on silica gel again (using 0-25% ((9: 1 MeOH / NH4OH) in DCM) as gradient eluent) to afford the purified title compound (117 mg, 63% yield). MS (apci) m / z = 482.2 (M + H).

Example 268: 6-ethoxy-4- (6- (6- (6-propoxynicotinoyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrudin-3-yl) pyrazolo [ 1,5-a] pyridine-3-carbonitrile and Example 269: 2,2,2-trifluoroacetate 6-ethoxy-4- (6- (6- (6-oxo-1-propyl-1,6-dihydropyridine-3carbonyl ) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrudin-3-yl) pyrazolo [1,5-a] pyrudine-3-carbonitrile.

_TfK 'y 0t ° L: SG J V .:

Ex. 2 & 9 O

In a solution of 6-ethoxy-4- (6- (6- (6-hydroxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5-a] pyrudine- 3-carbonitrile (example 267; 8 mg, 0.017 mmol) in DMSO (0.4 ml) was added NaH (0.6 mg, 0.025 mmol) and stirred for 20 min at ambient temperature. To the resulting suspension was added 1-iodopropane (17 μl, 0.17 mmol) and stirred overnight at 85 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and quenched with saturated NHAl (^ ().). The biphasic mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to independently provide the tautomeric starting material coupling products of the title compounds. Example 268: 6-ethoxy-4- (6- (6- (6-propoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3yl) pyridin-3-yl) pyrazolo 2,2,2-trifluoroacetate [ 1,5-a] pyridine-3-carbonitrile (1.2 mg, 14% yield). LCMS (apci) Tr = 2.01 min, m / z = 524.2 (M + H).

Example 269.

2,2,2-Trifluoroacetate 6-ethoxy-4- (6- (6- (6-oxo-1-propyl-1,6-dihydropyridine-3-carbonyl) -3,6diazabicyclo [3.1.1] heptane-3 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (4.8 mg, 55% yield). LCMS (apci) Tr = 1.73 min, m / z = 524.2 (M + H).

Example 270.

about

6-ethoxy-4- (6- (6- (6- (2-methoxyethoxy) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3 yl) pyrazolo [1,5- a] pyridine-3-carbonitrile.

In a solution of 6-ethoxy-4- (6- (6- (6-hydroxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5-a] pyrudine- 3-carbonitrile (example 267; 18 mg, 0.037 mmol) in DMSO (0.4 ml) was added NaH (1.8 mg, 0.075 mmol) and stirred for 20 min at ambient temperature. To the resulting suspension was added 1-bromo-2-methoxyethane (40 μl, 0.037 mmol) and stirred overnight at 85 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and quenched with saturated NHAl (^ ().). The biphasic mixture was extracted with DCM (3x). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-30% MeOH / EtOAc as eluent gradient) to afford the purified title compound (2.5 mg, 12% yield). MS (apci) m / z = 540.2 (M + H).

- 262 035568

Example 271.

N = \ X I

6-DTOi <cu-4- (0) -U3S, 5R) -4-U6- \ ieTOi <cuiiupu; iuii-3-u _B i) \ ieTu _B i) -3,5-; iu \ ieTu _B iiiuiiepa3uii -1-u _B i) iiupu; iuii-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A mixture of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 14.6 mg, 0.0518) and bis- (2.2, 2-trifluoroacetate) (2S, 6R) -1 - ((6-methoxypyridin-3-yl) methyl) -2.6 dimethylpiperazine (intermediate R17; 36 mg, 0.078 mmol) and K ₂ CO ₃ ( _TB ) (71.6 mg, 0.518 mmol) in DMSO (104 μl) was stirred overnight at 80 ° C. The reaction mixture was cooled to ambient temperature, then purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as eluent gradient) and chromatography again on silica gel (using 0-20% MeOH in DCM with 2% NH ₄ OH as gradient eluent) to afford the purified title compound (5.45 mg, 21% yield). MS (apci) m / z = 498.3 (M + H).

Example 272.

N = \

NH ₂ I

ABOUT

4- (6- (4 - ^ - leucyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl ^) - (1- (4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy)) pyrazolo [1,5a] pyridin-4-yl) pyridine- 2-yl) piperazin-1-yl) -4-methyl-1-oxopentan-2-yl) carbamate. In a solution of bisTPA-salt of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile (81 mg, 0.206 mmol) in DCM (6 ml) were sequentially added (tert-butoxycarbonyl) D-leucine (47.7 mg, 0.206 mmol), HATU (94.2 mg, 0.248 mmol) and DIEA (216 μl, 1.24 mmol) then stirred for 3 hours at ambient temperature. The resulting mixture was purified directly by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO _{3 was} added and extracted with 20% IPA in DCM. The organics were dried over MgSO ₄ , filtered and evaporated to give the title compound, which was used directly in the next step, assuming quantitative yield. MS (apci) m / z = 606.4 (M + H).

Stage 2: preparation of 4- (6- (4 - ^ - leucyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile. In a solution of tert-butyl ^) - (1- (4- (5- (3-cyano-6- (2hydroxyL-methylpropoxy ^ pyrazole D ^ pyridinL-yl ^ iridinAl-yl ^ iperazinL-yl ^ -methylloxopentan-2-yl) carbamate (step 1, assumed 125 mg, 0.21 mmol) in DCM (4 ml) was added TFA (2 ml) and stirred for 30 min at ambient temperature.After evaporation under reduced pressure, the reaction mixture was purified by reverse phase chromatography C18 (5-95% ACN in water with 0.1% TFA as gradient eluent) Fractions containing the desired product were collected, saturated NaHCO _{3 was} added and extracted with 20% IPA in DCM. The organics were dried over MgSO ₄ , filtered and evaporated to give the purified title compound (34 mg, 33% yield over 2 steps) MS (apci) m / z = 506.3 (M + H).

Example 273.

4- (6- (4- (dimethyl-0-leucyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile ...

Into a mixture of 4- (6- (4 - ^ - leucyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3- carbonitrile (34 mg, 0.067 mmol) and formaldehyde (50.1 μl, 0.672 mmol) in DCM (672 μl) was added NaBH (AcO) ₃ (71.3 mg, 0.336 mmol). After stirring overnight at

- 263 035568 ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO3 was added and extracted with 20% IPA in DCM. The organics were dried over MgSO4, filtered and evaporated to give the purified title compound (31 mg, 86% yield). MS (apci) m / z = 534.3 (M + H).

Example 274.

about

^) - 4- (6- (4- (2- (aminomethyl) -4-methylpentanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5- a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl ^) - (2- (4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy)) pyrazolo [1,5a] pyridin-4-yl) pyridine- 2-yl) piperazine-1-carbonyl) -4-methylpentyl) carbamate. In a solution of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile hydrochloride (intermediate P39; 52 mg , 0.112 mmol) in DMF (4 ml), HATU (51.0 mg, 0.151 mmol), ^) - 2 - (((tert-butoxycarbonyl) amino) methyl) -4-methylpentanoic acid (30.2 mg, 0.123 mmol) and DIEA (77.9 μl, 0.447), then stirred overnight at ambient temperature. The resulting mixture was purified directly by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO _{3 was} added and extracted with 20% IPA in DCM. The organics were dried over MgSO4, filtered and evaporated to give the title compound (51 mg, 74% yield). MS (apci) m / z = 620.4 (M + H).

Stage 2: preparation of ^) - 4- (6- (4- (2- (aminomethyl) -4-methylpentanoyl) piperazin-1-yl) pyridin-3-yl) 6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl (8) - (2- (4 (5 - (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridine-2 -yl) piperazine-1 carbonyl) -4-methylpentyl) carbamate (step 1; 51 mg, 0.082 mmol) in DCM (4 ml) was added TFA (2 ml) and stirred for 30 min at ambient temperature. After evaporation under reduced pressure, the reaction mixture was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO3 was added and extracted with 20% IPA in DCM. The organics were dried over MgSO ₄ , filtered and evaporated to give the purified title compound (35 mg, 82% yield). MS (apci) m / z = 520.3 (M + H).

Example 275.

about

^) - 4- (6- (4- (2 - ((dimethylamino) methyl) -4-methylpentanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazole [1 , 5 ny] pyridine-3-carbonitrile.

Into the mixture ^) - 4- (6- (4- (2- (aminomethyl) -4-methylpentanoyl) piperazin-1-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazolo [1, 5-a] pyridine-3-carbonitrile (33 mg, 0.0635 mmol) and formaldehyde (47.3 μl, 0.635 mmol) in DCM (635 μl), NaBH (AcO) ₃ (67.3 mg, 0.318 mmol) was added ... After stirring for 3 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO3 was added and extracted with 20% IPA in DCM. The organics were dried over MgSO ₄ , filtered and evaporated to give the purified title compound (13 mg, 37% yield). MS (apci) m / z = 548.3 (M + H).

- 264 035568

Example 276.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4- (6-methoxynicotinoyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a mixture of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P40; 25 mg, 0.064 mmol) in DCM (1.3 ml), 2-methoxy-5-pyridinecarboxylic acid (11.71 mg, 0.07644 mmol), HATU (29.07 mg, 0.07644 mmol) and DIEA (44, 38 μl, 0.2548 mmol), then stirred for 5 h at ambient temperature. The resulting mixture was purified directly by silica gel chromatography (using 40-100% EtOAc in a mixture of hexane isomers as gradient eluent) to give the semi-purified compound. The semi-purified compound was re-chromatographed on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to afford the purified specified in the title compound (14.91 mg, 44% yield). MS (apci) m / z = 528.2 (M + H).

Example 277.

4- (6- (4- (2-amino-2- (4-fluorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5- a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl (2- (4- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy)) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl ) piperazin-1-yl) -1 - (4-fluorophenyl) -2-oxoethyl) carbamate. In a mixture of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-α] pyridine-3carbonitrile hydrochloride (intermediate P39; 50 mg , 0.12 mmol), da-2 - ((tert-butoxycarbonyl) amino) -2- (4fluorophenyl) acetic acid (31 mg, 0.12 mmol) and HATU (133 mg, 0.35 mmol) in DCM ( 583 μl) DIEA (122 μl, 0.70 mmol) was added. The reaction mixture was stirred for 1 hour at ambient temperature. The resulting suspension was filtered under reduced pressure. The filtrate was purified directly by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA). The fractions containing the desired product were combined, diluted with a 4: 1 mixture of DCM: iso-PrOH, washed with saturated NaHCO3) and saturated aqueous sodium chloride solution. The organic layer was then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered, and evaporated under reduced pressure to give the title compound (61 mg, 81% yield). MS (apci) m / z = 644.4 (M + H).

Stage 2: obtaining 4- (6- (4- (2-amino-2- (4-fluorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazole [ 1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl (2- (4- (5- (3cyano-6- (2-hydroxy-2-methylpropoxy)) pyrazolo [1 E ^ pyridine ^ -yl ^ iridin ^ -yl ^ iperazin-1-yl) -1 (4-fluorophenyl) -2-oxoethyl) carbamate (step 1; 61 mg, 0.095 mmol) in DCM (948 μl) was added TFA (73 μl) and stirred overnight at ambient temperature. The reaction mixture was purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) Fractions containing the desired product were pooled and then partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO ^^ The organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure The residue was triturated in dichloromethane / hexane isomer mixture and then evaporated under reduced pressure to give the pure title compound (3.4 mg, 7% yield) MS (apci) m / z = 544.2 (M + H).

Example 278.

4- (6- (4- (2- (dimethylamino) -2- (4-fluorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2

- 265 035568 methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into a mixture of 4- (6- (4- (2-amino-2- (4-fluorophenyl) acetyl) piperazin-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1, 5-a] pyridine-3-carbonitrile (example 277; 30 mg, 0.055 mmol) in DCM (552 μl) formaldehyde (16.4 μl, 0.221 mmol) and NaBH (AcO) ₃ (58.5 mg, 0.276 mmol). After stirring for 1 hour at ambient temperature, the reaction mixture was filtered. The resulting filtrate was evaporated under reduced pressure and the residue was purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired compound were combined, then partitioned between 4: 1 DCM: iso-PrOH and saturated Nal 1CC) 3 _{| D! Od || 1} . The organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na2SO4 ( _TB ), filtered and evaporated under reduced pressure. The residue was triturated in dichloromethane / hexane isomer mixture and then evaporated under reduced pressure to give the purified title compound (13.7 mg, 43% yield). MS (apci) m / z = 572.3 (M + H).

Example 279.

N = \ but. D., Χ. ^. _kl

I if o''ο ι

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4- (isobutylsulfonyl) piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile hydrochloride (intermediate P39; 24, 1 mg, 0.0562 mmol) in DCM (500 μl) was added sequentially TEA (38.1 μl, 0.281 mmol) and isobutanesulfonyl chloride (8.07 μl, 0.0618 mmol). The resulting mixture was stirred overnight at ambient temperature and then evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent). Fractions containing the desired compound were combined and partitioned between 4: 1 DCM: iso-PrOH and saturated Nal 1CC) 3 _{| D! Od || 1} . The aqueous extracts were again extracted with a 4: 1 mixture of DCM: iso-PrOH (2x). The combined organic extracts were dried over anhydrous Na2SO4 ( _TB ), filtered and evaporated under reduced pressure to give the purified title compound (14.3 mg, 50% yield). MS (apci) m / z = 513.2 (M + H).

Example 280.

4- (6- (6 - ((6-ethylpyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2 -methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

Into a mixture of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyrudine dihydrochloride -3-carbonitrile (intermediate P43; 20 mg, 0.042 mmol) in DCM (0.5 ml), 6-ethylnicotinaldehyde (11.33 mg, 0.08379 mmol) and NaBH (AcO) ₃ (26.64 mg, 0.1257 mmol). After stirring for 3 h at ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 0-20% DCM / MeOH with 2% NH ₄ OH as gradient eluent) to afford the purified title compound (18.03 mg, yield 82%). MS (apci) m / z = 524.2 (M + H). Compounds in the table. V was prepared using a method similar to that described for the preparation of Example 280, replacing 6-ethylnicotinaldehyde with the appropriate aldehyde and DCM with DCE as the reaction solvent. The completion of the reactions was monitored by LCMS. Reaction times and the need for additional amounts of reagents were adjusted accordingly. Where marked (*), a few drops of glacial acetic acid were added after the addition of NaBH (AcO) ₃ . The title compounds were isolated after chromatographic purification using an appropriate gradient eluent. In case the TFA salt of the title compound was isolated during chromatography, chromatographic purification was followed by basic salt workup. Basic conditions include distribution processing TFA salt between DCM and 1: 1 DCM:. MeOH and saturated NaHCO ^^) (and optionally additional extraction with water and / or a saturated aqueous solution of sodium chloride), then separating the organic extracts, drying over anhydrous Na2SO ₄ ( _TB ), filtration and evaporation under reduced pressure to give the title compound as a free base 266,035,568.

Table V

No. Example Structure Chemical name MS (apci) m / z 281 N = \ Oh Ν 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- (4methoxybenzyl) 3,6diazabicyclo [3.1. 1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 525.2 (M + H) 282 Ν = \ BUT. JL X \ x? \ _Kl о - ^{N ν} ΧΧτΎ 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6isopropoxypyridin-3-yl) methyl) 3,6diazabicyclo [3.1. 1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 554.2 (M + H) 283 Ν = \ xN ^ A ~ X = F _N Η _Οχ . _ο ΛΑθ 4- (6- (6 - ((6- (tert-butyl) pyridin-3 yl) methyl) -3,6 diazabicyclo [3.1. 1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyrazol [1,5а] pyridine-3carbonitrile 552.4 (M + H) 284 Ν = \ χΝ ^ Λ ~ - ^ Ν HO. _k , ο Ν ^ν + .ΧΓ 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((5methoxypyrazin2-yl) methyl) -3,6diazabicyclo [3.1. 1] heptane-3yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3- 527.2 (M + H)

- 267 035568

carbonitrile 285 N = \ Η 0. _κ , X ° ^ Γ f II% X / 0 1 ^ QzN ^^ N 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6-methoxy5-methylpyridin3-yl) methyl) -3,6diazabicyclo [3.1. 1] heptane-3 yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 540.3 (M + H) 286 Ν = \ / ΝηΖ ^ Ν ^Ηθ χ-Ο ^ Υ'Ν Ρ _F Лгш ⁰ '' ⁴ 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6- (2,2,2trifluoroethoxy) pyridin-3 yl) methyl) -3,6diazabicyclo [3.1. 1] heptane-3yl) pyridine -3yl) pyrazolo [1,5а] pyridine-3carbonitrile 594.2 (M + H) 287 Ν = \ but.___ <? nJQ 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- (pyridine-3ylmethyl) -3,6diazabicyclo [3.1. 1] heptane-3yl) pyridine-3yl) pyrazole [1,5а] pyridine-3carbonitrile 496.2 (M + H) 288 Ν = \ BUT .___ _κ ,><0 Ν 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((5methylpyridin-3 yl) methyl) -3,6diazabicyclo [3.1. 1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine -3- 510.2 (M + H)

- 268 035568

carbonitrile 289 N = \ HO. + ^E A o- ^<:: ' ^ζ ' ^Λ / '> S-P A / V 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((2methoxythiazol-5yl) methyl) -3,6diazabicyclo [3.1. 1] heptane-3yl) pyridine -3yl) pyrazolo [1,5а] pyridine- 3carbonitrile 532.2 (M + H) 290 N = \ / NX $ n HO. _k , Ν 1 4- (6- (6 - ((6 (dimethylamino) pi ridin-3 yl) methyl) -3,6 diazabicyclo [3.1. 1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyrazol [1,5а] pyridine-3carbonitrile 539.25 (M + H) 291 Ν = \ ⁿ 0 \ w <. ΑΑχ k,? \ V v ^ Xf 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6-methoxy4-methylpyridin3-yl) methyl) -3,6diazabicyclo [3.1. 1] heptane-3 yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 540.3 (M + H) 292 Ν = \ η 0 \ JL _κ , b <0 _Ν 4- (6- (6 - ((3-fluoro-4methoxypyridin2-yl) methyl) -3,6diazabicyclo [3.1. 1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyrazol [1,5- 544.3 (M + H)

- 269 035568

Example 298.

a] pyridine-3carbonitrile 4- (6- (6 - ((6chloropyridazin-3yl) methyl) -3.6 diazabicyclo [3.1.

1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2-methylpropoxy) pyrazol [1,5а] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- ( (2methoxypyrimidi n-5-yl) methyl) -3,6 diazabicyclo [3.1.

1] heptane-3yl) pyridine -3yl) pyrazolo [1,5а] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((Ι-ΜβτππΙΗbenzo [c!] Imidazol5-yl) methyl ) -3,6 diazabicyclo [3.1.

] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 4- (6- (6 - ((6cyanopyridin-3 yl) methyl) -3,6 diazabicyclo [3.1.

1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2-methylpropoxy) pyrazol [1,5а] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- ( (6methylpyridazin3-yl) methyl) -3,6diazabicyclo [3.1.

1] heptane-3yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile

527.25 (M + H)

521.15 (M + H)

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - ((6-methoxypyridazin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3-yl) pyridin-3 -yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a mixture of 4- (6- (6 - ((6-chloropyridazin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) 6- (2- hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 293; 56.2 mg, 0.106 mmol) in MeOH (0.5 ml) was added 30 wt% NaOMe (98.3 μl , 0.529 mmol). The resulting mixture was stirred for 5 h at 60 ° C. After cooling to ambient temperature, the reaction

- 270 035568 the mixture was evaporated under reduced pressure. The residue was purified directly by silica gel chromatography (using 50-100% EtOAc in hexane isomers followed by 0-20% MeOH in EtOAc as gradient eluent) to afford the purified title compound (49.38 mg, 89% yield). MS (apci) m / z = 527.2 (M + H).

Example 299.

4- (6- (6 - ((2- (dimethylamino) thiazol-5-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 (2 -hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

In solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 52.8 mg, 0.111 mmol) and 2 (dimethylamino) thiazole-5-carbaldehyde (86.38 mg, 0.5530 mmol) in DCE (0.5 ml) NaBH (AcO) was added ₃ (140.6 mg, 0.6636 mmol). After stirring for 7 h at ambient temperature, the reaction mixture was diluted with DCM, extracted with water, then dried over anhydrous Na ₂ SO ₄ (. _Ra ), filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (using 0-50% DCM / MeOH as gradient eluent) to afford the purified title compound (54.2 mg, 90% yield). MS (apci) m / z = 545.2 (M + H).

Compounds in the table. W were prepared using a method similar to that described for the preparation of Example 299, replacing 2- (dimethylamino) thiazole-5-carbaldehyde with the appropriate aldehyde. The completion of the reactions was monitored by LCMS. Reaction times and the need for additional amounts of reagents were adjusted accordingly. Where (*) is marked, no water treatment was performed before chromatography. The title compounds were isolated after chromatographic purification using an appropriate gradient eluent. In case the TFA salt of the title compound was isolated during chromatography, chromatographic purification was followed by basic work-up. Basic work-up conditions include dissolving the TPA salt in DCM containing TEA (1 ml), extraction with water, then separating the organic extracts and evaporation under reduced pressure to give the title compound in free base form.

- 271 035568

Table W

No. Example Structure Chemical name MC (apci) ηι / ζ 300 BUT. N = A / N А ί т ~ ^ Ν <^ Ν 4- (6- (6 - ((1,2,3thiadiazole-4- yl) methyl) -3,6 diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) -6- (2-hydroxy- 2methylpropoxy) pyrazol [1,5-a] pyridine-3carbonitrile 503.1 (M + H) 301 BUT ^ Ν = \ _x n ^> A ~~ ί Ύ ^ Ν ^ Ν 'U-. H-H 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((1-isopropyl1Н-pyrazole-4yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3 yl) pyridin3-yl) pyrazole o [1,5а] pyridine-3carbonitrile 527.25 (M + H) 302 BUT. Ν = \, Ν ί I Qi ί 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- (thiazol-4ylmethyl) -3,6diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) pyrazole [1,5а] pyridine- 3carbonitrile 502.1 (M + H) 303 but. Ν = Α Ν ί Ύ ^ 0 ^ - Qi ' Γ- ~ Ζ. ~ ζ .- * A about 4- (6- (6 - ((3,5dimethylisoxazole-4yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) -6- (2-hydroxy- 2methylpropoxy) pyra zolo [1,5-a] pyridine 3-carbonitrile 513.2 (M + H)

- 272 035568

304 N = \, nA $ _n ^H к, CHA 0 N 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((1-methyl-1Hpyrazol-4-yl) methyl) 3,6diazabicyclo [3.1.1] g eptan-3 yl) pyridin3-yl) pyrazole o [1,5а] pyridine-3carbonitrile 499.2 (M + H) 305 N = \ ^H k, CHA 0 Ν ^{l <v} + k> n = n 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((1-methyl-1H1,2,3-triazol-4yl) methyl) -3,6diazabicyclo [3.1 0,1] heptane-3yl ) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 500.2 (M + H) 306 N = \, νΑ $ _ν Η 0 Λ Ax 'к, X 0 N / \ L Ϊ № = \ <AnA ^ ^N ' 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((1-methyl-1Nimidazol-4yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3 yl) pyridin3-yl) pyrazole o [1,5а] pyridine-3carbonitrile 499.2 (M + H) 307 N = \ N ^ A == _N η o. JL аАх- к, X 0 N LX № = \ 4- (6- (6 - ((1,5dimethyl-Shimidazol-4yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) - 6- (2-hydroxy2methylpropoxy) pyrazol [1,5-a] pyridine-3carbonitrile 513.2 (M + H)

- 273 035568

308

309

310

311

4- (6- (6 - ((1,3dimethyl-1H-pyrazol4-yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3-yl) pyridin3-yl) - 6- (2-hydroxy2methylpropoxy) pyrazol [1,5-а] pyridin-3-carbonitrile 4- (6- (6 - ((1-ethyl-1Hpyrazol-4-yl) methyl) 3,6 diazabicyclo [3.1.1] g eptan-3-yl) pyridine3 -yl) -6- (2-hydroxy2methylpropoxy) pyrazole [1,5-a] pyridine-3carbonitrile 4- (6- (6 - ((1,2dimethyl-Shimidazol-4yl) methyl) -3,6diazabicyclo [3.1. 1] g eptan-3-yl) pyridin3-yl) - 6- (2-hydroxy2methylpropoxy) pyrazol [1,5-a] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- ((5513.2 (M + H)

513.2 (M + H)

513.25 (M + H)

Example 312.

isopropylisoxazol3-yl) methyl) -3,6diazabicyclo [3.1.1] g eptan-3-yl) pyridin 3-yl) pyrazole o [1,5а] pyridine-3carbonitrile

528.2 (M + H)

4- (6- (6 - ((4-cyclopropylthiazol-2-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2 -methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 52 mg, 0.109 mmol) and 4cyclopropylthiazole-2-carbaldehyde (17.5 μL, 0.114 mmol) in DCE (1.09 mL) was added NaBH (AcO) ₃ (69.3 mg, 0.327 mmol). After stirring overnight at ambient temperature, the reaction mixture was diluted with DCE (1 ml) and additional 4-cyclopropylthiazole-2carbaldehyde (67 μl, 0.43 mmol) and NaBH (AcO) ₃ (69.3 mg, 0.327 mmol) were added ... The mixture was stirred for an additional 1.5 h at ambient temperature, diluted with water (20 ml) and then extracted with DCM (2x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na _: SO) | _{(| c: 1} , filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to give the title compound as a salt TFA. TFA salt was diluted with saturated Nal 1C () _dvodnd, then extracted with DCM (2x10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure to give the title compound (28.7 mg, 46% yield) MS (apci) m / z = 542.3 (M + H).

- 274 035568

Example 313.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - ((4-isopropylthiazol-2-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3 -yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 52 mg, 0.109 mmol) and 4-isopropyl-1,3-thiazole-2-carbaldehyde (16.9 μL, 0.109 mmol) in DCE (1.09 mL) was added NaBH (AcO) ₃ ( 69.3 mg, 0.327 mmol). After stirring overnight at ambient temperature, the reaction mixture was diluted with DCE (1 ml) and additional 4-cyclopropylthiazole-2carbaldehyde (67 μl, 0.43 mmol) and NaBH (AcO) ₃ (69.3 mg, 0.327 mmol) were added ... The reaction mixture was stirred for an additional 1.5 h at ambient temperature, diluted with water (20 ml) and then extracted with DCM (2x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was diluted with saturated NaHCO ^ (), then extracted with DCM (2x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (27.8 mg, 45% yield). MS (apci) m / z = 544.3 (M + H).

Example 314.

4- (6- (6 - ((4-ethylthiazol-2-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2 -methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

In a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 52 mg, 0.109 mmol) and 4ethyl-2-thiazolecarboxaldehyde (46.1 μl, 0.327 mmol) in DCE (1.09 ml) NaBH (AcO) 3 (139 mg, 0.654 mmol) was added ... After stirring for 4 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was diluted with saturated NaHCO ^ (), then extracted with DCM (2x10 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (15.8 mg, 27% yield). MS (apci) m / z = 530.3 (M + H).

Example 315.

4- (6- (6- (3,5-difluoro-4-methoxybenzyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2- methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 22 mg, 0.046 mmol) in DCE (230 μl) was added successively 3,5-difluoro-4-methoxybenzaldehyde (7.932 mg, 0.04608 mmol) and NaBH (AcO) ₃ (29.3 mg, 0.138 mmol). After stirring for 1 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to give the title compound (13.9 mg, 54% yield). MS (apci) m / z = 561.2 (M + H).

Compounds in the table. X was obtained using a method similar to that described for obtaining

- 275 035568 for example 315, replacing 3,5-difluoro-4-methoxybenzaldehyde with the corresponding aldehyde. The completion of the reactions was monitored by LCMS. Reaction times and the need for additional amounts of reagents were adjusted accordingly. The title compounds were isolated after chromatographic purification using an appropriate gradient eluent. In case the TFA salt of the title compound was isolated during chromatography, the chromatography was followed by a basic work-up. The main processing conditions included dissolution of the TPA salt in MeOH (1 ml), filtration through a base resin (Stratospheres MP-HCO ₃ , 100 mg), washing with MeOH until no product, as judged by UV, evaporation of the filtrate under reduced pressure and subsequent azeotropic distillation of the residual amount water with Et2O to give the purified free base of the title compound.

TableX

No. Example a Structure Chemical name MC (apci) ηι / ζ 316 BUT. N = \ X I ^ 0 ^^ τ ^ Ν ι L if 1 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((2methylpyridin-4yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridine -3yl) pyrazolo [1,5а] pyridine- 3carbonitrile 510.2 (M + H) 317 but./ No. \ X τ ~ ^ Ν F _F 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6 (trifluoromethyl) pyridin-3-yl) methyl) 3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [ 1.5а] pyridine-3carbonitrile 564.2 (M + H) 318 but ^ Ν = \ χ Τ ^ Ν ^ ti-XT 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((5methylpyrazin-2yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridine -3- 511.25 (M + H)

- 276 035568

Example 323.

yl) pyrazolo [1,5а] pyridine-3carbonitrile

6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6-methoxy2-methylpyridin-3 yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3 yl) pyridin-3yl) pyrazolo [1,5а] pyridin-3carbonitrile 4- (6- (6 - ((1Nimidazol-2yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy - 2methylpropoxy) pyrazol [1,5а] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((4-methyl-1Nimidazol-2yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3 yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 4- (6- (6 - ((1,5dimethyl-Shimidazol-2yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl ) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyrazol [1,5а] pyridine-3carbonitrile

485.2 (M + H)

513.2 (M + H)

4- (6- (6- (3-fluoro-4-methoxybenzyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride 3-carbonitrile (intermediate P43; 32.2 mg, 0.0675 mmol) in DCM (675 μl) and DIEA (29.4 μl, 0.169 mmol) were stirred for 5 min at ambient temperature, then 3-fluorine was added sequentially -4-methoxybenzaldehyde (20.8 mg, 0.135 mmol) and NaBH (AcO) ₃ (42.9 mg, 0.202 mmol). After stirring overnight at ambient temperature, the reaction mixture was passed through a syringe filter (0.45 μm), rinsing with DCM until no UV active substance was detected in the DCM washings. The combined DCM washings were purified by silica gel chromatography (using 0-100% DCM in hexane, then 0 100% (2% NH4OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to afford the title compound (22, 3 mg, yield 61%). MS (apci) m / z = 543.2 (M + H).

Compounds in the table. Y was prepared using a method similar to that described for the preparation of Example 323, substituting the corresponding aldehyde for 3-fluoro-4-methoxybenzaldehyde. The completion of the reactions was monitored by LCMS and, as such, the reaction times were adjusted accordingly. The title compounds were isolated after filtration with a syringe

- 277 035568 filter and chromatographic purification using a suitable gradient eluent. Table Y

No. Example a Structure Chemical name MS (apci) m / z 324 N = \ Cl 1 4- (6- (6- (3-chloro4methoxybenzyl) 3,6 diazabicyclo [3. 1.1] heptane-3yl) pyridine-3yl) -6- (2hydroxy-2methylpropoxy) pyrazolo [1.5а] pyridine-3carbonitrile 559.2 (M + H) 325 N = \ 4-' 6- (2-hydroxy-2methylpropoxy) 4- (6- (6- (4 (three fluorine ethox and) benzyl) -3,6diazabicyclo [3. 1.1] heptane-3yl) pyridine-3yl) pyrazole [1.5а] pyridine-3carbonitrile 579.2 (M + H) 326 About th pt / o— 6- (2-hydroxy-2methylpropoxy) 4- (6- (6- (4methoxy-2methylbenzyl) 3,6diazabicyclo [3. 1.1] heptane-3yl) pyridine-3yl) pyrazolo [1.5а] pyridine-3carbonitrile 539.2 (M + H)

- 278 035568

Example 330.

327

328

329

4- (6- (6- (3 - ((1-pyrazole-1yl) methyl) -4methoxybenzyl) 3,6 diazabicyclo [3.

1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy-2methylpropoxy) pyrazole [1.5 a] pyridine-3carbonitrile 4- (6- (6- (4- (3 (dimethylamino) propoxy) benzyl) -3 , 6diazabicyclo [3.

1.1] heptane-3yl) pyridine-3yl) -6- (2hydroxy-2methylpropoxy) pyrazolo [1.5а] pyridine-3carbonitrile

4- (6- (6- (3-fluoro4 (three fluorine ethox and) benzyl) -3,6diazabicyclo [3.

1.1] heptane-3yl) pyridine-3yl) -6- (2hydroxy -2methylpropoxy) pyrazole [1.5 a] pyridine-3carbonitrile

605.3 (M + H)

596.3 (M + H)

597.2 (M + H)

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - ((4-methoxypyridin-2-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3 -yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride 3-carbonitrile (intermediate P43; 30.1 mg, 0.0631 mmol) and DIEA (27.5 μl, 0.158 mmol) in DCM (631 μl) were stirred for 5 min at ambient temperature. To the reaction mixture were added sequentially 4-methoxypicolinaldehyde (8.65 mg, 0.0631 mmol) and NaBH (AcO) ₃ (26.7 mg, 0.126 mmol). The reaction mixture was stirred for 3 days at ambient temperature. The resulting suspension was diluted with a minimal amount of DCM, then MeOH was added dropwise until the mixture became homogeneous. The DCM / MeOH solution was purified directly by silica gel chromatography (using 0-100% DCM in hexane then 0-100% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to give the indicated in the title compound (27.2 mg, 82% yield). MS (apci) m / z = 526.2 (M + H).

Compounds in the table. Z were prepared and worked up using a method similar to that described for the preparation of Example 330, replacing 4-methoxypicolinaldehyde with the appropriate aldehyde. The completion of the reactions was monitored by LCMS and, as such, the reaction times were adjusted accordingly. The title compounds were isolated either by direct chromatographic purification using an appropriate eluent gradient or, where marked (*), chromatographic purification with the appropriate eluent was preceded by an aqueous reaction work-up consisting of dilution with DCM, extraction with saturated NaHCO ^^, drying the organic extracts over anhydrous MgSO ^), filtration and evaporation under reduced pressure.

- 279 035568

Table Z

No. Structure Chemical name MC (apci) ηι / ζ 331 N == \ ^ ^N 0jQ ° 4- (6- (6- (4 (difluoromethoxy) benzyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyrazole [1,5 -а] pyridine3-carbonitrile 561.2 (M + H). 332 BUT. Ν = \ ί I (Χ ^/ Α / \ ζΑ _Ν b 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6methylpyridin-3yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridine -3yl) pyrazolo [1,5а] pyridine- 3carbonitrile 510.2 (M + H) 333 BUT., Ν = \, νΑ $ _ν Jf Τ _ 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((4 (trifluoromethyl) thiazol-2-yl) methyl) 3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1 , 5а] pyridine-3carbonitrile 570.2 (M + H). 334 BUT. ο ο th ρΓ > —Ζ z-Y < A 4- (6- (6 - ((2,6dimethylpyridin-4yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyr azolo [ 1.5- 524.2 (M + H).

- 280 035568

497.2

M + H a1pyridine-3carbonitrile

6- (2-hydroxy-2methylpropoxy) -46-6-5m methyl isoxazol-3 yl) methyl) -3,6 diazabicyclo G 3.1.11 heptane-3yl (pyridine -3yl (pyrazolo 11.5а1pyridine-3carbonitrile

6- (2-hydroxy-2methylpropoxy) -4 (6- (6- (pyrazin-2ylmethyl) -3,6diazabicyclo G 3.1.11 heptan-3 yl) pyridin-3yl (pyrazole G 1,5а1pyridine-3carbonitrile

4- (6- (6 - ((6-ethoxy-5fluoropyridin-3 yl (methyl (-3,6diazabicyclo G 3.1.11 heptan-3 yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxyshire azolG1, 5-a1pyridine3-carbonitrile

4- (6- (6 - ((2,6dimethoxypyridin3-yl (methyl (-3,6diazabicyclo G 3.1.11 heptan-3 yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy) pyrazoloG 1, 5а] pyridine-3carbonitrile

4- (6- (6 - ((5,6dimethoxypyridin3-yl (methyl) -3,6diazabicyclo G 3.1.11 heptan-3 yl) pyridin-3-yl) 6- (2-hydroxy-2methylpropoxy (pyr azoloG 1, 5a1pyridine-3carbonitrile

Example 340.

4- (6- (6 - ((1-ethyl-b-oxo-1,6-dihydropyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3 yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride 3-carbonitrile (intermediate P43; 50 mg, 0.105 mmol) in DCM (524 μl) and TEA (43.8 μl, 0.314 mmol) were stirred for 5 min at room temperature. To the reaction mixture were added sequentially 1-ethyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde (23.7 mg, 0.157 mmol) and NaBH (AcO) ₃ (44.4 mg, 0.209 mmol). After stirring overnight at ambient temperature, additional 1-ethyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde and NaBH (AcO) _{3 were} added. The reaction mixture was stirred overnight at ambient temperature.

- 281 035568

The resulting suspension was diluted with DCM (1 ml) and washed with water (3x1 ml). The combined aqueous extracts were extracted with DCM (1 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution, passed through a PS filter and evaporated under reduced pressure to remove most of the solvent (approx. 1 ml of residue). The solution was diluted with heptane (1 ml) to form a suspension. The suspension was filtered under reduced pressure, washing with additional heptane (3x1 ml). The solids were collected and air dried to give the title compound (9.2 mg, 16% yield). MS (apci) m / z = 540.3 (M + H). Compounds in the table. AA was obtained, isolated and purified using a method similar to that described for the preparation of Example 340, substituting the corresponding aldehyde for 1-ethyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde.

The completion of the reactions was monitored by LCMS and, as such, the reaction times were adjusted accordingly. The title compounds were isolated purified after filtration using heptane or MTBE as washing solvent.

Table AA

Example 344.

Chemical name

6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((6-oxo-1,6dihydropyridin-3 yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((2-oxo-1,2dihydropyridin-4yl) methyl) -3,6diazabicyclo [3.1.1] heptane- 3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((1-methyl-2oxo-1,2dihydropyridin-4yl) methyl) -3 , 6diazabicyclo [3,1,1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile

MS (apci) m / z

512.3 (M + H)

512.3 (M + H)

526.2 (M + H)

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (2-isopropoxyethyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 20 mg, 0.0419 mmol) in DMSO (419 μl) was added 2- (2-bromoethoxy) propane (21.0 mg, 0.126 mmol) and TEA (28.4 μl, 0.209 mmol ). The resulting mixture was stirred for 16 h at 50 ° C, then for another 16 h at 70 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in hexane, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent ) to give the title compound (6.1 mg,

- 282 035568

28% yield). MS (apci) m / z = 491.3 (M + H).

Example 345.

4- (6- (6- (2,2-difluoroethyl) -3,6-diazabicyclo [3.1. 1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazole [ 1, 5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride Β-3-carbonitrile (intermediate P43; 31.3 mg, 0.0656 mmol) in DMF (656 μl) was added DIEA (57.1 μl, 0.328 mmol) and stirred for 15 min at ambient temperature. 2,2-Difluoromethyl trifluoromethanesulfonate (70.2 mg, 0.328 mmol) was added and the mixture was stirred for 1 hour at ambient temperature. The resulting mixture was diluted

Et2O (40 ml) and washed with water (3x10 ml). The organic extracts were dried over anhydrous MgSO ^), filtered under reduced pressure through a celite pad and evaporated under reduced pressure. The residue was dissolved in a minimum amount of DCM, and then MeOH was added dropwise to obtain a homogeneous solution, which was purified by chromatography on silica gel (using 0-100% DCM in hexane, then 0-100% (2% NH ₄ OH / 20% MeOH / 78 % DCM) in DCM as gradient eluent as gradient eluent) to give the title compound (9.1 mg, 30% yield). MS (apci) m / z = 469.2 (M + H).

Example 346.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (2,2,2-trifluoroethyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3-carbonitrile.

The title compound (17.6 mg, 51% yield) was prepared using the same method, work-up and purification as in Example 345 replacing 2,2-difluoroethyl trifluoromethanesulfonate with 2,2,2-trifluoroethyl triflate. MS (apci) m / z = 487.2 (M + H).

Example 347.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - ((3- (trifluoromethyl) -1,2,4-oxadiazol-5-yl) methyl) -3,6diazabicyclo [3,1 , 1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 33.2 mg, 0.0695 mmol) in DMF (695 μl) was added DIEA (60.6 μl, 0.348 mmol), then stirred for 15 min at ambient temperature before adding 5- (chloromethyl) -3- (trifluoromethyl) -1,2,4-oxadiazole (64.9 mg, 0.348 mmol). After stirring the resulting mixture for 1 h at ambient temperature, the reaction mixture was diluted with Et ₂ O (40 ml), then extracted with water (3x10 ml). The organic extracts were dried over anhydrous MgSO.4 _| v. Were filtered under reduced pressure through a celite pad and evaporated under reduced pressure. The residue was purified by silica gel chromatography (using 0-100% DCM in hexane then 0-100% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as eluent gradient) to give the indicated m / z = 555 , 2 (M + H).

Example 348.

in the title compound (22.2 mg, 58% yield). MS (apci)

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - ((5-methyl-1,3,4-oxadiazol-2-yl) methyl) -3,6

- 283 035568 diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 20 mg, 0.0419 mmol) in DMSO (837.9 μl) was added Cs ₂ CO ₃ ( _TB ) (54.60 mg, 0.1676 mmol) and 2- (chloromethyl) - 5-methyl-1,3,4oxadiazole (5.553 mg, 0.04189 mmol). The resulting mixture was stirred for 16 h at 50 ° C. After cooling to ambient temperature, the reaction mixture was partitioned between DCM (1 ml) and water (5 ml) and then extracted with DCM (3x5 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (5 ml), then dried over anhydrous № ^ O _{4 (solid),} filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% DCM in hexane then 0-60% (2% NH4OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to afford the title compound (10, 06 mg, yield 46%). MS (apci) m / z = 501.2 (M + H).

Example 349.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (pyrimidin-2-ylmethyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazole [ 1,5-a] pyridine-3-carbonitrile.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 40 mg, 0.084 mmol) in DMF (170 μl) was added 2- (chloromethyl) pyrimidine hydrochloride (0.015 g, 0.092 mmol) and TEA (58 μl, 0.42 mmol). The resulting mixture was stirred overnight at 50 ° C, then for an additional 16 hours at 70 ° C. After cooling to ambient temperature, the reaction mixture was poured into water (2 ml) and stirred vigorously. The resulting suspension was filtered under reduced pressure through a nylon membrane, washing the solids with water (2 ml) and Et ₂ O (2 ml). After the aqueous wash solution passed through the filter and the Et ₂ O was decanted from the top of the solids (approx. 5 min), the solids were dissolved in EtOAc / MeOH and evaporated under reduced pressure to give the title compound (30 mg , yield 66%). MS (apci) m / z = 497.2 (M + H).

Example 350.

4- (6- (6 - ((3-fluoro-5-methoxypyridin-2-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) 6- ( 2-hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

In solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 25.2 mg, 0.0528 mmol) and (3fluoro-5-methoxypyridin-2-yl) methyl methanesulfonate (43.5 mg, 0.185 mmol) in DMSO (500 μL) was added DIEA (46 , 0 μL, 0.264 mmol). The resulting mixture was stirred for 16 h at 70 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent). The fractions containing the desired compound were pooled, diluted 4: 1 DCM: i-PrOH and extracted with saturated Nal 1CX) _{3 (1 a one:.. 1} The organic extracts were dried over anhydrous № ^ O4 _(TV), filtered and evaporated under reduced pressure to give the purified title compound (9.5 mg, 33% yield) MS (apci) m / z = 544.3 (M + H).

Example 351.

4- (6- (6 - (^) - 1- (6-chloropyridin-3-yl) -2,2,2-trifluoroethyl) -3,6-diazabicyclo [3.1.1] heptane-3

- 284 035568 yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A mixture of ^) - 1- (6-chloropyridin-3-yl) -2,2,2-trifluoroethan-1-ol (43.2 mg, 0.204 mmol) and lutidine (25.1 μL, 0.216 mmol) in ACN ( 500 μl) was stirred for 10 min at -42 ° C (cooling bath with dry ice / ACN). Tf-O-Tf (35.3 μl, 0.210 mmol) was added slowly to the cold mixture. The resulting mixture was stirred for 1 h at -42 ° C before adding a solution of 4- (6- (3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2 α-methylpropoxy) pyrazolo [1,5-a] pyridine 3-carbonitrile (intermediate P44; 50 mg, 0.124 mmol) and DIEA (43.2 μl, 0.358 mmol) in DMA (500 μl). After stirring for 18 h at ambient temperature, the reaction mixture was directly purified by reverse phase chromatography (5-95% ACN in water with 0.1% TFA as eluent gradient) followed by repeated chromatography on silica gel (0-100% DCM in hexane, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to give the title compound (22 mg, 30% yield). MS (apci) m / z = 598.2 (M + H).

Example 352.

4- (6- (6 - (^) - 1- (6-chloropyridin-3-yl) -2,2,2-trifluoroethyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridine-3 -yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (41 mg, 56% yield) was obtained, isolated and purified using a procedure similar to that described in Example 351, replacing ^) - 1- (6-chloropyridin-3-yl) -2,2,2trifluoroethane-1 -ol ^) - 1- (6-chloropyridin-3-yl) -2,2,2-trifluoroethan-1-ol. MS (apci) m / z = 598.2 (M + H).

Example 353.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - (^) - 2,2,2-trifluoro-1- (6-methoxypyridin-3-yl) ethyl) -3,6diazabicyclo [ 3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into a solution 4- (6- (6 - (^) - 1- (6-chloropyridin-3-yl) -2,2,2-trifluoroethyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridine -3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (Example 351); 50 mg, 0.124 mmol) in MeOH (500 μl), 30 wt% NaOMe in MeOH (31.1 μl, 0.167 mmol) was added, followed by stirring overnight at 70 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0 100% DCM in hexane, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as eluent gradient) with obtaining the title compound (18 mg, 91% yield). MS (apci) m / z = 594.2 (M + H).

Example 354.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - (^) - 2,2,2-trifluoro-1- (6-methoxypyridin-3-yl) ethyl) -3,6diazabicyclo [ 3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (7.42 mg, 75% yield) was obtained, isolated and purified using a procedure similar to that described in Example 353, replacing 4- (6- (6 - (^) - 1) - (6-chloropyridine- 3-yl) -2,2,2trifluoroethyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5- a] pyridine-3-carbonitrile 4- (6- (6 - (^) - 1- (6-chloropyridin-3-yl) -2,2,2trifluoroethyl) -3,6-diazabicyclo [3.1.1] heptane- 3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (Example 352). MS (apci) m / z = 594.25 (M + H).

- 285 035568

Example 355.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6-isobutyryl-3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridine

3-yl) pyrazolo [1,5-a] pyridin-3-carbo nitrile.

Into a mixture of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 20 mg, 0.0419 mmol) and DIEA (36.5 μl, 0.209 mmol) in DCM (209 μl) wasobutyryl chloride (4.91 mg, 0.0461 mmol) was added and the mixture was stirred within 2 hours at ambient temperature. The resulting mixture was evaporated under reduced pressure, then purified by silica gel chromatography (using 50-100% EtOAc in a mixture of hexane isomers, followed by 0-20% MeOH in EtOAc as eluent gradient) to afford the title compound (9.31 mg, yield 47%). MS (apci) m / z = 475.2 (M + H). The compounds shown in table. BB were prepared and purified using a method similar to that described for the preparation of Example 355, substituting the corresponding acid chloride for isobutyryl chloride. The completion of the reactions was monitored by LCMS and, as such, the reaction times were adjusted accordingly. The title compounds were isolated by chromatographic purification using an appropriate gradient eluent.

Table BB

No. Structure Chemical name MS (apci) m / z 356 BUT. N = \ n / ^ N ί ΊΓ L it ijT 0 4- (6- (6 (cyclopropanecarbonyl) -3,6diazabicyclo [3.1L] heptane-3yl) pyridin-3-yl) -6 (2-hydroxy-2methylpropoxy) pyr azolo [1,5а] pyridine-3carbonitrile 473.2 (M + H) 357 BUT. pi r \ Y 0 4- (6- (6 (cyclobutanecarbonyl) -3,6diazabicyclo [3.1L] heptane-3yl) pyridin-3-yl) -6 (2-hydroxy-2methylpropoxy) pyr azolo [1,5a] pyridine-3carbonitrile 487.2 (M + H) 358 BUT.. '' (U N = \ I I i kJ 0 4- (6- (6 (cyclopentanecarbon yl) -3,6diazabicyclo [3.1L] heptane-3yl) pyridin-3-yl) -6 (2-hydroxy-2methylpropoxy) pyr azolo [1,5а] pyridine-3carbonitrile 501.3 (M + H) 359 BUT.. [ N = \ zN / - $ n L! JL -A 0 4- (6- (6 (cyclohexanecarbon yl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6 (2-hydroxy-2methylpropoxy) pyr azolo [1,5а] pyridine-3- 515.3 (M + H)

- 286 035568

carbonitrile 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- (3methylbutanoyl) -3,6di azabicyclo [3.1.1] heptan-3 yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile

Example 361: 6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (2,2,2-trifluoroacetyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridine) - 3-yl) pyrazolo [1,5-a] pyrudine-3-carbonitrile and example 362: 2,2,2-trifluoroacetate 1 - ((3-cyano-4- (6- (6- (2,2,2 -trifluoroacetyl) -3,6 diazabicyclo [3.1.1] heptan-3-yl) pyrudin-3-yl) pyrazolo [1,5-a] pyrudin-6-yl) oxy) -2-methylpropan-2-yl

Into a mixture of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride Β-3-carbonitrile (intermediate P43; 50 mg, 0.105 mmol) in DCM (524 μl) was added TEA (43.8 μl, 0.314 mmol). The resulting suspension was cooled in an ice bath, then 2,2,2-trifluoroacetic anhydride (26.4 mg, 0.126 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 1.5 h at ambient temperature. The resulting mixture was purified directly by C18 reverse phase chromatography (5-90% ACN / water as gradient eluent) to independently afford the title compounds as mono- and dis-coupling products of the starting material:

example 361: 6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (2,2,2-trifluoroacetyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrudin-3 -ul) pyrazolo [1,5-a] pyrudine-3-carbonitrile (18.3 mg, 35% yield). MS (apci) m / z = 501.2 (M + H);

example 362: 2,2,2-trifluoroacetate 1 - ((3-cyano-4- (6- (6- (2,2,2-trifluoroacetyl) -3,6diazabicyclo [3.1.1] heptan-3-yl)) pyrudin-3-yl)) pyrazolo [1,5-a] pyrudin-6-yl) oxy) -2-methylpropan-2-yl (26.8 mg, 42% yield). MS (apci) m / z = 597.2 (M + H).

Example 363.

4- (6- (6- (5-chloro-6-methoxy-nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyrudine-3-carbonitrile.

To a suspension of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyrudine dihydrochloride -3-carbonitrile (intermediate P43; 50 mg, 0.105 mmol) in DCM (2 ml), 5-chloro-6-methoxy-nicotinic acid (9.82 mg, 0.0524 mmol), HATU (23.9 mg, 0 , 0628 mmol) and DIEA (36.5 μl, 0.209 mmol), and stirred for 4 h at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using 50-100% EtOAc in a mixture of hexane isomers followed by 0-20% MeOH in EtOAc as eluent gradient) to afford the purified title compound (18.3 mg, 61% yield) ... MS (apci) m / z = 574.2 (M + H).

With the exception of the marked (*), compounds in table. CC was prepared using a method similar to that described for the preparation of Example 363, replacing 5-chloro-6-methoxy-nicotinic acid with the corresponding carboxylic acid (1.0-1.2 eq.). The completion of the reactions was monitored by LCMS. Thus, the reaction time and the addition of additional reagents were adjusted accordingly. The title compounds were isolated by chromatography using a suitable gradient eluent.

Table CC

No. Example a Structure Chemical name MS (apci) m / z 364 N = \ n ^ As = _n but. Ru O - ^N Aa / jA O 6- (2-hydroxy2- methylpropox and) -4- (6- (6- (5methoxypyraz in-2- carbonyl) -3,6 diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine 3-carbonitrile 541.2 (M + H) 365 Ν = \ NO .___ yC O Ν ^N n EED O 6- (2-hydroxy2-methylpropox _and ) -4- (6- (6 (quinoxaline6-carbonyl) 3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazole [1, 5-a] pyridine - 3-carbonitrile 561.2 (M + H) 366 N = \ 'V'A /' ···) ™ <O-L ^S 'AuSU O 2,2,2 trifluoroacetate 4- (6- (6 (benzo [c!] [1,3] d ioxol-5carbonyl) -3,6 diazabicyclo [3.1.1] heptane-3- 553.2 (M + H)

- 288 035568

367

368

369

yl) pyridin-3yl) -6- (2hydroxy-2methylpropox and) pyrazolo [1, 5-a] pyridine3carbonitrile 6- (2-hydroxy2methylpropox and) -4- (6- (6 (pyrimidin5-carbonyl) 3,6diazabicyclo [3.1 .1] heptane-3yl) pyridin-3yl) pyrazole [1, 5-a] pyridine3-carbonitrile 4- (6- (6- (4 (difluoromethoxy) benzoyl) 3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy-2methylpropox and) pyrazole [1,5а] pyridine-3carbonitrile

2,2,2 trifluoroacetate 4- (6- (6- (3chlor-4methoxybenzo yl) -3,6 diazabicyclo [3.1.1] heptane-3yl) pyridine-3511,2 (M + H)

575.2 (M + H)

573.2 (M + H)

- 289 035568

yl) -6- (2hydroxy-2methylpropox and) pyrazolo [1, 5-a] pyridine- 3carbonitrile 370 I 7 about i — Z. Z.-5 / o = / o / 4- (6- (6- (3fluoro-4methoxybenzo yl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridine-3- yl) -6- (2hydroxy-2methylpropox and) pyrazolo [1, 5-a] pyridine- 3-carbonitrile 557.2 (M + H) 371 N = \ 0./G 0 4- (6- (6- (3fluoro-4methylbenzoyl) -3,6 diazabicyclo [3.1.1] heptane-3yl) pyridine-3- yl) -6- (2hydroxy-2- methylpropox i) pyrazolo [1, 5-a] pyridine- 3-carbonitrile 541.2 (M + H) 372 N = \, nA $ n ^but ^ yuAyuAyu TFK S / A 0 2,2,2 trifluoroacetate 6- (2-hydroxy- 2- methylpropox and) -4- (6- (6- (4isopropoxybenzoyl) -3,6diazabicyclo [3.1.1] heptane-3- 567.25 (M + H)

- 290 035568

yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 373 ^BUT uu '(U N = \ CL ^ N II ^ Lj V 0 6- (2-hydroxy2-methylpropox _and ) -4- (6- (6 (tetrahydro2H-pyran-4carbonyl) -3.6diazabicyclo [3.1.1] heptane-3yl) pyridine 3yl) pyrazolo [1, 5-a] pyridine3 -carbonitrile 517.4 (M + H) 374 but. 0 ° ^ N = \ CL ~~ ^ N if ? ^N r '0 4 6- (2-hydroxy2- methylpropox h) -4- (6- (6 - ((S) tetrahydrofuran-2carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridine 3yl) pyrazolo [1, 5-a] pyridine3-carbonitrile 503.3 (M + H) 375 HO _V 'Ci N = \ ^ N ^ zA CL ^ N if / N ^ Z '0 4- (6- (6- (2cyclopropyl cetyl) -3,6 diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy-2methylpropox and) pyrazolo [ 1.5а] pyridine-3- 487.3 (M + H)

- 291 035568

376

377

378

carbonitrile 6- (2-hydroxy2methylpropox _and ) -4- (6- (6 (tetrahydrofu ran-3carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazole [1, 5-a] pyridine3- carbonitrile 6- (2-hydroxy2methylpropox and) -4- (6- (6 ((1R, 4R) -4methylcyclohexane-1carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine3-carbonitrile 6- (2-hydroxy2methylpropox and) -4- (6- (6 ((R) tetrahydrofu ran-2carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridine 3yl) pyrazolo [ 1, 5-a] pyridine 3-carbonitrile

503.25 (M + H)

503.25 (M + H)

- 292 035568

379

380

381

6- (2-hydroxy2methylpropox and) -4- (6- (6- (3hydroxy-3methylbutanoyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine3- carbonitrile 4- (6- (6- (3,3dimethylcyclobutane-1 carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy- 2methylpropox and) pyrazolo [1, 5- a] pyridine3-carbonitrile 6- (2-hydroxy2methylpropox _and ) -4- (6- (6 (3,3,3trifluoropropanoyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine 3-carbonitrile

505.25 (M + H)

- 293 035568

382 N = \ BUT. JL 0 4- (6- (6- (6 (difluoromethoxy) nicotinoyl) - 3.6 diazabicyclo [3.1.1] heptane-3yl) pyridine-3- yl) -6- (2hydroxy-2methylpropox and) pyrazole [1,5а] pyridine-3carbonitrile 576.2 (M + H) 383 ΝΑ- ^ _ν ^H O \ k, LA o Xr ^N ®r0 0 6- (2-hydroxy2-methylpropox _and ) -4- (6- (6-picolinoyl-3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5- a] pyridine3-carbonitrile 510.2 (M + H) 384 N = \> A $ _N 0 Αχ Ν 0 6- (2-hydroxy2-methylpropox _and ) -4- (6 (6-nicotinoyl- 3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine3-carbonitrile 510.25 (M + H)

- 294 035568

385

386

387

6- (2-hydroxy2methylpropox and) -4- (6- (6- (5methylpicolin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [

1.5а] pyridine-3carbonitrile

6- (2-hydroxy2methylpropox _and ) -4- (6- (6- (4methoxycyclohexane-1 carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5-a] pyridine3 -carbonitrile 6- (2-hydroxy2methylpropox and) -4- (6- (6- (3methylpicolin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [

1.5а] pyridine-3carbonitrile

- 295 035568

388 BUT. N = \ 1 \ X T ^ 0 ^^ 0 i r \ a. /) 0 6- (2-hydroxy2- methylpropox and) -4- (6- (6- (6- methylpicolin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 524.2 (M + H) 6- (2-hydroxy- 2- 389 H0.I N = \ X T - N ^ N 0 methylpropox _and ) -4- (6- (6- (5-methoxypicol inoyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 540.2 (M + H) 6- (2-hydroxy- 2- 390 BUT.. N = \ N ^ Z ~ X Ύ ~~ ^ N ^ N% ' ^N xP ^ ^N 0 methylpropox _and ) -4- (6- (6- (6-methylnicotin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 524.25 (M + H)

- 296 035568

391

392

393

6- (2-hydroxy2methylpropox _and ) -4- (6- (6- (4methylnicotin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [

1,5а] pyridine-3carbonitrile 6- (2-hydroxy2524,2 (М + Н) methylpropox _and ) -4- (6- (6 ((1R, 4R) -4hydroxycyclic ohexane-1carbonyl) -3,6diazabicyclo [3.1. 1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine 3-carbonitrile 6- (2-hydroxy2methylpropox _and ) -4- (6- (6- (2methylnicotin oil) -3,6diazabicyclo [3.1.1 ] heptane-3yl) pyridine-3yl) pyrazolo [1,5а] pyridine-3carbonitrile

531.3 (M + H)

- 297 035568

394

395

396

6- (2-hydroxy2methylpropox and) -4- (6- (6- (4methylpicolin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile

6- (2-hydroxy2methylpropox and) -4- (6- (6 ((1R, 3R) -3methoxycyclobutane-1 carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine3-carbonitrile 6- (2-hydroxy2methylpropox and) -4- (6- (6- (5methoxynicotinoyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [

1.5а] pyridine-3carbonitrile

- 298 035568

397

398

399

4- (6- (6- (4,4dimethylcyclohexane-1 carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy-2methylpropox and) pyrazolo [1, 5-a ] pyridine3-carbonitrile 6- (2-hydroxy2methylpropox and) -4- (6- (6 ((lS, 3S) -3methoxycyclobutane-1 carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5-a] pyridine 3-carbonitrile 6- (2-hydroxy2methylpropox i) -4- (6- (6- (4methoxypicol inoyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile

- 299 035568

400

401

402

4- (6- (6- (3,3dimethylcyclohexane-1 carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy-2methylpropox i) pyrazolo [1, 5-a ] pyridine3-carbonitrile 6- (2-hydroxy2methylpropox _and ) -4- (6- (6- (5methylnicotin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [

1.5а] pyridine-3carbonitrile

6- (2-hydroxy2methylpropox _and ) -4- (6- (6- (6methoxypicol inoyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [

1.5а] pyridine-3carbonitrile

540.2 (M + H)

- 300 035568

406

403

404

405

6- (2-hydroxy2methylpropox _and ) -4- (6- (6- (6 (trifluoromethyl) nicotinoyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazole [1, 5-a] pyridine3-carbonitrile 6- (2-hydroxy2methylpropox _and ) -4- (6- (6- (2 (tetrahydro2H-pyran-4yl) acetyl) 3.6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1 , 5-a] pyridine3-carbonitrile 4- (6- (6- (6ethylnicotino yl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy-2methylpropox and) pyrazolo [1, 5а] pyridine-3carbonitrile 6- (2-hydroxy2methylpropox and) -4- (6- (6- (6methoxy-5methylnicotin oil) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1, 5 -а] pyridine3-carbonitrile

578.2 (M + H)

531.3 (M + H)

538.3 (M + H)

554.2 (M + H) * Example 406 used 3 eq. HATU and used water

Example 407.

processing, including the extraction of the reaction mixture with saturated ΝΗ ^ Ι, β ^.) before chromatographic purification.

bis- (2,2,2-Trifluoroacetate) 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of tert-butyl 4- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperazine-1-carboxylate (example 29; 413 mg, 0.921 mmol) in DCM (8 ml) was added TFA (2 ml). After stirring for 1 hour at ambient temperature, the mixture was evaporated under reduced pressure to give the purified title compound (quantitative yield). MS (apci) m / z = 349.2 (M + H).

- 301 035568

Example 408.

4- (6- (6A-leucyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrαzolo [1,5-a ] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl ((2R) -1- (3- (5- (3-cyano-6- (2-hydroxy-2methylpropoxy)) pyrazolo [1,5-a] pyridin-4-yl) pyridine -2-yl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) -4methyl-1-oxopentan-2-yl) carbamate. In a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 60 mg, 0.126 mmol) in DMF (4 ml) was sequentially added (tert-butoxycarbonyl) -O-leucine (32.0 mg, 0.138 mmol), HATU (57.3 mg, 0.151 mmol ) and DIEA (57.3 μl, 0.503 mmol), then stirred overnight at ambient temperature. The resulting mixture was purified directly by silica gel chromatography (using 50-100% EtOAc in a mixture of hexane isomers as gradient eluent) to give the title compound (75 mg, 97% yield). MS (apci) m / z = 618.4 (M + H).

Stage 2: preparation of 4- (6- (6 - ^ - leucyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl ((2R) -1- (3- (5 (3-cyano-6- (2-hydroxy-2-methylpropoxy)) pyrazolo [1,5-a] pyridin-4-yl) pyridine- 2-yl) -3,6 diazabicyclo [3.1.1] heptan-6-yl) -4-methyl-1-oxopentan-2-yl) carbamate (stage 1; 75 mg, 0.12 mmol) in DCM (4) ml) was added TFA (2 ml) and stirred for 30 min at ambient temperature. After evaporation under reduced pressure, the reaction mixture was purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO3 was added and extracted with 20% IPA in DCM. The organic layer was dried over MgSO ₄ , filtered and evaporated. The material was further purified by silica gel chromatography (using 5-10% MeOH in DCM as gradient eluent) to afford the purified title compound (44, 70% yield). MS (apci) m / z = 518.3 (M + H).

Example 409.

4- (6- (6- (dimethyl-0-leucyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazole [ 1,5-a] pyridine-3-carbonitrile.

Into a mixture of 4- (6- (6A-leucyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy)) pyrazolo [1, 5-a] pyridine-3-carbonitrile (example 408; 40 mg, 0.0773 mmol) and formaldehyde (57.5 μl, 0.773 mmol) in DCM (773 μl) was added NaBH (AcO) ₃ (81.9 mg, 0.386 mmol). After stirring for 3 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (5-95% ACN in water with 0.1% TFA as gradient eluent). Fractions containing the desired product were collected, saturated NaHCO _{3 was} added and extracted with 20% IPA in DCM. The organics were dried over MgSO ₄ , filtered and evaporated. The material was then purified by silica gel chromatography (using 2-5% MeOH in DCM as gradient eluent) to afford the purified title compound (23 mg, 55% yield). MS (apci) m / z = 546.3 (M + H).

- 302 035568

Example 410.

4- (6- (6- (2-amino-2- (4-fluorophenyl) acetyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxy -2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl ((^) - 2- (3- (5- (3-cyano-6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridine- 2-yl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) -1- (4fluorophenyl) -2-oxoethyl) carbamate. Into a mixture of 4- (6- (3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 100 mg, 0.209 mmol), ^) - 2 - ((tert-butoxycarbonyl) amino) -2- (4-fluorophenyl) acetic acid (56.4 mg, 0.209 mmol) and HATU ( 240 mg, 0.628 mmol) in DMF (1.05 ml) was added DIEA (146 μl, 0.838 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature and then filtered. The resulting filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (using 0-10% CHCl3 / MeOH with 0-1% NH4OH as gradient eluent) to give the title compound (137.36 mg, quantitative yield). MS (apci) m / z = 656.2 (M + H).

Stage 2: preparation of 4- (6- (6 - (^) - 2-amino-2- (4-fluorophenyl) acetyl) -3,6-diazabicyclo [3.1.1] heptan-3yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl ((1 R) -2- (3 - (5 - (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridine2 -yl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) -1- (4-fluorophenyl) -2-oxoethyl carbamate (step 1; 137.36 mg, 0.209 mmol) in DCM (418 μl ) TPA (161 μL) was added and stirred for 70 min at ambient temperature After evaporation under reduced pressure, the reaction mixture was purified first by chromatography on silica gel (using CHCl3 / MeOH with 0-1% NH4OH as eluent gradient), then by chromatography on reverse phase C18 (5-95% ACN in water with 0.1% TFA as eluent gradient), then chromatography again on silica gel (5-10% MeOH in DCM with 1% NH4OH as eluent gradient) to obtain the purified indicated title compound (112.6 mg, 97% yield) MS (apci) m / z = 556.2 (M + H).

Example 411.

4- (6- (6- (2- (dimethylamino) -2- (4-fluorophenyl) acetyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -6- (2 -hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

Into a mixture of 4- (6- (6- (2-amino-2- (4-fluorophenyl) acetyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -6- (2 -hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 410; 102 mg, 0.184 mmol) in DCM (1.8 ml) was sequentially added with formaldehyde (82.7 μl, 1.10 mmol) and NaBH (AcO) ₃ (195 mg, 0.918 mmol). After stirring for 2 h at ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 0-10% CHCl ₃ / MeOH with 0-1% NH ₄ OH as gradient eluent) to provide the semi-purified title compound. The semi-purified compound was suspended in DCM, triturated with a mixture of hexane isomers, then evaporated under reduced pressure to provide the purified title compound (24.6 mg, 40% yield). MS (apci) m / z = 584.3 (M + H).

Example 412.

(S) -tetrahydrofuran-3-yl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) - 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate.

- 303 035568

In a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine- 3-carbonitrile (intermediate P44; 50 mg, 0.12 mmol) in DCM (618 μl) was successively added (^) - tetrahydrofuran-3-yl chloroformate (20 mg, 0.14 mmol) and TEA (17 μl, 0.12 mmol). After stirring for 1 h at ambient temperature, the reaction mixture was purified by C18 reverse phase chromatography (using 5-50% ACN / water as eluent gradient). Fractions containing the desired compound were combined and partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO3 ( _BODH ). The aqueous extracts were again extracted with a 4: 1 mixture of DCM: iso-PrOH (2x). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ (TB), filtered and evaporated under reduced pressure to give the purified title compound (64 mg, 99% yield). MS (apci) m / z = 519.3 (M + H).

Example 413.

N = \

BUT.

L IJL

ΧΝγθγχθ о О (R) -tetrahydrofuran-3-yl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridine-2- yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate.

The title compound (64 mg, 99% yield) was obtained, isolated and purified using a procedure similar to Example 412, substituting (H) -tetrahydrofuran-3-yl chloroformate for d) - tetrahydrofuran-3-yl chloroformate. MS (apci) m / z = 519.2 (M + H).

Example 414.

tetrahydro-2H-pyran-4-yl3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyrigin-4yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate.

The title compound (60 mg, 90% yield) was obtained, isolated and purified using a procedure similar to Example 412, substituting tetrahydro-2H-pyran-4-yl chloroformate for d) - tetrahydrofuran-3-yl chloroformate. MS (apci) m / z = 533.3 (M + H).

Example 415.

isobutyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -3,6-diazabicyclo [3.10, 1] heptane-6-carboxylate.

In solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 20 mg (0.0419 mmol) in DCM (400 μl), TEA (29.2 μl, 0.12 mmol) and isobutyl chloroformate (17.2 mg, 0.126 mmol) were added. for 2 h at ambient temperature, the reaction mixture was partitioned between DCM and saturated NH (I (h)). The aqueous extracts were re-extracted with DCM (3x). The combined organic extracts were dried over anhydrous Na2SO _{4 (TB),} filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (using 0-25% MeOH / EtOAc as eluent gradient) to afford the purified title compound (15.4 mg, 73% yield). MS (apci) m / z = 505.3 (M + H).

- 304 035568

Example 416.

Phenyl-3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) 3,6-diazabicyclo [3.1 0.1] heptane-6-carboxylate.

The title compound was prepared using the same procedure, work-up and purification as in Example 415, substituting phenyl chloroformate (3 equiv.) For isobutyl chloroformate (1 equivalent) and substituting DIEA (10 equiv.) For TEA (5 equiv.). In addition, the reaction time was extended to 4 hours. After similar workup and chromatography on silica gel (0-25% MeOH / EtOAc as gradient eluent), the purified title compound was isolated (20 mg, 30% yield). MS (apci) m / z = 525.2 (M + H).

Example 417.

3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -Nisobutyl-3,6-diazabicyclo [ 3.1.1] heptane-6-carboxamide.

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrαzolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 32.6 mg, 0.0806 mmol) in DMA (403 μl) DIEA (140 μl, 0.12 mmol) and 4-nitrophenyl chloroformate (19.5 mg, 0.0967 mmol) were added ... The resulting mixture was stirred for 1 h at ambient temperature, which allowed to obtain 4-nitrophenyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridine-4yl ) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate. To the reaction mixture was added 2methylpropan-1-amine (40 μl, 0.40 mmol) and stirred for 21 h at 80 ° C. After cooling to ambient temperature, the reaction mixture was quenched with water (10 ml) and extracted with DCM (3x5 ml). The combined organic extracts were washed with water (3x10 ml) and saturated sodium chloride solution (10 ml). The organic extracts were dried over anhydrous Na ^ O ^, filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent). Fractions containing the desired compound were combined and extracted with saturated NaHCO (^ ()). The aqueous extracts were again extracted with DCM (3x5 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 ml), dried over anhydrous Na ₂ SO ₄ (T _B ), filtered and evaporated under reduced pressure to give the purified title compound (18.2 mg, 45% yield) ... MS (apci) m / z = 504.3 (M + H). Compounds in the table. DD was prepared using a method similar to that described for preparation in Example 417, replacing 2-methylpropan-1-amine in the urea compound with the appropriate amine, and DMF was used in place of DMA. The completion of all reactions was monitored by LCMS and the reaction times were adjusted accordingly. Reactions were quenched with saturated N ^ Cl ^ ^ followed by aqueous workup similar to that described in Example 417. Target compounds were isolated using silica gel chromatography (using 0-25% MeOH / EtOAc as eluent gradient), omitting subsequent aqueous chromatographic workup.

- 305 035568

DD table

No. For example Structure Chemical name MC (apci) ηι / ζ 418 ΞΕ o 3-b pT / -Z. Z.-Y ABOUT 6- (2-hydroxy-2methylpropoxy) -4 (6- (6- (pyrrolidine1-carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazole [1,5а] pyridine-3carbonitrile 502.3 (M + H) 419 N = \ h _o C O 6- (2-hydroxy-2methylpropoxy) -4 (6- (6 - ((S) -3- methoxypyrrolidi n-1 -carbonyl) -3,6 diazabicyclo [3.1.1] heptane-3yl) pyridin-3yl) pyrazolo [1,5а] pyridine-3carbonitrile 532.3 (M + H) 420 t about kb 0 Г r-Z Зз * 4- (6- (6 - ((S) -3fluoropyrrolidine-1 carbonyl) -3,6diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) 6- (2- hydroxy-2methylpropoxy) pyrazolo [1 , 5а] pyridine-3- 520.3 (M + H) carbonitrile

Example 421.

2,2,2-trifluoroacetate 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -I- ( 6-methoxypyridin-3-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxamide.

To a solution of triphosgene at 0 ° C (18.6 mg, 0.0628 mmol) in DCM (250 μl), DIEA (72.4 μl, 0.419 mmol) and 6-methoxypyridin-3-amine (9.75 mg, 0 , 0786 mmol). The resulting mixture was stirred for 1 hour at 0 ° C. 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2hydroxyAmethylpropox ^ pyrazolo ^^^ pyridine 3-carbonitrile dihydrochloride (intermediate P43; 25 mg, 0.0524 mmol) was added to the cold (0 ° C) solution The resulting mixture was stirred overnight at ambient temperature and then quenched with water The biphasic mixture was extracted with DCM (3x) on a Biotage phase separation column The combined organic extracts were evaporated at reduced pressure and the crude residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound (13.4 mg, 46% yield). MS (apci) m / z = 555.2 (M + H).

Example 422.

2,2,2-trifluoroacetate 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridin-4yl) pyridin-2-yl) -I- (4 -methoxyphenyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxamide.

- 306 035568

To a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 30 mg, 0.0628 mmol) in DMA (750 μl) was added TEA (43.8 μl, 0.314 mmol) and 1-isocyanato-4-methoxybenzene (14.1 g, 0.0943 mmol). After stirring for 2 h at 50 ° C, the reaction mixture was cooled to ambient temperature, diluted with DCM and poured into water. The aqueous extracts were again extracted with DCM (3x), and the organic extracts were combined, dried over anhydrous Na _: SO) | _{(| c: 1} , filtered and evaporated under reduced pressure. The residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound (27 mg, yield 78%) MS (apci) m / z = 554.2 (M + H).

Example 423.

4- (6- (6- (benzylsulfonyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5- a] pyridine-3-carbonitrile.

Into a mixture of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 26.0 mg, 0.0545 mmol) in DCM (1.0 ml), TEA (29.6 μl, 0.218 mmol) and phenylmethanesulfonyl chloride (11.4 mg, 0.0599 mmol). After stirring the reaction mixture for 1 hour at ambient temperature, additional TEA (29.6 μl, 0.218 mmol) and phenylmethanesulfonyl chloride (11.4 mg, 0.0599 mmol) were added sequentially. The resulting mixture was stirred for 16 hours at ambient temperature and then evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent). Fractions containing the desired compound were combined and partitioned between 4: 1 DCM: iso-PrOH and saturated Naal 1CO) _{3 (aq} . _{1. The} aqueous extracts were again extracted with 4: 1 DCM: iso-PrOH (2x). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ (T _B ), filtered and evaporated under reduced pressure to give the purified title compound (25.2 mg, 83% yield) MS (apci) m / z = 559.2 (M + H) ...

Compounds in the table. EEs were obtained using a method similar to that described for the preparation of Example 423 substituting the corresponding sulfonyl chloride for phenylmethanesulfonyl chloride and, where marked (*), substituting DIEA for TEA. The completion of all reactions was monitored by LCMS. Reaction times and the need for additional amounts of reagents were adjusted accordingly. After chromatographic purification using an appropriate gradient eluent, the title compounds were isolated. Chromatography was followed by the basic workup described in Example 423 in a preparation in which an acidic modifier (eg 0.1% TFA) was used under gradient elution conditions.

- 307 035568

Table EE

No. Pr name Ra Structure Chemical name MS (apci) ιη / ζ 424 N = \ NO ___ CHA О kr ^N Λ 6- (2-hydroxy-2methylpropoxy) 4- (6- (6 - ((6methoxypyridine -3yl) sulfonyl) 3,6diazabicyclo [3. 1.1] heptane-3yl) pyridine-3yl) pyrazole o [1.5а] pyridine-3carbonitrile 576.2 (M + H) 425 Ν = \ CHA O N X 4- (6- (6 ((cyclopropylmethyl) sulfonyl) -3,6diazabicyclo [3. 1.1] heptane-3yl) pyridin-3yl) -6- (2hydroxy-2methylpropoxy) pyrazolo [1,5а] pyridine-3carbonitrile 523.5 (M + H) 426 b V) Z A '° / 0 about t 6- (2-hydroxy-2methylpropoxy) 4- (6- (6 (isobutylsulphonyl) -3,6diazabicyclo [3. 1.1] heptane-3yl) pyridine-3yl) pyrazole o [1.5а] pyridine-3carbonitrile 525.3 (M + H) 427 428 N = \ / N ^ A ^ N n JL / \ L if Ακψ N = \ ho ^^ _k , NA 0 y N Um- Av T 0 0 f 6- (2-hydroxy-2methylpropoxy) 4- (6- (6 (neopentylsulfonyl) -3,6diazabicyclo [3. 1.1] heptane-3yl) pyridine-3yl) pyrazolo [1,5- a] pyridine-3carbonitrile 6- (2-hydroxy-2methylpropoxy) 4- (6- (6 - ((2,2,2trifluoroethyl) sul phonil) -3,6 diazabicyclo [3. 1.1] heptane-3yl) pyridin-3yl) pyrazole o [1,5- a] pyridine-3carbonitrile 539.3 (M + H) 551.2 (M + H)

Example 429.

4- (6- (6 - ((cyclopropylmethyl) sulfonyl) -3,6-diazabicyclo [3.1L] heptan-3-yl) pyridin-3-yl) -6- (2methoxy-2-methylpropoxy) pyrazolo [1, 5-a] pyridine-3-carbonitrile.

- 308 035568

At ambient temperature 4- (6- (6 - ((cyclopropylmethyl) sulfonyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2) - methylpropoxy) pyrazolo [1.5a] pyridine-3-carbonitrile (example 425; 8.9 mg, 0.0170 mmol) was added to a stirred suspension of a 60 wt.% dispersion of NaH in mineral oil (1.36 mg, 0.218 mmol) in DMF (500 μl). Iodomethane (1.17 μl, 0.0187 mmol) was added to the resulting mixture and stirred for 16 h at ambient temperature. The resulting mixture was diluted with EtOAc, washed with water (3x) and saturated sodium chloride solution (1x). The organic extracts were dried over Na ₂ SO ₄ ( _mw ), then filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent). Fractions containing the desired compound were combined and partitioned between 4: 1 DCM: iso-PrOH and saturated NaHCO (^ ().). The aqueous extracts were again extracted with a 4: 1 mixture of DCM: iso-PrOH (2x). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (6.2 mg, 68% yield). MS (apci) m / z = 537.2 (M + H).

Example 430.

4- (6- (6- (isobutylsulfonyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-methoxy-2methylpropoxy) pyrazolo [1,5- a] pyridine-3-carbonitrile.

The title compound (6.6 mg, 35% yield) was obtained, isolated and purified using a procedure similar to Example 429, replacing 4- (6- (6 - ((cyclopropylmethyl) sulfonyl) -3,6 diazabicyclo [3.1 .1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine 3-carbonitrile on 6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (isobutylsulfonyl) -3,6 diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 426) ... MS (apci) m / z = 539.2 (M + H).

Example 431.

6- (2-methoxyethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3ul) pyridin-3-yl) pyrazole [1,5-a] pyridine-3-carbonitrile.

A mixture of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3ul) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3-carbonitrile (intermediate P71; 30 mg, 0.066 mmol) ^ CO3 ^) (11 mg, 0.079 mmol) and 1-bromo-2-methoxyethane (11 mg, 0.079) mmol) in DMF (400 μl) was stirred overnight at 90 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM, washed with water (3x) and saturated sodium chloride solution (1x). The organic extracts were dried over anhydrous Na ₂ SO ₄ ( _mw ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TPA salt was partitioned between DCM and saturated NaHCO (^^.). The organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The residue was triturated in dichloromethane / hexane isomer mixture to give the purified title compound (9.3 mg, 46% yield). MS (apci) m / z = 512.2 (M + H).

Example 432.

6- (2- (dimethylamino) ethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin 3-yl ) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3ul) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 26.9 mg, 0.0593 mmol) in

- 309 035568

DMA (119 μl) was sequentially added with Cs ₂ CO ₃ ( _TB ) (77.3 mg, 0.237 mmol) and (2 bromoethyl) dimethylamine (8.9 mg, 0.083 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, washed with water (3x) and saturated sodium chloride solution (1x). The organic extracts were combined, dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was diluted with 60:40 ACN / water with 2% TFA and the solution was purified by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent) to give the TFA salt of the title connections. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (1.2 mg, 4% yield). MS (apci) m / z = 525.3 (M + H).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (d, 1H), 8.18 (s, 1H), 8.12 (d, 1H), 8.08 (d, 1H), 7, 75 (dd, 1H), 7.60 (dd, 1H), 7.15 (d, 1H), 6.89 (d, 1H), 6.64 (d, 1H), 4.09 (t, 2H ), 3.89 (s, 3H), 3.77 (m, 4H), 3.55 (m, 4H), 2.99 (s, 1H), 2.91 (s, 1H), 2.78 (t, 3H), 2.65 (m, 1H), 2.35 (s, 6H), 1.63 (d, 1H).

Example 433.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((^) morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: obtaining tert-butyl ^) - 2 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane- 3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate

P71; 15.5 mg, 0.0342 mmol) in DMA (684 μl) CS ₂ CO ₃ ( _TB ) (12.2 mg, 0.0376 mmol) and ^) - tert-butyl-2- (bromomethyl) morpholine were added sequentially -4-carboxylate (14.4 mg, 0.0513 mmol) by blowing for 10 min through the reaction mixture Ar _(d) , and then again for 1 min after adding the amine. The reaction mixture was stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (10 ml) and washed with water (10 ml). The aqueous wash solution was again extracted with EtOAc (2x5 ml). The combined organic extracts were washed with water (2x10 ml) and saturated sodium chloride solution (10 ml), then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (22.3 mg, quantitative yield) ... MS (apci) m / z = 653.4 (M + H).

Stage 2: preparation of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6 - (( (S) -morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of tert-butyl ^) - 2 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane- 3yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (stage 1; 22.3 mg, 0.0342 mmol) in DCM (2, 2 ml) was added TFA (2.63 ml) and stirred for 20 minutes at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by C18 reverse phase chromatography (using 60-40% ACN / water with 2% TFA as gradient eluent). Fractions containing the desired compound were combined and extracted with saturated NaHCOx (10 ml) and DCM (2x10 ml). The combined organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the title compound (4.9 mg, 26% yield). MS (apci) m / z = 553.3 (M + H).

Example 434.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((^) 4-methylmorpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. Into a solution of 4- (6- (6 - ((6methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((^) -morpholine-2yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 433; 10 mg, 0.0181 mmol) in DCM (0.362 ml) formaldehyde (6.80 μl, 0.0905 mmol) and NaBH (AcO) ₃ (38.4 mg, 0.181 mmol). After stirring for 24 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. The crude residue was diluted with 60-40% ACN / water with 2% TFA and the solution was purified by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent) to give the TFA salt of the title connections.

- 310 035568

The TFA salt was dissolved in MeOH and passed through P1-HCO3 resin to give the title compound (4.1 mg, 40% yield). MS (apci) m / z = 567.3 (M + H).

Example 435.

6 - ((^) - 5,5-dimethylmorpholin-2-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane -3-yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl (2S) -2 - (((3-cyano-4- (6- (6 - ((6-methoxypyrigin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane -3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -5,5 dimethylmorpholine-4-carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 42 mg, 0.093 mmol) in DMF (464 μL) was added sequentially tert-butyl ^) - 5,5-dimethyl-2 (((methylsulfonyl) oxy) methyl) morpholine-4-carboxylate (30 mg, 0.093 mmol) and CS ₂ CO ₃ ( _TB ) (76 mg, 0.23 mmol). The reaction mixture was stirred for 36 h at ambient temperature, then at 60 ° C until the reaction reached 60% completion, as monitored by LCMS. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and extracted with water. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-50% EtOAc in a mixture of hexane isomers as eluent) to give the title compound (6.5 mg, 10% yield). MS (m / z) 681.3 [M + H].

Stage 2: preparation of 6 - ((^) - 5,5-dimethylmorpholin-2-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3yl) methyl) -3,6-diazabicyclo [3.1 .1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. A solution of tert-butyl (2S) -2 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl)) - 3,6-diazabicyclo [3.1.1] heptane -3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -5,5-dimethylmorpholine-4-carboxylate (step 1; 6.5 mg, 0.0095 mmol ) in 1: 1 TFA: DCM (2 ml) was stirred for 1 h at ambient temperature. The crude residue was diluted with 60-40% ACN / water with 2% TFA and the solution was purified by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent) to give the TFA salt of the title connections. The TFA salt was dissolved in MeOH and passed through P1-HCO3 resin to give the title compound. (4.1 mg, 74% yield). MS (apci) m / z = 581.3 (M + H).

Example 436.

about

4- (6- (6- (6-methoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P76; 40 mg, 0.090 mmol) in DCM (2.5 ml), 6-methoxy-nicotinic acid (16.5 mg, 0.108 mmol), HATU (41.0 mg , 0.108 mmol) and DIEA (62.6 μl, 0.359 mmol). After stirring overnight at ambient temperature, additional DIEA (220 μl, 1.26 mmol) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between DCM (40 ml) and saturated II ₄ C1 ( _Aq .) (40 ml). The aqueous extracts were again extracted with DCM (3x25 ml). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-10% MeOH in EtOAc as eluent gradient) to afford the purified title compound (19 mg, 36% yield). MS (apci) m / z = 581.3 (M + H).

Example 437.

- 311 035568

4- (6- (6 - ((6-methoxy-5-methylpyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -6- (2 -morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P76; 41 mg, 0.061 mmol) and 6methoxy-5-methylnicotinaldehyde (21 mg, 0.14 mmol) in DCM (2 ml), NaBH (AcO) ₃ (39 mg , 0.18 mmol). After stirring for 5 h at ambient temperature, the reaction mixture was partitioned between water and DCM, then extracted with DCM (3x). The combined organic extracts were dried over anhydrous Na ₂ SO _{4 (} TB), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-20% MeOH in DCM with 0.2% NH4OH as gradient eluent) to afford the title compound (22 mg, 62% yield). MS (apci) m / z = 581.3 (M + H).

Example 438.

4- (6- (6 - ((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) 6- ( 2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P76; 50 mg, 0.074 mmol) and 5 chloro-6-methoxy-nicotinaldehyde (31 mg, 0.18 mmol) in DCM (3 ml), NaBH (AcO) ₃ (57 mg , 0.27 mmol). After stirring the reaction mixture overnight at ambient temperature, additional NaBH (AcO) 3 (38 mg, 0.18 mmol) was added and the reaction mixture was stirred for an additional 5 h at ambient temperature. The reaction mixture was partitioned between water and DCM, then extracted with DCM (3x). The combined organic extracts were dried over anhydrous Na ^ Oy ^, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-20% MeOH in DCM with 0.2% NH4OH as gradient eluent) to afford the title compound (7 mg, 16% yield). MS (apci) m / z = 601.3 (M + H).

Example 439.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 25.8 mg, 0.0569 mmol) in DMA (113.8 μL) CS ^ O ^) (74.14 mg, 0.2276 mmol) was added sequentially and (2chloroethyl) morpholine (15.65 μl, 0.1138 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and sequentially extracted with water (3x) and saturated sodium chloride solution (1x). The combined organic extracts were washed with saturated aqueous sodium chloride solution, then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was diluted with 6040% ACN / water with 2% TFA and the solution was purified by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent) to give the TFA salt of the title compound. The TFA salt was dissolved in MeOH and passed through P1-HCO3 resin to give the title compound. (8.8 mg, 27% yield). MS (apci) m / z = 567.3 (M + H).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (d, 1H), 8.34 (m, 2H), 8.09 (d, 1H), 7.83 (dd, 1H), 7, 71 (dd, 1H), 7.28 (d, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.26 (t, 2H), 3.89 (m, 5H ), 3.79 (d, 2H), 3.72 (t, 4H), 3.64 (m, 4H), 2.87 (t, 2H), 2.70 (m, 1H), 2.62 (t, 4H), 1.69 (d, 1H).

Example 440.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- ( 3

- 312 035568 oxo-1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: Preparation of 2,2,2-trifluoroacetate 6- (2-chloroethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) 3,6-diazabicyclo [3.1.1] heptane -3-yla) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. To a solution of 6hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile (intermediate P71; 75 mg, 0.165 mmol) in DMF (1654 μL), anhydrous K ^ O ^) (112 mg, 0.827) and 1-chloro-2-iodoethane (45.4 μL, 0.496 mmol). The reaction mixture was stirred overnight at ambient temperature. The resulting mixture was diluted with EtOAc and extracted with water, then the organic extracts were dried over anhydrous Na ₂ SO ₄ (T _B ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water: ACN with 0.1% TFA as gradient eluent) to afford the title compound. (60 mg, 66% yield). MS (apci) m / z = 516.2 (m + H).

Stage 2: preparation of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6- (2 - (3-oxo-1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a solution of 2,2,2 trifluoroacetate 6- (2-chloroethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3- yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (step 1; 6.5 mg, 0.0095 mmol) in DMA (635 μl) was added 2-oxopiperazine (9.53 mg , 0.0952 mmol) and stirred overnight at 80 ° C. Additionally, 2-oxopiperazine (3.18 mg) was added and the mixture was stirred overnight at 80 ° C. The reaction mixture was purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TFA salt was purified by silica gel chromatography (using 0-10% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the title compound (1.17 mg, 6% yield). MS (apci) m / z = 580.4 (M + H).

Example 441.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1methylpiperidine- 4-yl) oxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 4 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3) yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) piperidine-1 carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 50 mg, 0.11 mmol) in DMA (1103 μl), Cs ₂ CO ₃ (t _B ) (108 mg, 0.33 mmol) and tert- butyl 4-bromopiperidine-1-carboxylate (35 mg, 0.13 mmol), then stirred for 48 h at 60 ° C. Additionally, tert-butyl 4-bromopiperidine-1-carboxylate (29 mg) was added and the reaction mixture was stirred for 3 days at 60 ° C. After cooling to ambient temperature, the reaction mixture was partitioned between DCM (10 ml) and water (10 ml) and then extracted with DCM (5x10 ml). The combined organic extracts were dried over anhydrous NaSO ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 010% MeOH in EtOAc as eluent gradient) to afford the purified title compound (21 mg, 27% yield). MS (apci) m / z = 637.3 (M + H).

Stage 2: preparation of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3yl) pyridin-3-yl) -6- (piperidine -4-yloxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. To a solution of tert-butyl 4 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3) -yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl ) pyridin-3yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) piperidine-1-carboxylate (stage 1: 21 mg, 0.033 mmol) in DCM (1 ml), TPA (1 ml) was added and stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (using 0-10% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the title compound (20 mg, quantitative yield) in acceptable purity for the following stages. MS (apci) m / z = 537.2 (M + H).

Stage 3: preparation of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6 - (( 1-methylpiperidin-4-yl) oxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. Into a mixture of 4 (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (piperidin4- yloxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (stage 2; 20 mg, 0.033 mmol) in DCM (523 μL) formaldehyde (9.83 μL, 0.131 mmol) and NaBH (AcO) ₃ ( 55.4 mg, 0.262 mmol). After stirring for 4 h at ambient temperature, the reaction mixture was diluted with MeOH, then filtered. The filtrate was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers and then 0-10% MeOH in DCM with 0.1% NH4OH in

313 035568 as gradient eluent) to afford the purified title compound (2.5 mg, 17% yield). MS (apci) m / z = 551.3 (M + H).

Example 442.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1methylpiperidine Ch- iOmethox-pyrazolo-ChD-pyridine-3-carbonitrile.

Stage 1: obtaining 2,2,2-trifluoroacetate tert-butyl 4 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3yl) methyl) -3,6-diazabicyclo [3.1. 1] heptan-3,2-yl) pyridin-3-yl) pyrαzolo [1,5-a] nyridin-6yl) oxy) methyl) piperidine-1-carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrαzolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 50 mg, 0.11 mmol) in DMA (1103 μl), Cs ₂ CO ₃ ( _TB ) (108 mg, 0.33 mmol) and tert-butyl -4- (bromomethyl) piperidine-1-carboxylate (46 mg, 0.17 mmol), then stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the purified title compound (49 mg, 58% yield ). MS (apci) m / z = 651.4 (M + H).

Stage 2: Preparation of bis- (2,2,2-trifluoroacetate) 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (piperidin-4-ylmethoxy) pyrazolo [1,5-a] pyridin-3carbonitrile. In a solution of 2,2,2-trifluoroacetate tert-butyl-4 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3yl) methyl) -3,6-diazabicyclo [3.1.1 ] heptan-3-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridin-6yl) oxy) methyl) piperidine-1-carboxylate (step 1; 49 mg, 0.064 mmol) in DCM (1 ml) added TFA (1 ml) and stirred overnight at ambient temperature. The reaction mixture was treated with additional TFA (1 ml) and left stirring until LCMS indicated complete consumption of starting material. The reaction mixture was evaporated under reduced pressure and the residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound (30 mg, 70% yield). MS (apci) m / z = 551.3 (M + H).

Stage 3: preparation of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6 - (( 1-methylpiperidin-4-yl) methoxy) pyrαzolo [1,5-a] nyridine-3-carbonitrile. To a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan3-yl) pyridine- 3-yl) -6- (piperidin-4-ylmethoxy) pyrαzolo [1,5-a] nyridine-3-carbonitrile (stage 2; 15 mg, 0.0226 mmol) in DCM (500 μl) formaldehyde (16 , 8 μL, 0.226 mmol) and NaBH (AcO) 3 (23.9 mg, 0.113 mmol). After stirring overnight at ambient temperature, additional NaBH (AcO) 3 (23.9 mg, 0.113 mmol) was added and the reaction was stirred at ambient temperature until LCMS indicated complete consumption of starting material. The reaction mixture was purified directly by silica gel chromatography (using 0-10% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the purified title compound (1 mg, 8% yield). MS (apci) m / z = 565.4 (M + H).

Example 443.

6 - ((1- (2-methoxyethyl) piperidin-4-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] hentane -3-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridine- 3-yl) -6- (piperidin-4-ylmethoxy) pyrαzolo [1,5-a] pyridine-3carbonitrile (example 442, step 2; 15 mg, 0.023 mmol) in DMA (112.8 μl) potassium carbonate was added sequentially (16 mg, 0.11 mmol) and 1-bromo-2-methoxyethane (4.6 μl, 0.045 mmol). After stirring overnight at 60 ° C, the reaction mixture was cooled to ambient temperature and then purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to give the salt TPA specified in the title of the compound. The TPA salt was dissolved in MeOH and passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (6 mg, 43% yield). MS (apci)

- 314 035568 m / z = 609.3 (M + H).

Example 444.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6- (2- ( 1 methylpiperidin-4-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 4- (2 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) ethyl) piperidine-1carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P71; 47.5 mg, 0.105 mmol) in DMA (1047 μl), Cs ₂ CO ₃ ( _mB ) (102 mg, 0.314 mmol) and tert-butyl -4- (2bromoethyl) piperidine-1-carboxylate (61.2 mg, 0.209 mmol), then stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with water (2 ml). The resulting suspension was filtered and the solids were washed with water (10 ml) and Et ₂ O (5 ml), then dried under reduced pressure to give the purified title compound (51.5 mg, 74% yield). MS (apci) m / z = 665.4 (M + H).

Stage 2: Preparation of bis- (2,2,2-trifluoroacetate) 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- (piperidin-4-yl) ethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile. To a solution of tert-butyl 4- (2 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl ) pyridin-3-yl) pyrαzolo [1,5-a] pyridin-6-yl) oxy) ethyl) piperidine-1-carboxylate (stage 1; 51.5 mg, 0.0775 mmol) in DCM (1 ml) was added TPA (1.5 ml) and stirred for 1 hour at ambient temperature. The reaction mixture was evaporated under reduced pressure to give the title compound (61.4 mg, quantitative yield). MS (apci) m / z = 565.3 (M + H).

Stage 3: preparation of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6- (2 - (1-methylpiperidin-4-yl) ethoxy) pyrazolo [1 D ^ pyridine-3-carbonitrile. To a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan3-yl) pyridine- 3-yl) -6- (2- (piperidin-4-yl) ethoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile (stage 2; 30.7 mg, 0.0387 mmol) in DCM (1000 μl) was added sequentially formaldehyde (5.82 μl, 0.0775 mmol) and NaBH (AcO) ₃ (24.6 mg, 0.116 mmol). After stirring for 30 min at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-10% MeOH in DCM with 0.1% NH4OH as eluent gradient) with obtaining the purified title compound (1.61 mg, 7% yield). MS (apci) m / z = 579.3 (M + H).

Example 445.

6- (2- (1- (2-methoxyethyl) piperidin-4-yl) ethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.10 , 1] heptan-3-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

In a mixture of bis- (2,2,2-trifluoroacetate) 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridine- 3-yl) -6- (2- (piperidin-4-yl) ethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (Example 444, step 2; 31 mg, 0.039 mmol) in DMA (196 μl) sequentially potassium carbonate (27 mg, 0.20 mmol) and 1-bromo-2-methoxyethane (7.4 μL, 0.078 mmol) were added. The resulting mixture was stirred at 60 ° C until LCMS indicated complete consumption of starting material. The reaction mixture was cooled to ambient temperature and purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TPA salt was dissolved in MeOH, passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (17.1 mg, 70% yield). MS (apci) m / z = 623.4 (M + H).

- 315 035568

Example 446.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2 (pyrrolidine -1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 28 mg, 0.062 mmol) in DMF (309 μL) was added sequentially to ₂ CO ₃ ( _TB ) (26 mg, 0.19 mmol) and 1- (2- chloroethyl) pyrrolidine (9.9 mg, 0.074 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was evaporated under reduced pressure. The crude residue was dissolved in 1 ml of 60:40 ACN / water with 2% TFA and purified by C18 reverse phase chromatography (using 5-95% ACN in H2O with 0.1% TFA as eluent gradient) to give the TFA salt of the above in the connection header. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (22 mg, 65% yield). MS (apci) m / z = 551.3 (M + H).

Example 447.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- ( 2oxopyrrolidin-1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2 (2-oxopyrrolidine -1-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P77; 42 mg, 0.063 mmol) in DCM (500 μl) was added 6-methoxy-3-pyridinecarboxaldehyde (42.9 mg 0.313 mmol) and NaBH (AcO) ₃ (133 mg, 0.625 mmol). After stirring the reaction mixture for 3 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the title compound as the TFA salt of the title compound. The TPA salt was dissolved in MeOH, passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (6.80 mg, 19% yield). MS (apci) m / z = 565.3 (M + H).

Example 448.

6- (azetidin-3-ylmethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl ) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) azetidine-1 carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 75.8 mg, 0.167 mmol) in DMA (334 μl), Cs ₂ CO ₃ ( _TB ) (218 mg, 0.669 mmol) and tert-butyl ether 3 α-bromomethylazetidine-1-carboxylic acid (62.7 mg, 0.251 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was evaporated under reduced pressure, then purified by silica gel chromatography (using 010% MeOH in DCM with 0.1% NH4OH as eluent gradient) to afford the purified title compound (52.4 mg, 50 % output). MS m / z = 623.4 (M + H).

Stage 2: Preparation of 6- (azetidin-3-ylmethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridine -3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. To a solution of tert-butyl 3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridine-3 -yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) azetidine-1-carboxylate (stage 1; 52.4 mg, 0.0841 mmol) in DCM (1 ml) was added TFA (1 ml) and stirred for 1 hour at ambient temperature.

- 316 035568

The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 1 ml of 60:40 ACN / water with 2% TFA and purified by C18 reverse phase chromatography (using 5-95% ACN in H ₂ O with 0.1% TFA as gradient eluent) to give the TFA salt of the title compound. The TFA salt was dissolved in MeOH, passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (43.2 mg, 98% yield). MS (apci) m / z = 523.2 (M + H).

Example 449.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1methylazetidine- 3-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6- (azetidin-3-ylmethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrudine -3-yl) pyrazolo [1,5-a] pyrudin-3-carbonitrule (example 448, step 2; 20 mg, 0.038 mmol) in DCM (0.38 ml) formaldehyde (14.4 μl, 0.191 mmol ) and NaBH (AcO) ₃ (81.1 mg, 0.383 mmol). The reaction mixture was stirred at ambient temperature until LCMS indicated complete consumption of starting material. The resulting mixture was purified directly by C18 reverse phase chromatography (using 5-95% ACN in H20 with 0.1% TFA as gradient eluent) to provide the TFA salt of the title compound. The TPA salt was dissolved in MeOH, passed through P1-HCO3 resin, then dried over anhydrous Na ₂ SO4 ( _ra ), filtered and evaporated under reduced pressure to give the purified title compound (4.1 mg, 20% yield). MS (apci) m / z = 537.3 (M + H).

Example 450.

6 - ((1-acetylazetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrule.

Stage 1: obtaining tert-butyl-3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane-3- yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) azetidine-1carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 50 mg, 0.11 mmol) in DMF (551 μL), K ^ Oy ^ (46 mg, 0.33 mmol) and tert-butyl ether 3- bromomethylazetidine-1-carboxylic acid (33 mg, 0.13 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in 1 ml of 60:40 ACN / water with 2% TFA and purified by C18 reverse phase chromatography (using 5-95% ACN in H2O with 0.1% TFA as eluent gradient) to give the TFA salt of connection header. The TPA salt was dissolved in MeOH, passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (41 mg, 59% yield). MS (apci) m / z = 623.3 (M + H).

Stage 2: Preparation of 6 - ((1-acetylazetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) 3,6-diazabicyclo [3.1.1] heptane -3-yl) pyrugin-3-yl) pyrazolo [1,5-a] pyrugin-3-carbonutrile. Tert-butyl 3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridine ) -3ul) pyrazolo [1,5-a] pyrudin-6-yl) oxy) methyl) azetidine-1-carboxylate (41 mg, 0.066 mmol) was dissolved in 1: 1 TPA: DCM (2 ml) and stirred for 1 hour at ambient temperature. The solution was evaporated under reduced pressure. The residue was dissolved in DCM (0.3 ml) and TEA (18.57 μl, 0.1332 mmol) was added followed by acetic anhydride (9.38 μl, 0.1 mmol). The reaction mixture was stirred for 48 h at ambient temperature until LCMS indicated complete consumption of starting material. The reaction solution was diluted with DCM (20 ml) and washed with saturated aqueous sodium chloride solution (3x10 ml), and dried over anhydrous MgSO ₄ ( _ra ), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 10% MeOH in DCM with 0.1% NH ₄ OH as gradient eluent) to afford the title compound (13.4 mg, 36% yield). MS (apci) m / z = 565.3 (M + H).

- 317 035568

Example 451.

6 - ((3-fluorozetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl ) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -3 fluoroazetidine-1-carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrαzolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 51.5 mg, 0.114 mmol) in DMF (0.5 ml), Cs ₂ CO ₃ ( _mB ) (148 mg, 0.454 mmol) and tert-butyl -3- (bromomethyl) azetidine-1-carboxylate (45.7 mg, 0.170 mmol), then stirred at 60 ° C until LCMS indicated complete consumption of starting material. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (10% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the purified title compound (81 mg, quantitative yield). MS m / z = 641.3 (M + H).

Stage 2: Preparation of 6 - ((3-fluorozetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) 3,6-diazabicyclo [3.1.1] heptane -3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. In solution tert-butyl 3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridine -3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -3-fluoroazetidine-1-carboxylate (step 1; 81 mg, 0.13 mmol) in DCM (2 ml) was added TFA (2 ml) and stirred for 1 hour at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TFA salt was dissolved in MeOH, passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (15 mg, 22% yield). MS (apci) m / z = 541.3 (M + H).

Example 452.

6 - ((3-fluoro-1-methylazetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane- 3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In solution 6 - ((3-fluorozetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3- yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 451, step 2; 13 mg, 0.0240 mmol) in DMA (0.2 ml) formaldehyde (9, 03 μl, 0.120 mmol) and NaBH (AcO) ₃ (51 mg, 0.240 mmol). The reaction mixture was stirred at 60 ° C until LCMS indicated complete consumption of starting material. The reaction mixture was evaporated under reduced pressure and the crude residue was dissolved in 1 ml of 60:40 ACN / water with 2% TFA and purified by C18 reverse phase chromatography (using 5-95% ACN in H2O with 0.1% TFA as gradient eluent ) to give the TFA salt of the title compound. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin, then evaporated under reduced pressure to give the purified title compound (6.4 mg, 48% yield). MS (apci) m / z = 555.3 (M + H).

Example 453.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((3methylαzetidine- 3-yl) methoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl ) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -3 methylazetidine-1-carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrαzolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 50 mg, 0.110 mmol) in DMA (0.3 ml), C ^ CO ^) (144 mg, 0.441 mmol) was added successively and

- 318 035568 tert-butyl-3- (bromomethyl) -3-methylazetidine-1-carboxylate (30.8 μl, 0.110 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, washed with water (3x) and saturated sodium chloride solution (1x). The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure. The crude residue was dissolved in 1 ml of 60:40 ACN / water with 2% TFA and purified by C18 reverse phase chromatography (using 5-95% ACN in H2O with 0.1% TFA as eluent gradient) to give the TFA salt of the above in the connection header. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin, then evaporated under reduced pressure to give the purified title compound (38.9 mg, 55% yield). MS m / z = 637.3 (M + H).

Stage 2: preparation of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -6 - (( 3-methylazetidin-3-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile. A solution of tert-butyl 3 - (((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridine- 3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -3-methylazetidine-1-carboxylate (stage 1; 38.9 mg, 0.0611 mmol) in a 1: 1 mixture of DCM : TFA (ml) (stirred for 1 h at ambient temperature. The crude residue was dissolved in 1 ml of 60:40 ACN / water with 2% TFA and purified by C18 reverse phase chromatography (using 5-95% ACN in H2O with 0.1% TFA as eluent gradient) to give the TFA salt of the title compound The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin and then evaporated under reduced pressure to afford the purified title compound (9 mg, 41% yield) MS (apci) m / z = 537.2 (M + H).

Example 454.

6 - ((1,3-dimethylazetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3- yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into solution 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -6 - ((3- methylazetidin-3-yl) methoxy) pyrazolo [1,5-a] pyrigine-3-carbonitrile (Example 453, step 2; 16 mg, 0.0298 mmol) in DMA 0.1 ml, formaldehyde (11.2 μl , 0.149 mmol) and NaBH (AcO) ₃ (63.2 mg, 0.298 mmol). The reaction mixture was stirred overnight at 60 ° C. The reaction mixture was cooled to ambient temperature and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% LS \: water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TPA salt was dissolved in MeOH, passed through P1-HCO3 resin, dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure to give the purified title compound (5.6 mg, 34% yield). MS (apci) m / z = 551.3 (M + H).

Example 455.

6 - ((1 - (2-methoxyethyl) -3-methylazetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1. 1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a mixture of 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -6 - ((3- methylazetidin-3-yl) methoxy) pyrazolo [1,5-a] pyrigine-3-carbonitrile (Example 453, step 2; 17.3 mg, 0.03224 mmol) in DMA 0.15 ml potassium carbonate (22 , 28 mg, 0.1612 mmol) and 1-bromo-2-methoxyethane (6.06 μl, 0.0645 mmol). The resulting mixture was stirred overnight at 70 ° C. The reaction mixture was cooled to ambient temperature and purified directly by C18 reverse phase chromatography (using 5-95% LC: water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TPA salt was dissolved in MeOH, passed through aP1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (10.26 mg, 54% yield). MS (apci) m / z = 595.3 (M + H).

- 319 035568

Example 456.

6 - ((1-acetyl-3-methylazetidin-3-yl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane- 3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into solution 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -6 - ((3- methylazetidin-3-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 453, step 2; 31.7 mg, 0.0591 mmol) in DCM was added sequentially TEA (16.47 μl, 0 , 1181 mmol) and acetic anhydride (6.32 μl, 0.0886 mmol). The resulting mixture was stirred at ambient temperature until LCMS indicated complete consumption of starting material. The reaction mixture was diluted with DCM (40 ml), washed with saturated aqueous sodium chloride solution (3x20 ml), then dried over anhydrous MgSO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was dissolved in DCM (2 ml) then purified using silica gel chromatography (using 010% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the title compound (19 mg, 56% yield). MS (apci) m / z = 579.3 (M + H).

Example 457.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((3methyloxetane- 3-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (6.2 mg, 20% yield) was obtained, isolated and purified using a procedure similar to Example 432 substituting 3- (bromomethyl) 3-methyloxetane for (2-bromoethyl) dimethylamine. MS (apci) m / z = 538.3 (M + H).

Example 458.

about

4- (6- (6- (6-methoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((3metuloxetan-3-yl) methoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6- (6-methoxy-nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) pyrazolo [1,5-a] pyridine- 3-carbonitrile (intermediate P72; 36 mg, 0.077 mmol) in DCM (0.2 ml), HATU (35.13 mg, 0.09240 mmol), 3- (bromomethyl) -3-methyloxetane (10.60 μl , 0.0924 mmol) and DIEA (53.29 μl, 0.3080 mmol). After stirring the reaction mixture for 3 days at ambient temperature, K ₂ CO3 ( _TB ) (4 eq.) Was added. The resulting mixture was stirred overnight at 50 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 0-20% DCM / MeOH as gradient eluent), then triturated with MTBE to give the title compound (1.13 mg, 3% yield). MS (apci) m / z = 552.2 (M + H).

Example 459.

6 - ((1R, 3R) -3-hydroxycyclobutoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyridine -3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1d, 3d) -3-hydroxycyclobutoxy) pyrazolo [1,5- a] pyridine-3-carbonitria (intermediate P78; 55 mg, 0.14 mmol) in DCM (1.0 ml), 6-methoxy-nicotinaldehyde (22 mg, 0.16 mmol) and glacial acetic acid (1.6 μl , 0.027 mmol), then stirred for 10 min at ambient temperature before

- 320 035568 by treatment with NaBH (AcO) ₃ (43 mg, 0.2 mmol). The reaction mixture was stirred for 2 hours at ambient temperature in a sealed vessel. The resulting mixture was evaporated and the residue was purified by C18 reverse phase chromatography (5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the title compound as the TFA ester. The TPA ether was diluted with MeOH (1 ml) and K ₂ CO ₃ ( _TB ) (0.19 g, 1.4 mmol) was added. The resulting mixture was stirred overnight at ambient temperature, then evaporated under reduced pressure. The residue was diluted with DCM (20 ml) and the resulting suspension was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (using 25% acetone in DCM with 0.05% NH ₄ OH as eluent) to give the title compound (11 mg, 15% yield). MS (apci) m / z = 524.2 (M + H).

Example 460.

6 - (((^^) - 3-hydroxycyclobutyl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl ) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 25 mg, 0.0551 mmol) in DMA (551 μl), Cs ₂ CO ₃ ( _TB ) (53.9 mg, 0.165 mmol) and uuc (1s , 3s) -3 (bromomethyl) cyclobutan-1-ol (10.9 mg, 0.0662 mmol), then stirred overnight at 100 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TFA salt was dissolved in MeOH (1 ml), passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (6.2 mg, 21% yield). MS (apci) m / z = 538.3 (M + H).

Example 461.

6- (2- (azetidin-3-yl) ethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3- yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of tert-butyl 3- (2 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] hept-3 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) ethyl) azetidine-1carboxylate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P71; 50 mg, 0.110 mmol) in DMA (0.55 ml) was successively added K ₂ CO ₃ ( _TB ) (61 mg, 0.44 mmol) and tert -butyl-3- (2iodoethyl) azetidine-1-carboxylate (41 mg, 0.13 mmol), then stirred overnight at 60 ° C. Additional tert-butyl 3- (2-iodoethyl) azetidine-1-carboxylate (41 mg, 0.13 mmol) was added and the reaction mixture was stirred at 60 ° C until LCMS indicated complete consumption of starting material. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and washed with water (3x) and saturated aqueous sodium chloride solution (lx). The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the purified title compound (70 mg, quantitative yield). MS m / z = 637.4 (M + H).

Stage 2: Preparation of 4 6- (2- (azetidin-3-yl) ethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane -3-yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile. In solution tert-butyl 3- (2 - ((3-cyano-4- (6- (6) - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) ethyl) α-zetidine-1-carboxylate (stage 1; 40.1 mg, 0.0630 mmol) in DCM (2 ml) was added TFA (2 ml) and stirred at ambient temperature until LCMS indicated complete consumption of starting material. The reaction mixture was evaporated under reduced pressure to give the TFA salt of the title compound. The TFA salt was purified by silica gel chromatography (using 5-95% DCM / MeOH with 1% NH4OH as gradient eluent) to afford the purified title compound (9 mg, 36.2% yield). MS (apci) m / z = 537.2 (M + H).

- 321 035568

Example 462.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- ( 1methylazetidin-3-yl) ethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into a solution of bis- (2,2,2-trifluoroacetate) 4 6- (2- (azetidin-3-yl) ethoxy) -4- (6- (6 - ((6-methoxypyridin-3yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (example 461, step 2; 34 mg, 0.0523 mmol) in DMA (0.26 ml) formaldehyde (7.26 μl, 0.261 mmol) and NaBH (AcO) ₃ (111 mg, 0.523 mmol) were added sequentially. The reaction mixture was stirred overnight at 60 ° C. The reaction mixture was cooled to ambient temperature and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% ASA water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TFA salt was dissolved in MeOH (5 ml), passed through P1HCO3 resin and evaporated under reduced pressure to give the purified title compound (5 mg, 17% yield). MS (apci) m / z = 551.4 (M + H).

Example 463.

2 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) acetamide.

The title compound was prepared using a procedure similar to that described for Example 460, except that the reaction was carried out at 60 ° C, ACN was replaced with DMA as reaction solvent, 4 eq. CsiCO ^), 2-bromoacetamide (1.5 equiv.) Were replaced with cis (18.33) -3 (bromomethyl) cyclobutan-1-ol as alkyl halide, and the purification step was skipped. Upon completion, the reaction mixture was cooled to ambient temperature. The reaction mixture was filtered and evaporated under reduced pressure to give the purified title compound (28 mg, 96% yield). MS (apci) m / z = 511.2 (M + H).

Example 464.

2 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -N-methylacetamide.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 25 mg, 0.055 mmol) in DMA (551 μL) was added successively Cs ^ O ^) (72 mg, 0.22 mmol), KI (9.2 mg, 0.055 mmol) and 2-χλορ-Νmethylacetamide (8.9 mg, 0.083 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was evaporated under reduced pressure and the residue was purified by C18 reverse phase chromatography (using 5-95% ACU water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO ₃ resin and evaporated under reduced pressure to give the purified title compound (8.5 mg, 29% yield). MS (apci) m / z = 525.2 (M + H).

Example 465.

2 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridine

- 322 035568

-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -H, N-dimethylacetamide.

The title compound (5.74 mg, 16% yield) was obtained, isolated and purified using a procedure similar to Example 432 substituting chloroacetyldimethylamine for (2-bromoethyl) dimethylamine. MS (apci) m / z = 539.2 (M + H).

Example 466.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1methyl- 111-imidazol-5-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (11 mg, 30% yield) was obtained and purified using a procedure similar to that described in example 470, except that 4 eq. Cs ^ O ^) and 5 (chloromethyl) -1-methyl-1H-imidazole (1.5 equiv.) Were replaced with N (2-chloroethyl) imidazole hydrochloride as the alkyl halide. MS (apci) m / z = 548.2 (M + H).

Example 467.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1methyl- 1H-imidazol-4-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 25 mg, 0.055 mmol) in DMA (551 μl), CsiCO ^) (54 mg, 0.17 mmol) and 4- (chloromethyl) -1-methyl -1Nimidazole (11 mg, 0.083 mmol), then stirred overnight at 100 ° C. After cooling to ambient temperature, the reaction mixture was partitioned between DCM and water. The resulting organic extracts were purified by chromatography on silica gel (using a column of 0-10% MeOH with 1% NH4OH as eluent gradient) and then by re-chromatography on silica gel (using 0-100% EtOAc in a mixture of hexane isomers, then 0- 10% MeOH in EtOAc as gradient eluent) to give the purified title compound (4 mg, 13% yield). MS (apci) m / z = 548.2 (M + H).

1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 8.35 (d, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.77 (dd , 1H), 7.62 (dd, 1H), 7.48 (d, 1H), 7.18 (d, 1H), 7.03 (d, 1H), 6.71 (d, 1H), 6 , 67 (d, 1H), 5.08 (s, 2H), 3.92 (s, 3H)), 3.82 (m, 4H), 3.69 (s, 3H), 3.59 (m , 4H), 2.69 (m, 1H), 1.66 (d, 1H).

Example 468.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 (oxazol-2- ylmethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (11 mg, 30% yield) was prepared and purified using a procedure similar to that described in example 460, except that the reaction was carried out at ambient temperature, DMF was replaced with DMA as reaction solvent, 4 eq. Cs ₂ CO ₃ (. _Ra ), 2-chloromethyloxazole (2.9 equiv.) Was replaced with cis (H ^) - 3- (bromomethyl) cyclobutan-1-ol as alkyl halide, and a gradient eluent of 0-50% water / ACN with 0.1% TPA. The TPA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound. MS (apci) m / z = 535.2 (M + H).

Example 469.

- 323 035568

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((4methyloxazole- 2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-car bonitrile.

The title compound (11 mg, 30% yield) was prepared and purified using a procedure similar to that described in example 460, except that the reaction was carried out at ambient temperature, DMF was replaced with DMA as reaction solvent, 4 eq. Cs ₂ CO ₃ ( _TB ), 2- (chloromethyl) -4-methyloxazole was replaced by (^^) - 3- (bromomethyl) cyclobutan-1-ol, cis as alkyl halide, and used as eluent gradient 0-50% water / ACN with 0.1% TPA. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound. MS (apci) m / z = 549.3 (M + H).

Example 470.

6- (2- (1 H-imidazol-1-yl) ethoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane-3 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 30 mg, 0.066 mmol) in DMA (132 μl), K ^ O ^) (9.1 mg, 0.066 mmol) and N- (2-chloroethyl) imidazole hydrochloride were added sequentially (13 mg, 0.079 mmol), then stirred overnight at 60 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, washed with water (3x) and saturated sodium chloride solution (1x). The organic extracts were dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 60:40 MeCN / water with 2% TFA as gradient eluent) to give the TFA salt of the title compound. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (19 mg, 52% yield). MS (apci) m / z = 548.3 (M + H).

Example 471.

N = \ Ji T sacht 4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) - 6 (pyridin-3-ylmethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (2.8 mg, 9% yield) was prepared and purified using a procedure similar to Example 446 except DMA was used in place of DMF, 4 eq. C ^ CO3 ^) and 3- (iodomethyl) pyridine hydroiodide (1.5 equiv.) Were replaced by 1- (2chloroethyl) pyrrolidine as the alkyl halide. MS (apci) m / z = 545.2 (M + H).

Example 472.

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1methyl- III-imidazole ^ -yl ^ ethox ^ pyrazolo ^ D ^ pyridine-3-carbonitrile.

The title compound (2.8 mg, 9% yield) was prepared and purified using a procedure similar to Example 446 except DMA was used in place of DMF, 4 eq. Cs ^ O ^) and 2- (chloromethyl) -1-methyl-III-imidazole were replaced by 1- (2chloroethyl) pyrrolidine as the alkyl halide. MS (apci) m / z = 548.3 (M + H).

Example 473.

- 324 035568

4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((8) 3,3,3-trifluoro-2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P71; 25 mg, 0.055 mmol) in DMA (551.3 μl), Cs ₂ CO ₃ ( _TB ) (53.88 mg, 0.1654 mmol) and ^ ) - (-) - 3,3,3-trifluoro-1,2epoxypropane (7.160 μl, 0.08269 mmol), then stirred overnight at 80 ° C. An additional amount of ^) - (-) - 3,3,3-trifluoro-1,2-epoxypropane (2.38 μl) was added and the reaction mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% EtOAc in a mixture of hexane isomers, then 0-10% MeOH in EtOAc as eluent gradient), then again by chromatography on reverse phase C18 (using 5-95% water-ACN with 0.1% TFA gradient eluent) to give the TFA salt of the title compound. The TFA salt was dissolved in MeOH (5 ml), passed through P1-HCO3 resin and evaporated under reduced pressure to give the purified title compound (1 mg, 3% yield). MS (apci) m / z = 566.2 (M + H).

Example 474.

6 - (^) - 2-hydroxypropoxy) -4- (6- (6 - ((5-methoxypyrazin-2-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan3-yl) pyridine-3- yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 ((R) -2- hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P80; 25 mg, 0.0404 mmol) in DCE (202 μl) was added successively 5-methoxypyrazine-2-carbaldehyde (11 mg, 0.081 mmol), then NaBH (AcO) ₃ (26 mg, 0.12 mmol). After stirring for 1 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to give the title compound (10 mg, 48% yield). MS (apci) m / z = 513.2 (M + H).

Example 475.

N = \

BUT. JL

4- (6- (6 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) 6- ( (R) -2-hydroxypropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

The title compound (1.36 mg, 6% yield) was prepared and purified using a procedure similar to Example 474 followed by LCMS to complete the reaction and replace 5methoxypyrazine-2-carbaldehyde with 5-fluoro-6-methoxynicotinaldehyde. MS (apci) m / z = 530.2 (M + H).

Example 476.

No. \ ⁿ about. to,

Υ oh Ν oh

6 - (^) - 2-hydroxypropoxy) -4- (6- (6- (6-methoxy-nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

Into a solution of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2hydroxypropoxy) pyrazolo [1,5-a] pyridin-3 -carbonitrile (intermediate P81; 75 mg, 0.19 mmol) in DCM (3842 μL), 2-methoxy-5-pyridinecarboxylic acid (35.30 mg, 0.2305 mmol), HATU (87.65 mg, 0 , 2305 mmol) and DIEA (133.8 μl, 0.7684 mmol) were stirred for 2 h at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using a gradient of 50-100% EtOAc in a mixture of hexane isomers followed by 0-20% MeOH in EtOAc as eluent gradient) to afford the title compound (47.92 mg, 47% yield) ... MS (apci) m / z = 526.2 (M + H).

- 325 035568

Example 477.

6 - (^) - 2-hydroxypropoxy) -4- (6- (6 - ((5-methoxypyrazin-2-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan3-yl) pyridine-3- yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (7.91 mg, 38% yield) was prepared and purified using a procedure similar to Example 474, followed by LCMS to confirm completion of the reaction, substituting for bis- (2,2,2-trifluoroacetate) 4- ( 6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 ((R) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile on bis- (2,2,2-trifluoroacetate) 4- (6- (3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((S) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P83). MS (apci) m / z = 513.2 (M + H).

Example 478.

N = \

Η0 ^ ₀ ΛΛρ _{Ν F}

4- (6- (6 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) 6- ( (S) -2-hydroxypropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

The title compound (5.37 mg, 25% yield) was prepared and purified using a procedure similar to Example 474, followed by LCMS to confirm completion of the reaction, substituting 5-fluoro-6- for 5-methoxypyrazine-2-carbaldehyde. methoxynicotinaldehyde, and replacing bis- (2,2,2trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile on bis- (2,2,2-trifluoroacetate) 4- (6- (3,6diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl ) -6 - ((S) -2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P83). MS (apci) m / z = 530.2 (M + H).

Example 479.

N = \

HO ^ _o AXp _{N Cl} 'A #

4- (6- (6 - ((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) 6- ( (S) -2-hydroxypropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

The title compound (4.66 mg, 26% yield) was prepared and purified using a procedure similar to Example 474, followed by LCMS to confirm completion of the reaction, substituting 5-chloro-6- for 5-methoxypyrazine-2-carbaldehyde. methoxy-nicotinaldehyde, and replacing bis- (2,2,2 trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2- hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile on bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridine -3-yl) -6 - ((S) -2-hydroxypropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P83). MS (apci) m / z = 546.2 (M + H).

Example 480.

4- (6- (6 - ((6- (difluoromethoxy) pyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) -6 - ((S ) -2-hydroxypropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

The title compound (9.19 mg, 52% yield) was prepared and purified using a procedure similar to Example 474 followed by LCMS to confirm completion of the reaction substituting 6- (difluoromethoxy) nicotinaldehyde for 5-methoxypyrazine-2-carbaldehyde and replacing bis- (2,2,2trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - (^) - 2-hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile on bis- (2,2,2-trifluoroacetate) 4- (6- (3,6diazαbicyclo [3.1.1] heptαn-3-yl) pyridin-3-yl ) -6 - ((S) -2-hydroxypopoxy) pyrazolo [1,5-a] pyridine-3

- 326 035568 carbonitrile (intermediate P83). MS (apci) m / z = 548.2 (M + H).

Example 481.

about

6 - (^) - 2-hydroxypropoxy) -4- (6- (6- (6-methoxy-nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 ((S) -2- hydroxypropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P83; 20 mg, 0.032 mmol) in DCM (646.4 μl), 2-methoxy-5-pyridinecarboxylic acid (5.942 mg, 0.03880 mmol), HATU (14.75 mg, 0.03880 mmol) and DIEA (22.53 μl, 0.1293 mmol), and stirred for 2 h at ambient temperature. The reaction mixture was purified directly by chromatography on silica gel (using a gradient of 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to give of the title compound (13.85 mg, 81% yield). MS (apci) m / z = 526.2 (M + H).

Example 482.

6 - (^) - 2,3-dihydroxypropoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3-yl) pyridine- 3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (5.74 mg, 16% yield) was prepared and purified using a procedure similar to that described in Example 460, substituting (R) - for (R) - 3- (bromomethyl) cyclobutan-1-ol, cis 4 chloromethyl-2,2-dimethyl-1,3-dioxolane (1.2 eq.). MS (apci) m / z = 528.3 (M + H).

Example 483.

6 - (^) - 3- (dimethylamino) -2-hydroxypropoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane-3- yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Stage 1: preparation of bis (2,2,2-trifluoroacetate) tert-butyl ((2R) -3 - ((3-cyano-4- (6- (6 - ((6methoxypyridin-3-yl) methyl) - 3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin6-yl) oxy) -2-hydroxypropyl) carbamate. In a solution of 6-hydroxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) 3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [ 1,5-a] pyridine-3-carbonitrile (intermediate P71; 50 mg, 0.110 mmol) in DMA (221 μL) was added sequentially to ₂ CO3 ( _TB ) (60.9 mg, 0.441 mmol) and ^)) - 1 - (tert-butoxycarbonyl) -2,3-oxiranylamine (22.9 μl, 0.132 mmol), then stirred for 16 h at 60 ° C. Additionally, ^) - 1- (tert-butoxycarbonyl) -2,3-oxiranylamine (9.54 μL) was introduced and the reaction mixture was stirred again for 16 h at 60 ° C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, washed with water (3x) and then with saturated sodium chloride solution (1x). The organic extracts were dried over anhydrous Na ₂ SO ₄ ( _TB ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound (19.5 mg, 28% yield). MS m / z = 627.3 (M + H) Step 2: Preparation of bis- (2,2,2-trifluoroacetate) 6 - (^) - 3-amino-2-hydroxypropoxy) -4- (6- (6 - ((6methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1. ^ Heptan-3-yl ^ iridin-3-yl ^ irazolo ^ A ^ pyridine3-carbonitrile. In a solution of tert-butyl ((2R) -3 - ((3-cyano-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -2-hydroxypropyl) carbamate (step 1; 16.2 mg, 0.0258 mmol) in DCM (1 ml), added TPA (1 ml) and stirred in 1 h at ambient temperature The reaction mixture was evaporated under reduced pressure to give the title compound, assuming quantitative yield MS m / z = 527.3 (M + H).

Stage 3: obtaining 6 - (^) - 3- (dimethylamino) -2-hydroxypropoxy) -4- (6- (6 - ((6-methoxypyridine-3

- 327 035568 yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. In a mixture of bis (2,2,2-trifluoroacetate) 6 - (^) - 3-amino-2-hydroxypropoxy) -4- (6- (6 - ((6-methoxypyridin-3yl) methyl) -3.6 -diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (19.5 mg, 0.0258 mmol) in DCM (258 μL) was added sequentially formaldehyde (19.2 μl, 0.258 mmol) and NaBH (AcO) ₃ (27.4 mg, 0.129 mmol). After stirring overnight at ambient temperature, the reaction mixture was diluted with EtOAc, washed with water (3x) and then with saturated sodium chloride solution (1x). The organic extracts were dried over anhydrous Na ₂ SO ₄ ( _mw ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the purified title compound (6.2 mg, 43% yield). MS (apci) m / z = 555.3 (M + H).

Example 484.

6 - ((1-hydroxycyclopropyl) methoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptan-3-yl) pyridin 3-yl ) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In solution, 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6 - ((1hydroxycyclopropyl) methoxy) pyrazolo [1,5-a] pyridine dihydrochloride 3-carbonitrile (intermediate P84; 50.7 mg, 0.107 mmol) and 6-methoxy-nicotinaldehyde (137.1 mg, 1.943 mmol) in DCM (1.0 ml) were added successively NaBH (AcO) ₃ (514.8 mg, 2.429 mmol) and 3 drops of glacial acetic acid. The resulting mixture was stirred for 16 hours at ambient temperature, then additional 6-methoxy-nicotinaldehyde (29.3 mg, 0.213 mmol) and NaBH (AcO) ₃ (45.2 mg, 0.213 mmol) were added sequentially. The resulting mixture was stirred for 20 hours at ambient temperature. The reaction mixture was purified directly by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent) to afford the title compound as a TFA salt. The TPA salt was diluted with a 4: 1 mixture of DCM: iso-PrOH and extracted with saturated NaHCO (^ ().). The organic extracts were dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure. The residue was re-purified by silica gel chromatography (using 1-30% DCM-MeOH with 2% NH4OH as gradient eluent) to afford the purified title compound (13.2 mg, 24% yield). MS (apci) m / z = 524.2 (M + H).

Example 485.

about

6- (2-hydroxy-2-methylpropoxy) -4- (6- (3- (6-methoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3 -car bonitrile.

Stage 1: obtaining tert-butyl-6- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5a] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylate. In an inert atmosphere (N2 (^) with mechanical stirring, 4- (3) -diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (49.3 g, 249 mmol) in DMSO (200 ml) was added 6fluoropyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 58 g, 178 mmol) and DIEA (93.1 ml, 533 mmol) and stirred for 42 h at 90 ° C. After cooling to ambient temperature, the reaction mixture was poured into ice water (2 L). The aqueous mixture was stirred for 15 min before adding heptane (1 L). The two-phase mixture was vigorously stirred for 2 h. The resulting biphasic suspension was filtered under reduced pressure and the solids washed sequentially with water (3x200 ml) and heptane (3x200 ml) to give a product mixture containing 5-20% of the title compound, tert-butyl 6- (5- ( 3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane 3-carboxylate, together with regioisomer, tre t-butyl-3- (5- (3-cyano-6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -3,6-diazabicyclo [ 3.1.1] heptane-6 carboxylate (intermediate P43, step 1) (92 g, quantitative yield). The regioisomeric mixture was transferred to stage 2 without separation (note: under these reaction conditions, tert-butyl ester of 3,6-diazabicyclo [3.1.1] heptane-6-carboxylic acid can partially isomerize into the regioisomer, tert-butyl ester of 3,6-diazabicyclo [3.1.1 ] heptane-3-carboxylic acid). MS (apci) m / z = 505.3 (M + H).

Stage 2: preparation of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) -6- (2- 328 035568 hydroxy-2-methylpropoxy) pyrazolo dihydrochloride [1 , 5-a] pyridine-3-carbonitrile. In an inert atmosphere (N ₂ ( _r )) at 0 ° C, a solution of the regioisomeric mixture of tert-butyl 6- (5- (3-cyano-6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5] -a] pyridine- 4-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-3 carboxylate and tert-butyl 3- (5- (3-cyano-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (step 1; 92 g, 182 mmol) in DCM (456 ml) was added dropwise TFA over 15 min (281 ml). The resulting mixture was left to warm to ambient temperature. After stirring for 3 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure. Under an inert atmosphere (N2 ( _r )), the resulting oil was diluted with MeOH (600 ml) and cooled to 0 ° C. A cold (0 ° C) solution was added dropwise over 15 min with 5 M HCl in propanol (365 mL, 1823 mmol). After stirring for 30 min at ambient temperature, the resulting mixture was filtered under reduced pressure, washing the solids with MeOH (150 ml). Under an inert atmosphere (Ν ₂ ( _γ )), the crude solids were suspended in 4: 1 MTBE: MeOH (500 ml), cooled to 0 ° C, then 5 M HCl in propanol (73 ml, 364.6 mmol) was re-added. After stirring for 15 min at ambient temperature, the resulting suspension was filtered, washing the solids with 4: 1 MTBE: MeOH (200 mL). The solids were collected and dried under reduced pressure to give a product mixture containing 5-20% of the title compound 4- (6- (3,6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3yl) dihydrochloride -6- (2-hydroxy-2-methylpropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile together with its regioisomer, dihydrochloride 4- (6- (3,6-diazabicyclo [3.1.1] heptane-3 -yl) pyridin-3-yl) -6- (2-hydroxy-2methylnropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile (intermediate P43, step 2) (80.2 g, quantitative yield). The regioisomeric mixture was transferred to step 3 without separation. MS (apci) m / z = 405.2 (M + H).

Stage 3: preparation of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (3- (6-methoxy-nicotinoyl) -3,6 diazabicyclo [3.1.1] hepman-6-yl) pyridin-3) -yl ) pyrαzolo [1,5-a] pyridine-3-carbonitrile. In a solution of the regioisomeric mixture, 4- (6- (3,6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile, together with its regioisomer, dihydrochloride 4- (6- (3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6- (2-hydroxy-2- methylpropoxy) pyrazolo [1.5a] pyridine-3-carbonitrile (step 2; 2.16 g, 4.52 mmol) in DMSO (22.6 ml) 6-methoxy-nicotinic acid (0.831 g, 5.43 mmol) was added sequentially , DIEA (2.52 ml, 14.5 mmol) and HATU (2.06 g, 5.43 mmol). The reaction mixture was stirred for 1 hour at ambient temperature. The resulting suspension was filtered under reduced pressure, and the solids were collected. The solids were recrystallized from hot EtOAc by cooling to ambient temperature overnight. The crystalline material was collected by filtration, and the filtrate was evaporated under reduced pressure. The residue from the filtrate was purified by silica gel chromatography. The residue from the chromatographic purification and the solids collected by filtration were combined and dissolved in ACN (12 ml). The mixture was stirred at 82 ° C, then cooled to ambient temperature, diluted with water (18 ml) and stirred for 2 days at ambient temperature. The resulting slurry was filtered under reduced pressure to afford a product mixture (1.63 g, 67% yield) containing 520% of the title compound, 6- (2-hydroxy-2-methylpropoxy) -4- (6- (3- ( 6methoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3 carbonitrile together with the regioisomer 6- (2) -hydroxy-2- methylpropoxy) -4- (6- (6- (6-methoxynicotinoyl) 3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3 - carbonitrile.

The regioisomeric mixture was separated in step 4.

Step 4: Isolation of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (3- (6-methoxy-nicotinoyl) -3,6 diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A solution of the regioisomeric mixture of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (3- (6-methoxynicotinoyl) -3,6diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile and 6- (2-hydroxy2-methylpropoxy) -4- (6- (6- (6-methoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3 -yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (50 mg, 0.0927 mmol) in 60:40 ACN: water with 2% TFA (1.2 ml) was purified by chromatography on reverse phase C18 (using 25-75% ACN: water with 0.1% TPA as gradient eluent) to independently prepare the TPA salt 6- (2-hydroxy-2methylpropoxy) -4- (6- (3- (6- methoxy-nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. The TPA salt was diluted with saturated NaHCO ₃ , _H. ,, _{ul l} (10 ml) and extracted with DCM (2x10 ml). The combined organic extracts were dried over anhydrous NaNO ₄ ( _ta ), filtered and evaporated under reduced pressure to give the title compound (26.4 mg, 53% recovery), free of regioisomer. MS (apci) m / z = 540.3 (M + H).

- 329 035568

Example 486.

4- (6- (4-benzyl-3-oxo-1-yl) pyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine3-carbonitrile.

In a microwave treatment vessel, in a solution of 4- (6-fluoropyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 25.0 mg , 0.0766 mmol) and 1benzylpiperazin-2-one (58.2 mg, 0.306 mmol) in DMA (2 ml) was added TEA (52.0 μl, 0.383 mmol). The reaction vessel was tightly closed and the reaction mixture was subjected to microwave irradiation at 150 ° C for 14 h. The reaction mixture was cooled to ambient temperature, then diluted with EtOAc, washed with water (3x) and saturated aqueous sodium chloride solution (1x), then evaporated at reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as gradient eluent) to afford the TFA salt of the title compound. The TPA salt was dissolved in 4: 1 DCM / iso-PrOH and extracted with saturated NaHCO ₃ ( _βod ). The organic extracts were dried over anhydrous Na _: SC) | _{(| c: 1} , filtered and evaporated under reduced pressure to give the purified title compound (14.3 mg, 38% yield) MS (apci) m / z = 497.2 (M + H).

Example 487.

^) - 6- (2-hydroxy-2-methylpropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) -2-methylpiperazin-1yl) pyridin-3-yl) pyrazole [ 1,5-a] pyridine-3-carbonitrile.

To a solution of bis- (2,2,2-trifluoroacetate) ^) - 6- (2-hydroxy-2-methylpropoxy) -4- (6- (2-methylpiperazin1-yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3-carbonitrile (intermediate P85; 13 mg, 0.0205 mmol) in DCE (512 μL), 6-methoxynicotinaldehyde (5.62 mg, 0.0410 mmol) and NaBH (AcO) ₃ ( 13.0 mg, 0.0615 mmol). After stirring the reaction mixture for 1 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH4CH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to give the title compound (1.80 mg, 17% yield). MS (apci) m / z = 528.3 (M + H).

Example 488.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) -4,7-diazaspiro [2.5] octan7-yl) pyridin-3 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (4,7-diazaspiro [2.5] octan-7-yl) pyridin-3-yl) -6- (2hydroxy-2-methylpropoxy ) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P86; 20 mg, 0.031 mmol) in DCE (155 μl) was added successively 6-methoxynicotinaldehyde (8.5 mg, 0.062 mmol) and NaBH (AcO) ₃ (20 mg, 0.093 mmol). After stirring the reaction mixture for 1 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in hexane, then 0-60% (2% NH4OH 20% MeOH / 78% DCM) in DCM in as eluent gradient) to give the title compound (1.0 mg, 6% yield). MS (apci) m / z = 540.3 (M + H).

Example 489.

- 330 035568

6- (2-hydroxy-2-methylpropoxy) -4- (6- (9 - ((6-methoxypyridin-3-yl) methyl) -3-oxa-7,9diazabicyclo [3.3.1] nonan-7 yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate 4- (6- (3-oxa-7,9-diazabicyclo [3.3.1] nonan-7-yl) pyridin-3yl) -6- (2-hydroxy- 2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P87; 28 mg, 0.042 mmol) in DCM (1 ml), TEA (27 μL, 0.19 mmol), 6 methoxy nicotinaldehyde (8, 5 mg, 0.062 mmol) and NaBH (AcO) ₃ (27 mg, 0.13 mmol) After stirring the reaction mixture for 12 h at ambient temperature, the reaction mixture was diluted with water and extracted with DCM. The organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 10% MeOH / DCM with 1% NH4OH as eluent) to give the title compound (7.5 mg, 31% yield). MS (apci) m / z = 556.3 (M + H).

Example 490.

N = \ fr ⁰ 'ΑΝχΑ / Ν o

6- (2-hydroxy-2-methylpropoxy) -4- (6- (9- (6-methoxynicotinoyl) -3-oxa-7,9diazabicyclo [3.3.1] nonan-7-yl) pyridin-3-yl) pyrazolo [1, 5 ^] pyridine-3-carbonitrile.

Into a mixture of bis- (2,2,2-trifluoroacetate 4- (6- (3-oxa-7,9-diazabicyclo [3.3.1] nonan-7-yl) pyridin-3-yl) -6 (2-hydroxy -2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P87; 28 mg, 0.042 mmol), 6-methoxy-nicotinic acid (15 mg, 0.097 mmol) and HATU (27 mg, 0.071 mmol) in DMSO (600 μl) was added TEA (27 μl, 0.19 mmol) After stirring for 12 h at ambient temperature, the reaction mixture was poured into water (5 ml) and stirred for 1 h at ambient temperature. The resulting suspension was filtered. washing with water The solids were collected and purified by silica gel chromatography (using 10% MeOH / DCM with 1% NH4OH as eluent) to afford the purified title compound (5 mg, 21% yield) MS (apci) m / z = 570.2 (M + H).

Example 491.

4- (5-fluoro-6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) 6- ( 2-hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) -5-fluoropyridin-3yl) -6- (2-hydroxy- 2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (14 mg, 0.0215 mmol) (intermediate P88; 28 mg, 0.064 mmol) in DCE (108 μl) was added sequentially 6 methoxy nicotinaldehyde (5.90 mg , 0.0430 mmol) and NaBH (AcO) ₃ (13.7 mg, 0.0646 mmol). After stirring the reaction mixture for 1 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH4OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to give the title compound (6.17 mg, 53% yield). MS (apci) m / z = 544.2 (M + H).

Example 492.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) -5- methylpyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) -5-methylpyridin-3yl) -6- (2-hydroxy- 2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P89; 10 mg, 0.0155 mmol) in DCE (77.3 μL) was added successively 6-methoxynicotinaldehyde (4.24 mg, 0, 0309 mmol) and NaBH (AcO) ₃ (9.83 mg, 0.0464 mmol). After stirring for 1 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM)

- 331 035568 in DCM as gradient eluent) to give the title compound (3.41 mg, 41% yield). MS (apci) m / z = 540.2 (M + H).

Example 493.

N = \

HCk 'L & aU'

4- (5- (6 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) 6- ( 2-hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

To a solution of bis- (2,2,2-trifluoroacetate) 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2hydroxy-2-methylpropoxy ) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P90; 25 mg, 0.0395 mmol) in DCE (197 μl) 5-fluoro-6-methoxy-nicotinaldehyde (12.2 mg, 0.0789 mmol) and NaBH (AcO) ₃ (25.1 mg, 0.118 mmol). After stirring for 1 h at ambient temperature, the reaction mixture was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-60% (2% NH ₄ OH / 20% MeOH / 78% DCM) in DCM as gradient eluent) to afford the title compound (8.17 mg, 38% yield). MS (apci) m / z = 545.2 (M + H).

Example 494.

6- (2-hydroxy-2-methylpropoxy) -4- (5- (6 - ((5-methoxypyrazin-2-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2 -yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (2.1 mg, 10% yield) was prepared and purified using a procedure similar to Example 493 substituting 5-methoxypyrazine-2-carboxaldehyde for 5-fluoro-6-methoxy-nicotinaldehyde. MS (apci) m / z = 528.2 (M + H).

Example 495.

4- (5- (6 - ((6- (difluoromethoxy) pyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2 yl) -6- (2 -hydroxy-2-methylpropoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

The title compound (3.81 mg, 17% yield) was prepared and purified using a procedure similar to Example 493 substituting 6 (difluoromethoxy) nicotinaldehyde MS (apci) m / z = 563 for 5-fluoro-6-methoxy-nicotinaldehyde , 2 (M + H).

Example 496.

6- (2-hydroxy-2-methylpropoxy) -4- (4- (6- (6-methoxynicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) phenyl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into a solution of 4- (4- (3,6-diazabicyclo [3.1.1] heptan-3-yl) phenyl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile ( intermediate P49; 20 mg, 0.05 mmol) in DCM (600 μl), 6-methoxy-nicotinic acid (8.350 mg, 0.05452 mmol), HATU (22.62 mg, 0.05948 mmol) and DIEA (34, 54 μl, 0.1983 mmol). After stirring for 4 h at ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 50-100% EtOAc in hexane isomers followed by 0-20% MeOH in EtOAc as gradient eluent) to afford the purified title compound (20.48 mg, 77% yield). MS (apci) m / z = 539.2 (M + H).

- 332 035568

Example 497.

6- (2-hydroxy-2-methylpropoxy) -4- (2- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3-yl) pyrimidine-5 -yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into solution 4- (2- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrimidin-5-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P91; 54 mg, 0.11 mmol) in DCM (1 ml) was added successively 6-methoxynicotinaldehyde (23 mg, 0.17 mmol), NaBH (AcO) ₃ (120 mg, 0.56 mmol ) and DMA (500 μl). After stirring overnight at ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 5% MeOH in DCM as eluent) to give the title compound (29 mg, 48% yield). MS (apci) m / z = 527.2 (M + H).

Example 498.

1 - ((3-chloro-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol.

In a solution of 2,2,2-trifluoroacetate 1 - ((4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -3chloropyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol (intermediate P92; 50 mg, 0.098 mmol) in DMA (750 μl), TEA (150 μl, 0.098 mmol), 6-methoxy-nicotinaldehyde (40 mg, 0 , 29 mmol) and NaBH (AcO) ₃ (62.1 mg, 0.293 mmol). After stirring for 3 h at ambient temperature, the reaction mixture was quenched with water and extracted with DCM (3x). The combined organic extracts were dried over anhydrous NaSO ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-20% MeOH (2% NH ₄ OH / DCM as gradient eluent) to give the title compound (49.5 mg, 95% yield) MS (apci) m / z = 535.2 (M + H).

Example 499.

1 - ((3-chloro-4- (6- (6 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridine-3 -yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol.

The title compound (45 mg, 83% yield) was prepared and purified using a procedure similar to Example 498 substituting 5-fluoro-6methoxy-nicotinaldehyde for 6-methoxy-nicotinaldehyde. MS (apci) m / z = 553.2 (M + H).

Example 500.

2,2,2-trifluoroacetate 1 - ((3-chloro-4- (6- (6 - ((6- (difluoromethoxy) pyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3 -yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol.

The title compound was prepared using a procedure similar to that described for Example 498 substituting b- (difluoromethoxy) nicotinaldehyde for 6-methoxy-nicotinaldehyde using excess TEA (6 eq.) And increasing the reaction time from 3 hours to overnight. After C18 reverse phase chromatography (using 5-95% ACN / water with 0.1% TFA as gradient eluent), the title compound was isolated (17.2 mg, 44% yield). MS (apci) m / z = 571.2 (M + H).

- 333 035568

Example 501.

2,2,2-trifluoroacetate 1 - ((3-chloro-4- (6- (6 - ((6-ethoxy-5-fluoropyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane- 3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) -2-methylpropan-2-ol.

The title compound was prepared using a procedure similar to that described in Example 498 substituting 6-ethoxy-5-fluoro-nicotinaldehyde for 6-ethoxy-5-fluoro-nicotinaldehyde using excess TEA (6 equiv) and increasing the reaction time from 3 hours to overnight. After purification by C18 reverse phase chromatography (using 5-95% ACN / water with 0.1% TFA as gradient eluent), the title compound (13.5 mg, 33% yield) MS (apci) m / z = 567.2 (M + H).

Example 502.

2,2,2-trifluoroacetate 3- (5- (3-chloro-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridin-4yl) pyridin-2-yl) -M- ( 6-methoxypyridin-3-yl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxamide.

To a cold (0 ° C) solution of triphosgene (16.6 mg, 0.0561 mmol) in DCM (250 μl), DIEA (64.6 μl, 0.374 mmol) and 6-methoxypyridin-3-amine (8.70 mg , 0.0701 mmol). The resulting mixture was stirred for 1 hour at 0 ° C. 2,2,2-trifluoroacetate 1 - ((4- (6- (3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) -3-chloropyrazolo [1,5-a] pyridine- 6-yl) oxy) -2-methylpropan-2-ol (intermediate P92; 30 mg, 0.0467 mmol) was added to a cold (0 ° C) triphosgene solution. The resulting mixture was stirred overnight at ambient temperature and then quenched with water. The biphasic mixture was extracted with DCM (3x) in a PS frit. The combined organic extracts were evaporated under reduced pressure and the crude residue was purified by C18 reverse phase chromatography (using 5-95% water-ACN with 0.1% TFA as gradient eluent) to give the purified title compound (11.5 mg, 44% yield). MS (apci) m / z = 564.2 (M + H).

Example 503.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (2 - ((6-methoxypyridin-3-yl) methyl) -2,7diazaspiro [3.5] nonan-7-yl) pyridin-3 yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Step 1: Preparation of tert-butyl 2 - ((6-methoxypyridin-3-yl) methyl) -2,7-diazaspiro [3.5] nonane-7-carboxylate. To a suspension of tert-butyl 2,7-diazaspiro [3,5] nonane-7-carboxylate hydrochloride (100 mg, 0.381 mmol) in 1,2-dichloroethane (761 μL) was added 6-methoxynicotinaldehyde (104 mg, 0.761 mmol) followed by sodium triacetoxyhydroborate (242 mg, 1.14 mmol). After stirring overnight at ambient temperature, the reaction mixture was directly purified by silica gel chromatography (30-100% EtOAc in hexane isomers) to afford the title compound (100 mg, 76% yield). LCMS m / z 348.2 [M + H].

Step 2: Preparation of bis (2,2,2-trifluoroacetate) 2 - ((6-methoxypyridin-3-yl) methyl) -2,7diazaspiro [3,5] nonane. To a solution of tert-butyl 2 - ((6-methoxypyridin-3-yl) methyl) -2,7 diazaspiro [3,5] nonane-7-carboxylate (100 mg, 0.288 mmol) in DCM (3 ml) was added TFA (3 ml). After stirring at room temperature for 1 hour, the reaction mixture was evaporated under reduced pressure to give the title compound, which was used directly in the next step, assuming quantitative yield. LCMS m / z 248.1 (M + H).

Stage 3: preparation of 6- (2-hydroxy-2-methylpropoxy) -4- (6- (2 - ((6-methoxypyridin-3-yl) methyl) -2,7diazaspiro [3,5] nonan-7-yl ) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile. A mixture of bis- (2,2,2 trifluoroacetate) 2 - ((6-methoxypyridin-3-yl) methyl) -2,7-diazaspiro [3.5] nonane (131.1 mg, 0.27 mmol), 4 ( 6-fluoropyridin-3-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P42; 40 mg, 0.12 mmol) and K ₂ CO ₃ (169 mg, 1.2 mmol) in DMSO (613 μl) was stirred for

- 334,035,568 nights at 80 ° C. The reaction mixture was distributed between DCM and water (10 ml each). The aqueous layer was extracted with DCM (3x10 ml). The organic extracts were combined and washed with saturated aqueous sodium chloride solution (10 ml), then dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexane followed by 0-20% MeOH in EtOAc) to give the title product as a solid (16 mg, 24% yield). LCMS m / z: 554.2 (M + H).

Example 504.

6-ethoxy-4- (6- (4- (6-methoxypyridin-3-yl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Via a mixture of 6-ethoxy-4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine3-carbonitrile dihydrochloride (intermediate P94; 50 mg, 0.12 mmol), 5 -bromo-2-methoxypyridine (23.04 μl, 0.1780 mmol), KOtBu (66.58 mg, 0.5934 mmol), Pd ₂ (dba) ₃ -CHCl ₃ (6.142 mg, 0.005934 mmol) and X-phos (11.31 mg, 0.02373 mmol) in toluene (1187 μl) was purged with N ₂ ( _r ) for 30 seconds. The reaction vessel was tightly closed and the reaction mixture was stirred for 17 h at 100 ° C. The reaction mixture was cooled to ambient temperature and partitioned between water (10 ml) and DCM (10 ml). After phase separation, the aqueous extracts were washed with additional DCM (3x5 ml). The combined DCM extracts were dried over anhydrous Na ^ O ^), filtered, and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-55% ACN in water as eluent gradient) to afford the purified title compound (2.8 mg, 5% yield). A significant amount of the additional title compound remained in the aqueous extracts. The aqueous extracts were evaporated under reduced pressure and the residue was purified by C18 reverse phase chromatography (using 5-45% ACN in water as gradient eluent) to provide additional purified title compound (6 mg, 11% yield). The title compound isolated from both chromatographic purifications was combined (9 mg, 16% yield). MS (apci) m / z = 456.2 (M + H).

Example 505.

tert-Butyl (1S, 4S) -5- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -2.5diazabicyclo [2.2.1] heptane-2-carboxylate.

Suspension of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 100 mg, 0.354 mmol), tert-butyl (^^) - 2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (84.3 mg, 0.425 mmol) and DIEA (185 μl, 1.06 mmol) in DMSO (886 μl) were stirred for 23 h at 90 ° C. Additional tert-butyl (^^) - 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (ca. 20 mg, 0.10 mmol) was added and the mixture was stirred for an additional 3 days at 90 ° C. After cooling to ambient temperature, the resulting suspension was stirred for 2 hours. The suspension was filtered under reduced pressure, washing the solids sequentially with a few drops of DMSO and MTBE (3x1 ml). The filtrate was slowly poured into water (7 ml) and the suspension was stirred for 1 hour at ambient temperature. The aqueous suspension was filtered under reduced pressure and the solids were washed with water (3x5 ml) and heptane (3x5 ml). The isolated solids from both filtrates were combined to provide the purified title compound (149.2 mg, 90% yield). MS (apci) m / z = 461.2 (M + H).

Example 506.

4- (6 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo dihydrochloride 335 035568

[1,5-a] pyridine-3-carbonitrile.

At ambient temperature, to a suspension of tert-butyl (^^) - 5- (5- (3-11iano-6ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -2.5 - diazabicyclo [2.2.1] heptane-2-carboxylate (example 505; 88.8 mg, 0.193 mmol) in MeOH (386 μl) was added concentrated (12 M) HCl (321 μl, 3.86 mmol). The resulting solution was stirred for 17 h at ambient temperature, then diluted with additional MeOH (1 ml). The mixture was evaporated under reduced pressure and the residue was suspended in MTBE (2 ml) and MeOH (0.5 ml). The resulting suspension was rapidly stirred and sonicated, and then filtered under reduced pressure. The solids were washed with MTBE and EtOAc, and dried under reduced pressure to give the purified title compound (64.2 mg, 77% yield). MS (apci) m / z = 361.2 (M + H).

Example 507.

N = \ if I

6-ethoxy-4- (6 - ((^^) - 5- (6-methoxypyridin-3-yl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3yl) pyrazole [1 , 5-a] pyridine-3-carbonitrile.

Through a mixture of 4- (6 - ((^^) - 2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 506; 25 mg, 0.058 mmol), 5-bromo-2methoxypyridine (11.20 μl, 0.08654 mmol), KOtBu (22.66 mg, 0.2019 mmol), Pd ₂ (DBA) ₃ -CHCl ₃ (2.986 mg, 0.002885 mmol) and X-phos (5.501 mg, 0.01154 mmol) in toluene (576.9 μl) were purged with N ₂ (r) for 30 seconds. The reaction vessel was tightly closed and the reaction mixture was stirred for 2 days at 100 ° C. The reaction mixture was cooled to ambient temperature, then directly purified by C18 reverse phase chromatography (using 5-65% ACN in water as eluent gradient) to afford the purified title compound (12.5 mg, 44% yield). MS (apci) m / z = 468.2 (M + H).

Example 508.

6-ethoxy-4- (6- (1-tosyl-1,6-diazaspiro [2.5] octan-6-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

Mixture of 4- (6- (4-amino-4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (intermediate P93); 78.5 mg, 0.200 mmol), TsCl (114 mg, 0.600 mmol), DMAP (4.89 mg, 0.0400 mmol) and TEA (139 μl, 1.00 mmol) in DCM (3 ml) were stirred for 1.5 hours at ambient temperature. Additional TsCl (38 mg, 0.20 mmol) was added. After stirring for an additional 15 h at ambient temperature, the mixture was purified directly by silica gel chromatography (using 0-50% EtOAc in hexane isomer as gradient eluent) to afford the title compound (55 mg, 52% yield). MS (apci) m / z = 529.2 (M + H).

Example 509.

6-ethoxy-4- (6- (1- (phenylsulfonyl) -1,6-diazaspiro [2,5] octan-6-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

In a suspension of 4- (6- (4-amino-4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P93; 40 mg, 0.10 mmol) and TEA (57 μl, 0.41 mmol) in DCM (2 ml) benzenesulfonyl chloride (32.52 μl, 0.2548 mmol) and DMAP (1.245 mg, 0.01019 mmol) were added sequentially. The resulting mixture was stirred for 22 hours at ambient temperature. The reaction mixture was purified directly by silica chromatography

336 035568 gel (using 0-70% EtOAc in a mixture of hexane isomers as gradient eluent) to afford the title compound (26 mg, 50% yield). MS (apci) m / z = 515.2 (M + H).

Compounds in the table. FF was prepared using a method similar to that described in the synthesis of 6ethoxy-4- (6- (1- (phenylsulfonyl) -1,6-diazaspiro [2.5] octan-6-yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine 3-carbonitrile (Example 509), replacing benzenesulfonyl chloride with the appropriate sulfonyl chloride. When preparing Example 510, no DMAP was added. The completion of the reactions was monitored by LCMS. After chromatographic purification using an appropriate gradient eluent, the title compounds were isolated.

FF table

No. Example a Structure Chemical name MS apci (m / z) 510 N == \ Ji Τ ν y-V γχ 6-ethoxy-4- (6- (1 - ((4fluorophenyl) sulfon yl) -1,6- diazaspiro [2.5] octa n-6-yl) pyridin-3yl) pyrazolo [1.5а] pyridine-3carbonitrile 533.1 (M + H) 511 Ν == \ χ Τ ν 6-ethoxy-4- (6- (1 - ((6methoxypyridin-3yl) sulfonyl) -1,6diazaspiro [2.5] octa n-6-yl) pyridin-3yl) pyrazole o [1,5а] pyridine-3carbonitrile 546.1 (M + H) 512 Ν = \ Ji Τ ΥνΛ B / I γχ 6-ethoxy-4- (6- (1 - ((4methoxyphenyl) sulphonyl) -1.6- diazaspiro [2.5] octa n-6-yl) pyridin-3yl) pyrazolo [1.5а] pyridine-3carbonitrile 545.2 (M + H)

Example 513.

6-ethoxy-4- (6- (1- (4-fluorobenzoyl) -1,6-diazaspiro [2,5] octan-6-yl) pyridin-3-yl) pyrazolo [1,5a] pyridin-3- carbonitrile.

In a suspension of 4- (6- (4-amino-4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P93; 40 mg, 0.10 mmol) and TEA (56.82 μl, 0.4077 mmol) in DCM (2 ml) was added 4-fluorobenzoyl chloride (14.67 μl, 0.1223 mmol) and stirred for 45 min at ambient temperature. To the mixture was added MsCl (9.466 μl, 0.1223 mmol), stirred for 1 h at ambient temperature, and then DBU (2 drops) was added. The resulting mixture was stirred for an additional 15 hours at ambient temperature and then for 1.5 hours at 40 ° C. After cooling to ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (using 0-50% EtOAc in a mixture of hexane isomers as eluent gradient) to afford the title compound (11 mg, 22% yield). MS (apci) m / z = 497.1 (M + H).

Example 514.

6-ethoxy-4- (6- (1 - (4-methoxybenzoyl) -1,6-diazaspiro [2,5] octan-6-yl) pyridin-3-yl) pyrazolo [1,5a] pyridin-3- carbonitrile.

In a suspension of 4- (6- (4-amino-4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P93; 40 mg, 0.10 mmol) and TEA (56.8 μl,

- 337 035568

0.408 mmol) in DCM (2 ml) was added 4-methoxybenzoyl chloride (16.6 μl, 0.122 mmol) and stirred for 45 min at ambient temperature. To the mixture was added MsCl (9.47 μl, 0.122 mmol), stirred for 2 h at ambient temperature, and then DBU (2 drops) was added. The resulting mixture was stirred for an additional 15 hours at ambient temperature and then for 1.5 hours at 4 ° C 0 ° C. After cooling to ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (using 0-50% EtOAc in a mixture of hexane isomers as gradient eluent) to afford the title compound (3 mg, 6% yield). MS (apci) m / z = 509.2 (M + H).

Example 515.

6-ethoxy-4- (6- (1- (6-methoxynicotinoyl) -1,6-diazaspiro [2.5] octan-6-yl) pyridin-3-yl) pyrazolo [1.5a] pyridin-3- carbonitrile.

In a suspension of 4- (6- (4-amino-4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P93; 40 mg, 0.10 mmol) and TEA (56.8 μl, 0.408 mmol) in DCM (1 ml) was added a solution of 6-methoxynicotinoyl chloride hydrochloride (intermediate R22; 21.0 mg, 0.122 mmol) in DCM (0.5 ml) and stirred within 45 minutes at ambient temperature. To the mixture was added MsCl (9.46 μl, 0.122 mmol), stirred for 30 min at ambient temperature, and then DBU (61.6 μl, 0.408 mmol) was added. The resulting mixture was stirred for 2 h at 40 ° C. After cooling to ambient temperature, the reaction mixture was purified directly by silica gel chromatography (using 0-50% EtOAc in hexane isomers with 2% TEA as gradient eluent) to afford the title compound (12 mg, 23% yield). MS (apci) m / z = 510.2 (M + H).

Example 516.

4- (6- (1-benzoyl-1,6-diazaspiro [2.5] octan-6-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3carbonitrile.

Step 1: Obtaining (4-benzamido-1- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) piperidin-4-yl) methylmethanesulfonate. In a suspension of 4- (6- (4-amino-4- (hydroxymethyl) piperidin-1yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P93; 40 mg, 0.10 mmol) and TEA (56.8 μl, 0.408 mmol) in DCM (2 ml) was added benzoyl chloride (14.2 μl, 0.122 mmol) and stirred for 30 min at ambient temperature. To the mixture was added MsCl (9.47 μl, 0.122 mmol) and stirred for 1.5 h at ambient temperature. The mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (using 0-100% EtOAc in a mixture of hexane isomers as eluent gradient) to afford the title compound (28 mg, 48% yield). MS (apci) m / z = 479.1 (M + H).

Stage 2: preparation of 4- (6- (1-benzoyl-1,6-diazaspiro [2,5] octan-6-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile ... In a solution of (4-benzamido-1- (5- (3-cyano-6ethoxypyrazolo [1 ^^ pyridin ^ -yl ^ iridin ^ -yl ^ iperidin ^ -yl ^ methyl methanesulfonate) (stage 1; 28 mg, 0.049 mmol) in THF (1 ml) DBU (15 μl, 0.097 mmol) was added. The resulting mixture was stirred 15 h at ambient temperature, then 1 h at 50 ° C. After cooling to ambient temperature, the reaction mixture was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (using 0-50% EtOAc in a mixture of hexane isomers as gradient eluent) to give the title compound (22 mg, 94% yield) MS (apci) m / z = 479.1 (M + H).

Example 517.

- 338 035568 tert-butyl 2- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -2,7 diazaspiro [4,5] decane-7 -carboxylate.

A suspension of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 108 mg, 0.383 mmol), tert-butyl-2,7-diazaspiro [ 4,5] decane-7-carboxylate (110 mg, 0.459 mmol) and DIEA (200 μl, 1.15 mmol) in DMSO (957 μl) were stirred for 23 h at 90 ° C. Additional tert-butyl 2,7-diazaspiro [4.5] decane-7-carboxylate (ca. 20 mg, 0.083 mmol) was added. The resulting mixture was stirred for an additional 3 days at 9 ° C 0 ° C. After cooling to ambient temperature, the reaction mixture was slowly poured into water (8 ml). The resulting suspension was stirred for 2 hours at ambient temperature before vacuum filtration. The isolated solids were washed with water (3x5 ml), then dissolved in MTBE (25 ml). The MTBE solution was dried over anhydrous Na ₂ SO ₄ ( _ra ), filtered and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 555% ACN in water as eluent gradient) to afford the purified title compound (56 mg, 29% yield). MS (apci) m / z = 503.25 (M + H).

Example 518.

4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5a] pyridine-3-carbonitrile dihydrochloride.

In a solution of tert-butyl 2- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -2,7diazaspiro [4,5] decane-7- carboxylate (example 517; 54 mg, 0.11 mmol) in DCM (1.1 ml) was added 5-6N. HCl in iso-PrOH (430 μl, 2.1 mmol). The reaction mixture was stirred for 1 h at ambient temperature, then diluted with MTBE (2 ml). The resulting suspension was filtered under reduced pressure and the solids were collected to give the title compound (45 mg, 87% yield). MS (apci) m / z = 403.2 (M + H).

Example 519.

6-ethoxy-4- (6- (7- (6-methoxypyridin-3-yl) -2,7-diazaspiro [4.5] decan-2-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine- 3-carbonitrile.

Via a mixture of 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (Example 518); 25 mg, 0.053 mmol), 5-bromo-2methoxypyridine (10.21 μl, 0.07888 mmol), KOtBu (29.50 mg, 0.2629 mmol), Pd ₂ (dba) ₃ -CHCl ₃ (2.722 mg, 0.002629 mmol) and X-phos (5.014 mg, 0.01052 mmol) in toluene (525.9 μl) was purged with N _{2 (r)} for 30 seconds After the reaction vessel was tightly closed in an atmosphere of N ₂ ( _r ), the reaction mixture was stirred for 26 h at 100 ° C. After cooling to ambient temperature, the reaction mixture was evaporated in vacuo. The crude residue was purified by C18 reverse phase chromatography (using 5-50% ACN in water as eluent gradient) to afford the purified title compound (14 mg, 50% yield). MS (apci) m / z = 510.2 (M + H).

Example 520.

N = \

Jl Τ h ARA) X — Ν tert-butyl (S) -2- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyrigin-2-yl) -2, 7diazaspiro [4,5] decane-7-carboxylate.

Suspension of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate

- 339 035568

P6; 108 mg, 0.383 mmol), tert-butyl ^) - 2,7-diazaspiro [4.5] decane-7-carboxylate (purchased from WuXi AppTes, 110 mg, 0.459 mmol) and DIEA (200 μL, 1.15 mmol ) in DMSO (957 μl) was stirred for 3 h at 90 ° C. Additional tert-butyl (d) - 2,7-diazaspiro [4.5] decane-7 carboxylate (18 mg, 0.075 mmol) was added. The resulting mixture was stirred for an additional 24 hours at 90 ° C. After cooling to ambient temperature, the reaction mixture was slowly poured into water (8 ml). The resulting suspension was stirred for 15 minutes at ambient temperature and then filtered under reduced pressure. The isolated solids were washed with water (3x5 ml) and dried under high vacuum overnight to give the purified title compound (166 mg, 84% yield). MS (apci) m / z = 503.2 (M + H).

Example 521.

^ -NH dihydrochloride ^) - 4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5a] pyridine-3-carbonitrile.

Method A. A solution of tert-butyl (S) -2- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -2,7-diazaspiro [4, 5]] decane-7-carboxylate (example 520; 150 mg, 0.298 mmol) in 5-6N. HCl in iso-PrOH (1.19 ml, 5.97 mmol) was stirred for 2 h at ambient temperature before diluting with EtOH (1 ml). The resulting suspension was stirred for 15 min and then filtered under reduced pressure. The recovered solids were washed sequentially with EtOH (3x200 μl) and Et ₂ O (3x1 ml), and set aside. The filtrate was diluted with MeOH and evaporated under reduced pressure. The solid residue was combined with the solids after filtration and dried under high vacuum overnight to provide the purified title compound (141 mg, 99% yield). MS (apci) m / z = 403.2 (M + H).

Method B. Racemic 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (Example 518; 10 mg, 0.021 mmol) was partitioned between saturated Na ^ O ^^.) and CHCl ₃ . After phase separation, the organic extracts were dissolved in a mixture of solvents MeOH: IPA: DIEA (80: 20: 0.1), then subjected to SFC chiral HPLC (ChiralTech IA; 5 to 70% solvent A in solvent B; solvent A = MeOH: IPA : DIEA / 80: 20: 0.1; solvent B = CO ₂ ) Fractions containing peak 1 of this chiral separation were isolated, combined and evaporated under reduced pressure to give ^) - 4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (3.5 mg, 83% yield). MS (apci) m / z = 403.2 (M + H). Chirality was determined by comparing chiral HPLC of the compound obtained from peak 1 with dihydrochloride (R) -4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1 , 5-a] pyridine-3-carbonitrile prepared according to Method A to obtain (R) -4- (6- (2.7 diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6- ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (3.5 mg, 83% yield).

Example 522.

tert-butyl (R) -2- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -2,7diazaspiro [4,5] decane- 7-carboxylate.

Suspension of 6-ethoxy-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P6; 108 mg, 0.383 mmol), tert-butyl ^) - 2.7- diazaspiro [4,5] decane-7-carboxylate (purchased from WuXi AppTec, 110 mg, 0.459 mmol) and DIEA (200 μl, 1.15 mmol) in DMSO (957 μl) were stirred for 3 h at 90 ° C. Additional tert-butyl (d) - 2,7-diazaspiro [4.5] decane-7-carboxylate (18 mg, 0.075 mmol) was added. The resulting mixture was stirred for an additional 24 hours at 90 ° C. After cooling to ambient temperature, the reaction mixture was slowly poured into water (8 ml). The resulting suspension was stirred for 2 hours at ambient temperature before vacuum filtration. The isolated solids were washed with water (3x5 ml) and then dried under high vacuum overnight to give the purified title compound (180 mg, 93% yield). MS (apci) m / z = 503.2 (M + H).

- 340 035568

Example 523.

Dihydrochloride (^) - 4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5а] pyridine-3-carbonitrile.

Method A. A solution of tert-butyl ^) - 2- (5- (3-cyano-6-ethoxypyrazolo [1,5-a] pyridin-4-yl) pyridin-2yl) -2,7-diazaspiro [4,5 ] decane-7-carboxylate (example 522; 160 mg, 0.318 mmol) in 5-6N. HCl in iso-PrOH (1.27 ml, 6.37 mmol) was stirred for 2 h at ambient temperature before diluting with EtOH (1 ml). The resulting suspension was stirred for 15 min and then filtered in vacuo. The recovered solids were washed sequentially with EtOH (3x200 μl) and Et ₂ O (3x1 ml), and set aside. The filtrate was diluted with MeOH and evaporated under reduced pressure. The solid residue was combined with the solids after filtration and dried under high vacuum overnight to give the purified title compound (141 mg, 93% yield). MS (apci) m / z = 403.2 (M + H).

Method B. Racemic 4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6ethoxypyrαzolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 518 ); 10 mg, 0.021 mmol) was partitioned between saturated NaiCO ^ (.) And CHCl ₃ . After phase separation, the organic extracts were dissolved in a solvent mixture MeOH: HnC: DIEA (80: 20: 0.1), then subjected to SFC chiral HPLC (ChiralTech IA; 5 to 70% solvent A in solvent B; solvent A = MeOH: HnC : DIEA / 80: 20: 0, l; solvent B = CO ₂ ). Fractions containing peak 2 of this chiral resolution were independently isolated, combined, and evaporated under reduced pressure to give ^) - 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3yl) -6- ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (4 mg, 94% yield). MS (apci) m / z = 403.2 (M + H). Chirality was determined by comparing chiral HPLC of the compound prepared according to Method A to obtain ^) - 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6ethoxypyrαzolo [1 , 5-a] pyridine-3-carbonitrile.

Example 524. N = \ \ _- Ν ο

(R) -4- (6- (7-acetyl-2,7-diαzaspiro [4.5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrαzolo [1,5-a] pyridine-3carbonitrile.

Into a mixture of dihydrochloride (^) - 4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6ethoxypyrαzolo [1,5-a] pyridine-3-carbonitrile (example 523; 5.7 mg, 0.012 mmol) and acetyl chloride (1.3 μl, 0.018 mmol) in DCM (60 μl), DIEA (6.3 μl, 0.036 mmol) was added and stirred for 30 min at ambient temperature. The mixture was diluted with DCM (1 ml), then washed sequentially with saturated NaHCO ^^ (1 ml) and water (1 ml), filtered through a PS filter and evaporated under reduced pressure to give the title compound (2.5 mg, 47% yield ). MS (apci) m / z = 445.2 (M + H).

Example 525.

N = \ \ —Ν

Ο (S) -4- (6- (7-acetyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3carbonitrile.

A mixture of dihydrochloride (^) - 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (example 521 ; 5.3 mg, 0.011 mmol) and acetyl chloride (1.2 μl, 0.017 mmol) in DCM (56 μl), DIEA (5.8 μl, 0.033 mmol) was added and stirred for 30 min at ambient temperature. The mixture was diluted with DCM (1 ml), then washed sequentially with saturated NaHCO ^ Bo ^) (1 ml) and water (1 ml), filtered through a PS filter and evaporated under reduced pressure to give the title compound (1.6 mg, 32 % output). MS (apci) m / z = 445.2 (M + H).

- 341 035568

Example 526.

N = \ ί I γ ^ Ν '—A-n

^) - 4- (6- (7-cyclopropyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5а] pyridine-3-carbonitrile.

A mixture of dihydrochloride (^) - 4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5а] pyridine-3-carbonitrile (example 523 ; 25 mg, 0.0526 mmol), (1-ethoxycyclopropoxy) trimethylsilane (52.9 μL, 0.263 mmol), dry 4A molecular sieves and acetic acid (63.2 μL, 1.05 mmol) in MeOH (526 μL) stirred for 5 min at ambient temperature before adding NaBH ₃ CN (19.8 mg, 0.316 mmol). The resulting mixture was stirred for 27 h at 50 ° C, then cooled to ambient temperature and filtered. The filtrate was directly purified by C18 reverse phase chromatography (5-50% ACN in water) to afford the title compound (9.7 mg, 42% yield). MS (apci) m / z = 443.2 (M + H).

Example 527.

N = \

JLxX

U) -4- (6- (7-cyclopropyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5a] pyridine-3-carbonitrile.

In a solution of dihydrochloride (Sh) -4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (example 521; 10 mg, 0.025 mmol) in DCM (1 ml) were added sequentially (1-ethoxycyclopropoxy) trimethylsilane (20 μl, 0.099 mmol) and NaBH ₃ CN (3.1 mg, 0.050 mmol). After stirring overnight at ambient temperature, the reaction mixture was sequentially added with acetic acid (14 μl, 0.25 mmol) and Me ₄ N (AcO) ₃ BH (13 mg, 0.050 mmol). The reaction mixture was stirred for 3 days before sequentially adding additional (1-ethoxycyclopropoxy) trimethylsilane (20 μl, 0.099 mmol) and NaBH ₃ CN (3.1 mg, 0.050 mmol). The mixture was stirred for an additional 2 days before the addition of dry molecular sieves (20 mg). The mixture was stirred for the last 24 hours at ambient temperature. The resulting suspension was filtered and the solids washed with DCM (2x2 ml). The DCM filtrate was washed with 1N. NaOH ^^.) (1 ml) on a PS frit, then evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 0-60% ACN / water as gradient eluent) to afford the title compound (1.3 mg, 12% yield). MS (apci) m / z = 443.2 (M + H).

Example 528.

(R) -6-ethoxy-4- (6- (7-methyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

In a mixture of dihydrochloride (III) -4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (example 521; 20 mg, 0.042 mmol) and formaldehyde (37 wt.% In water; 31.52 μl, 0.4207 mmol) in DCM (210.3 μl) NaBH (AcO) ₃ (178.3 mg, 0.8414 mmol) was added then stirred for 10 minutes at ambient temperature. The reaction mixture was partitioned between EtOAc (1 ml) and 2 M NaOH ^ ow.) (1 ml). After phase separation, the organic extracts were evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-40% ACN in water as eluent gradient) to afford the purified title compound (9.6 mg, 55% yield). MS (apci) m / z = 417.2 (M + H).

- 342 035568

Example 529.

^) - 6-ethoxy-4- (6- (7-methyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

In a mixture of (^) - 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 523 ; 15 mg, 0.032 mmol) and formaldehyde (37 wt% in water; 23.7 μl, 0.316 mmol) in DCM (158 μl), NaBH (AcO) ₃ (134 mg, 0.631 mmol) was added, then stirred for 10 min at ambient temperature. The reaction mixture was partitioned between EtOAc (1 ml) and 2M _# OII _{IK01 [Ci} (1 ml). After phase separation, the aqueous phase was re-extracted with additional EtOAc (1 ml). The organic extracts were combined and evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 5-95% ACN in water as eluent gradient) to afford the purified title compound (13 mg, 99% yield). MS (apci) m / z = 417.25 (M + H).

Example 530.

^) - 6-ethoxy-4- (6- (7-ethyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

In a mixture of (^) - 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 523 ; 15 mg, 0.032 mmol) and acetaldehyde (7.5 mg, 0.063 mmol) in DCM (158 μl) was added NaBH (AcO) ₃ (40 mg, 0.19 mmol), then stirred overnight at ambient temperature. The reaction mixture was partitioned between EtOAc (1 ml) and 2 M NaOI 1 _{(aq1 and} (1 ml). After phase separation, the aqueous phase was re-extracted with additional EtOAc (1 ml). The organic extracts were combined and evaporated under reduced pressure. The crude residue was purified by chromatography on reverse phase C18 (using 5-60% ACN in water as gradient eluent) to give the purified title compound (8.5 mg, 63% yield) MS (apci) m / z = 431.2 (M + H).

Example 531.

N = \

Jf Ύ k / V-N

^) - 6-ethoxy-4- (6- (7-isopropyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) pyrazolo [1,5а] pyridine-3-carbonitrile.

A mixture of dihydrochloride (^) - 4- (6- (2,7-diazaspiro [4,5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (example 523 ; 15 mg, 0.032 mmol) and 2-iodopropane (5.90 mg, 0.0347 mmol) in DCM (158 μl) was added DIEA (5.50 μl, 0.0316 mmol), then the reaction vessel was tightly closed. The reaction mixture was stirred for 18 h at 50 ° C. Additional 2-iodopropane (one drop) and DIEA (one drop) were added, the vessel was resealed tightly and the mixture was stirred for an additional 2 h at 50 ° C. After cooling to ambient temperature, the mixture was directly purified by C18 reverse phase chromatography (using 5-95% ACN in water as eluent gradient) to afford the title compound (10.3 mg, 73% yield). MS (apci) m / z = 445.3 (M + H).

Example 532.

- 343 035568

Formate (^) - 6-ethoxy-4- (6- (7-isopropyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a mixture of dihydrochloride (^) - 4- (6- (2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (example 521; 15 mg, 0.032 mmol) and 2-iodopropane (5.9 mg, 0.035 mmol) in DCM (158 μl) was added DIEA (16 μl, 0.035 mmol), then the reaction vessel was tightly closed. The reaction mixture was stirred for 18 hours at ambient temperature. Additional 2-iodopropane (one drop) and DIEA (one drop) were added, the vessel was resealed tightly and the mixture was stirred for 2 hours at 50 ° C. After cooling to ambient temperature, the mixture was directly purified by C18 reverse phase chromatography (using 5-40% ACN in water with 0.1% formic acid as gradient eluent) to afford the title compound (6.7 mg, yield 48 %). MS (apci) m / z = 445.3 (M + H).

Example 533.

tert-butyl 7- (5- (3-cyano-6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -1,7diazaspiro [3,5] nonane -1-carboxylate.

In a suspension of 4- (6-fluoropyridin-3-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P95; 400 mg, 1.09 mmol) in DMSO (2.5 ml) DIEA (570.5 μl, 3.266 mmol) and tert-butyl 1,7-diazaspiro [3.5] nonane-1-carboxylate (345.0 mg, 1.524 mmol) were added and then stirred for 17 h at 90 ° C. After cooling to ambient temperature, the resulting suspension was diluted with water (10 ml), stirred for 1 hour at ambient temperature, and then filtered. The isolated solids were washed with water and dried under high vacuum overnight to provide the purified title compound (650.6 mg, quantitative yield). MS (apci) m / z = 574.3 (M + H).

Example 534.

4- (6- (1-isobutyryl-1,7-diazaspiro [3.5] nonan-7-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Into solution 4- (6- (1,7-diazaspiro [3,5] nonan-7-yl) pyridin-3-yl) -6- (2morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (intermediate P96; 25 mg, 0.046 mmol) in DMA (500 μl), DIEA (23.9 μl, 0.137 mmol), isobutyric acid (6.36 μl, 0.0686 mmol) and HATU (26.1 mg, 0.0686 mmol). The reaction mixture was stirred for 1 hour at ambient temperature. The resulting suspension was diluted with water to dissolve the precipitate and the solution was directly purified by C18 reverse phase chromatography (using 595% ACN / water as eluent gradient) to afford the title compound (10.4 mg, 42% yield). MS (apci) m / z = 544.3 (M + H).

Example 535.

^) - 4- (6- (4- (2- (3-chlorophenyl) -2-hydroxyacetyl) piperazin-1-yl) pyridin-3-yl) -6- (2-methoxy-2methylpropoxy) pyrazolo [1, 5-a] pyridine-3-carbonitrile.

In solution 6- (2-methoxy-2-methylpropoxy) -4- (6- (piperazin-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile dihydrochloride (example 246; 25 mg , 0.052 mmol) and ^) - 2- (3-chlorophenyl) -2 hydroxyacetic acid (10 mg, 0.052 mmol) in DCM (520 μl), DIEA (55 μl, 0.313 mmol) and HATU (22 mg, 0.057 mmol), then stirred for 16 h at ambient temperature. The resulting mixture was diluted with water (20 ml) and was extracted with DCM (3x20 ml). The organic extracts were combined and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-100% acetone / hexane isomer mixture as a gradient

- 344 035568 eluent) to afford the purified title compound (27 mg, 42% yield). MS (apci) m / z = 575.2 (M + H).

Example 536.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (6- (6-methoxypyridin-3-yl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

Via a mixture of 4- (6- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-hydroxy2-methylpropoxy) pyrazolo [1,5-a] pyridine dihydrochloride -3-carbonitrile (intermediate P43; 100 mg, 0.210 mmol), 5-bromo-2-methoxypyridine (40.66 μL, 0.3142 mmol), KOtBu (117.5 mg, 1.047 mmol), Pd ₂ (dba) ₃ - CHCl ₃ (10.84 mg, 0.01047 mmol) and X-phos (19.97 mg, 0.04189 mmol) in toluene (1047 μl) were purged with _{2 (γ)} for 30 seconds. After the reaction vessel was tightly closed in an atmosphere of Ν ₂ ( _Γ ), the reaction mixture was stirred for 90 min at 100 ° C. After cooling to ambient temperature, the reaction mixture was partitioned between DCM (10 ml) and water (10 ml). After phase separation, the aqueous extracts were washed with additional DCM (3x5 ml). The organic extracts were combined, dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The resulting crude residue was purified by C18 reverse phase chromatography (using 5-55%

ACN in water and again using 5-45% ACN in water as gradient eluents) to afford the purified title compound (4 mg, 4% yield). MS (apci) m / z = 512.2 (M + H).

Example 537.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4- (6-methoxynicotinoyl) -1,4-diazepan-1-yl) pyridin-3yl) pyrαzolo [1,5-a] pyridine- 3-carbonitrile.

A mixture of bis- (2,2,2-trifluoroacetate) 4- (6- (1,4-diazepan-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5- a] pyridine-3-carbonitrile (intermediate P98; 50 mg, 0.0788 mmol), DIEA (68.6 μL, 0.394 mmol), HATU (89.9 mg, 0.236 mmol) and 6-methoxy nicotinic acid (36.2 mg, 0.236 mmol) in DMF (500 μl) was stirred overnight at room temperature. Additional DIEA (50 μl, 0.287 mmol), 6-methoxy-nicotinic acid (30 mg, 0.196 mmol) and HATU (50 mg, 0.131 mmol) were added to the reaction mixture and stirred for an additional 5 h at ambient temperature. The reaction mixture was diluted with DCM and quenched with saturated NH (1).). After phase separation, the aqueous extracts were washed with additional DCM (3x). The combined organic extracts were then dried over anhydrous Na ^ O ^), filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography (using 0-20% MeOH [1% NH ₄ OH] / EtOAc as gradient eluent) to afford the purified title compound (42.7 mg, quantitative yield). MS (apci) m / z = 542.3 (M + H).

Example 538.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4-picolinoyl-1,4-diazepan-1-yl) pyridin-3-yl) pyrazolo [1,5a] pyridine-3-carbonitrile.

The title compound (37.5 mg, 93% yield) was prepared using a procedure similar to that described for (6- (2-hydroxy-2-methylpropoxy) -4- (6- (4- (6-methoxy-nicotinoyl) -1, 4-diazepan-1yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (Example 537), replacing 6-methoxy-nicotinic acid with picolinic acid MS (apci) m / z = 512.25 (M + H).

- 345 035568

Example 539.

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl) -1,4-diazepan-1yl) pyridin-3-yl) pyrazolo [1 , 5-a] pyridine-3-carbonitrile.

A mixture of bis- (2,2,2-trifluoroacetate) 4- (6- (1,4-diazepan-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5- a] pyridine-3-carbonitrile (intermediate P98; 50 mg, 0.0788 mmol), TEA (54.9 μl, 0.394 mmol), NaBH (AcO) ₃ (50.1 mg, 0.236 mmol) and 6-methoxynicotinaldehyde ( 32.4 mg, 0.236 mmol) in DMF (500 μl) was stirred overnight at ambient temperature. The reaction mixture was diluted with DCM and quenched with saturated NHqCl ^ (.). After phase separation, the aqueous extracts were washed with additional DCM (3x). The combined organic extracts were then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0-20% MeOH / EtOAc as eluent gradient) to afford the purified title compound (33.8 mg, 81% yield). MS (apci) m / z = 528.3 (M + H).

Example 540.

N = \ but. hLzi + L w. , ___ χ ^ ° ^ ιί% yy 7 = n __ ^ Ν—>

6- (2-hydroxy-2-methylpropoxy) -4- (6- (4- (pyridin-2-ylmethyl) -1,4-diazepan-1-yl) pyridin-3yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (39 mg, 99% yield) was prepared in a manner similar to that described for 6- (2-hydroxy-2-methylpropoxy) -4- (6- (4 - ((6-methoxypyridin-3-yl) methyl ) -1,4-diazepan-1yl) pyridin-3-yl) pyrαzolo [1,5-a] pyridine-3-carbonitrile (Example 539), replacing 6methoxynicotinaldehyde with picolinaldehyde. MS (apci) m / z = 498.3 (M + H).

Example 541.

4- (6- (4 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -1,4-diazepan-1-yl) pyridin-3-yl) -6- (2-hydroxy-2 methylpropoxy) pyrαzolo [1,5-a] pyridine-3-carbonitrile.

Into a solution of bis- (2,2,2-trifluoroacetate) 4- (6- (1,4-diazepan-1-yl) pyridin-3-yl) -6- (2-hydroxy-2methylpropoxy) pyrazolo [1,5 -a] pyridine-3-carbonitrile (intermediate P98; 50 mg, 0.0788 mmol) in DMA (500 μl) was added 5-fluoro-6-methoxy-nicotininaldehyde (36.7 mg, 0.237 mmol), TEA (77 μl, 0 , 55 mmol) and (NaBH (AcO) ₃ (50 mg, 0.237 mmol), then stirred overnight at ambient temperature.Add additional TEA (77 μL, 0.55 mmol), NaBH (AcO) to the reaction mixture ₃ (50 mg, 0.237 mmol) and 5-fluoro-6-methoxy-nicotininaldehyde (36.7 mg, 0.237 mmol) and then stirred at ambient temperature until LCMS indicated complete consumption of starting material. The reaction mixture was purified directly by chromatography on silica gel (using 0-25% EtOAc / MeOH as eluent gradient) and again by C18 reverse phase chromatography (using 5-95% ACN in water with 0.1% TFA as eluent gradient) to give the crude title e compounds in the form of a TPA salt. The TPA salt was neutralized with 1 M NaOH and saturated aqueous sodium chloride solution and then extracted with EtOAc. The organic extracts were then dried over anhydrous Na ^ O ^), filtered and evaporated under reduced pressure to give the purified title compound (30 mg, 70% yield). MS (apci) m / z = 546.2 (M + H).

- 346 035568

Example 542.

^) - 4- (5- (4- (2- (3-chlorophenyl) -2-hydroxyacetyl) piperazin-1-yl) pyrazin-2-yl) -6ethoxypyrazolo [1,5-a] pyridine 3-carbonitrile.

In a mixture of bis- (2,2,2-trifluoroacetate) 6-ethoxy-4- (5- (piperazin-1-yl) pyrazin-2-yl) pyrazolo [1,5a] pyridine-3-carbonitrile (intermediate P101; 35 mg, 0.061 mmol), ^) - (-) - 3-chloromandelic acid (14 mg, 0.073 mmol), HATU (25 mg, 0.067 mmol) in DCM (606 μl), DIEA (32 μl, 0.18 mmol ), then stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (using 0100% EtOAc in a mixture of hexane isomers, followed by 0-10% MeOH in EtOAc as eluent gradient) and the fractions containing the desired product were combined and evaporated under reduced pressure. The residue was triturated with MeOH. The resulting precipitate was collected by filtration to give the purified title compound (6 mg, 19% yield). MS (apci) m / z = 518.1 (M + H).

Example 543.

6-ethoxy-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2yl) pyrazolo [1,5 -a] pyridine-3-carbonitrile.

Into a mixture of bis- (2,2,2-trifluoroacetate) 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P103; 20 mg, 0.034 mmol) in DCM (679 μl) was added 6-methoxynicotinaldehyde (14 mg, 0.10 mmol) and NaBH (AcO) ₃ (36 mg, 0.17 mmol), then stirred overnight at ambient temperature. The reaction mixture was purified by silica gel chromatography (0-10% MeOH in DCM with 0.1% NH ₄ OH) to afford the purified title compound (15 mg, 92% yield). MS (apci) m / z = 483.2 (M + H).

Example 544.

6-ethoxy-4- (5- (6 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3yl) pyrazin-2-yl) pyrazole [1,5-a] pyridine-3-carbonitrile.

Into a mixture of bis- (2,2,2-trifluoroacetate) 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile (intermediate P103; 20 mg, 0.034 mmol) in DCM (679 μl) was added 5-fluoro-6-methoxynicotininaldehyde (16 mg, 0.10 mmol) and NaBH (AcO) 3 (36 mg, 0, 17 mmol), then stirred overnight at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using 0-10% MeOH in DCM with 0.1% NH ₄ OH as gradient eluent) to afford the purified title compound (14 mg, 82% yield). MS (apci) m / z = 501.2 (M + H).

Compounds in the table. GG was prepared using a method similar to that described in the synthesis of 6ethoxy-4- (5- (6 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3.6 diazabicyclo [3.1.1] heptane-3- yl) pyrazine-2yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (Example 544), replacing 5-fluoro-6-methoxy-nicotininaldehyde with the appropriate aldehyde. Reactions were monitored for completion by LCMS as these reaction times were adjusted accordingly. After chromatographic purification using an appropriate gradient eluent, the title compounds were isolated.

- 347 035568

GG table

No. Example Structure Chemical name MS apci (m / z) 545 X 'o— 4- (5- (6 - ((5-chloro-6methoxypyridin-3 yl) methyl) -3,6diazabicyclo [3.1.1] he ptan-3-yl) pyrazin-2yl) -6- ethoxypyrazolo [1,5а] pyridine-3carbonitrile 517.1 (M + H) 546 Ν = \ νΧ - $ _ν X т I 6-ethoxy-4- (5- (6 - ((6ethylpyridin-3yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2yl) pyrazolo [1,5а] pyridine-3carbonitrile 481.2 (M + H) 547 -about y y ' 6-ethoxy-4- (5- (6- (3fluoro-4- methoxybenzyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2yl) pyrazolo [1,5а] pyridine-3carbonitrile 500.2 (M + H) 548 N = \ X t 6-ethoxy-4- (5- (6 - ((5methoxypyridine-2yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2yl) pyrazolo [1,5а] pyridine-3carbonitrile 483.2 (M + H)

Example 549.

4- (5- (6 - ((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) 6- ( 2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In a solution of bis- (2,2,2-trifluoroacetate) 4- (5- (3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2morpholinoethoxy) pyrazolo [1 , 5-a] pyridine-3-carbonitrile (intermediate P106; 22.2 mg, 0.0329 mmol) in DCM (658.2 μL), 5-chloro-6-methoxy-nicotinaldehyde (28.23 mg, 0.1646 mmol) and NaBH (AcO) ₃ (69.75 mg, 0.3291 mmol), then stirred overnight at ambient temperature. The reaction mixture was filtered through a PVDF disk syringe filter (0.45 μm). The filtrate was purified directly by chromatography on silica gel (using 0-100% DCM in a mixture of hexane isomers, then 0-10% MeOH in DCM with 0.1% NH ₄ OH as gradient eluents). Fractions containing the desired product were evaporated under reduced pressure azeotropically with Et ₂ O to give the purified title compound (13.08 mg, 66% yield). MS (apci) m / z = 602.2 (M + H).

Example 550.

4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6- (2morpholinoethoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

The title compound (2.07 mg, 7% yield) was prepared using a procedure similar to that described for the synthesis of 4- (5- (6 - ((5-chloro-6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3yl) pyrazin-2-yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (Example 549), replacing (5-chloro- 6-methoxy-nicotinaldehyde to 6-methoxy-nicotinaldehyde and additional chromatography

348 035568 graphical purification (using a silica gel column and 0-10% MeOH in EtOAc as gradient eluent). MS (apci) m / z = 568.3 (M + H).

Example 551.

4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6 (((S) morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

In solution tert-butyl (2S) -2 - (((3-cyano-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptane-3 -yl) pyrazin-2-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P112; 55.9 mg, 0.0855 mmol) in DCM (2.0 ml) was added TFA (1 ml, 13.1 mmol) and stirred for 2 h at ambient temperature. The resulting mixture was evaporated under reduced pressure to give the TFA salt. TFA salt The residue was purified and converted to the free base by chromatography on silica gel (using 0-20% DCM / MeOH / ⁰ 2% o NH ₄ OH as eluent gradient) to give the purified title compound (19 mg, yield: 40% ). MS (apci) m / z = 554.3 (M + H).

Example 552.

4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) -6 (((R) morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

The title compound (1.6 mg, 3% yield) was prepared using a procedure similar to that described for the synthesis of 4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [ 3.1.1] heptane-3yl) pyrazin-2-yl) -6 - (((S) -morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (Example 551), replacing tert-butyl ^) - 2 - (((3-cyano-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3- yl) pyrazin-2-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P112) on tert-butyl (2R) -2 - (((3- cyano-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) methyl) morpholine-4-carboxylate (intermediate P111). MS (apci) m / z = 554.3 (M + H).

Example 553.

6 - ((3-fluorozetidin-3-yl) methoxy) -4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3- yl) pyrazin-2-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile.

To the solution of tert-butyl 3 - (((3-cyano-4- (5- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl ) pyrazin-2-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) methyl) -3-fluoroazetidine-1carboxylate (intermediate P115; 48 mg, 0.075 mmol) in DCM (1.0 ml) was added TFA (1 ml, 13.1 mmol) and stirred for 1 h at ambient temperature. The resulting mixture was diluted with DCM (10 ml) and neutralized by extraction with saturated NaHCO ₃ ( _βod ) (10 ml). The biphasic mixture was extracted with additional DCM (3x) and the combined DCM extracts were evaporated under reduced pressure. The residue was triturated with DCM (1 ml) and pentane (5 ml). The resulting precipitate was collected by vacuum filtration and dried under high vacuum to give the purified title compound (20 mg, 49% yield). MS (apci) m / z = 542.2 (M + H).

Example 554.

4- (2- (6 - ((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrimidin-5

- 349 035568 yl) -6- (2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile.

A mixture of 5-chloro-6-methoxy-nicotinaldehyde (59.56 mg, 0.3471 mmol), 4- (2- (3,6 diazabicyclo [3.1.1] heptan-3-yl) pyrimidin-5-yl) -6- ( 2-morpholinoethoxy) pyrazolo [1,5-a] pyridine-3carbonitrile (intermediate P117; 31 mg, 0.069 mmol) and NaBH (AcO) ₃ (147.1 mg, 0.6943 mmol) in DCM (694.3 μl) stirred overnight at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using 0-10% MeOH in EtOAc with 0.1% NH4OH as gradient eluent) to afford the purified title compound (15.19 mg, 35% yield). MS (apci) m / z = 602.3 (M + H).

Example 555.

N = \ ^Ν SHU

4- (2- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyrimidin-5-yl) -6- (2morpholinoethoxy) pyrazole [1,5-a] pyridine-3-carbonitrile.

A mixture of 6-methoxy-nicotinaldehyde (47.6 mg, 0.347 mmol), 4- (2- (3,6-diazabicyclo [3.1.1] heptane-3ul) pyrimidin-5-yl) -6- (2-morpholinoethoxy) pyrazole [ 1,5-a] pyridine-3-carbonitrile (intermediate P117; 31 mg, 0.069 mmol) and NaBH (AcO) ₃ (147 mg, 0.694 mmol) in DCM (694 μl) were stirred overnight at ambient temperature. The reaction mixture was purified directly by silica gel chromatography (using 0-10% MeOH in DCM with 0.1% NH4OH as gradient eluent) to afford the purified title compound (7.37 mg, 19% yield). MS (apci) m / z = 568.3 (M + H).

Example 556.

N = \, ν ^ Α-ci i I Y I

3- (5- (3-chloro-6-methoxypyrazolo [1,5-a] pyridin-4-yl) pyrαzin-2-yl) -6 - ((6-methoxypyridin-3yl) methyl) -3,6- diazabicyclo [3.1.1] heptane.

In a mixture of 3-chloro-6-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazolo [1,5-a] pyridine (intermediate P98; 75 mg , 0.24 mmol), 3- (5-chloropyrazin-2-yl) -6 - ((6-methoxypyridin-3-yl) methyl) -3,6 diazabicyclo [3.1.1] heptane (intermediate R25; 108 mg) 0.16 mmol), X-phos (15 mg, 0.032 mmol) and Pd ₂ (dba) ₃ (7.4 mg, 0.0081 mmol) in dioxane (810 μL) was added 2 M KyPO ^^.) (243 μL, 0.49 mmol). The mixture was purged with Ar _(d) and then the reaction vessel was tightly closed. The reaction mixture was stirred overnight at 80 ° C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and sequentially extracted with water and saturated aqueous sodium chloride solution. The organic extracts were dried over anhydrous Na ^ O ^), filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography (using 10% MeOH in DCM with 0.1% NH4OH as gradient eluent). The fractions containing the desired product were evaporated under reduced pressure and the residue was triturated with DCM (0.5 ml) and pentane (1 ml). The precipitate was collected by filtration and dried in vacuo to afford the purified title compound (10 mg, 13% yield). MS (apci) m / z = 478.1 (M + H).

Example 557.

2- (6-methoxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) pyrazolo [ 1,5-a] pyridin-3-yl) propanenitrile.

A mixture of 2- (4-bromo-6-methoxypyrazolo [1,5-a] pyridin-3-yl) propanenitrile (intermediate P120; 33 mg, 0.12 mmol), 6 - ((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane (intermediate R28 ; 42 mg, 0.099 mmol), Pd (PPh ₃ ) ₄ (11 mg, 0.0099 mmol) and 2 M Na ^ O ^^.) (250 μl, 0.50 mmol) in dioxane (1 ml) were stirred in for 15 hours at 80 ° C. The reaction mixture was evaporated under reduced pressure. The crude residue was purified by C18 reverse phase chromatography (using 0-30% ACN in water with 0.1% TFA as

- 350 035568 as eluent gradient), converted to the free base with saturated NaHCO _{3 (BogH} .), Extracted with DCM and evaporated to give the pure title compound (33 mg, 67% yield). MS (apci) m / z = 496.2 (M + H).

Example 558.

2- (6-methoxy-4- (6- (6 - ((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) pyridin3-yl) pyrazolo [ 1,5-a] pyridin-3-yl) acetonitrile.

A mixture of 2- (4-brom-6-methoxypyrazolo [1,5-a] pyridin-3-yl) acetonitrile (intermediate P122; 32 mg, 0.12 mmol), 6 - ((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane (intermediate R28 ; 42 mg, 0.099 mmol), Pd (PPh ₃ ) ₄ (11 mg, 0.0099 mmol) and 2 M Na ^ O ^^) (250 μl, 0.50 mmol) in dioxane (1 ml) were stirred for 15 h at 80 ° C. The reaction mixture was evaporated in vacuo. The crude residue was purified by C18 reverse phase chromatography (using 0-30% ACN in water with 0.1% TFA as gradient eluent), converted to the free base with saturated NaHCO ^^), extracted with DCM and evaporated to give the purified indicated in the title compound (36 mg, 75% yield). MS (apci) m / z = 482.2 (M + n).

Compounds in the table. HH was obtained using a method similar to that described in the synthesis of 6-ethoxy-4- (5- (6 - ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane -3-yl) pyrazin-2yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (Example 544), replacing 5-fluoro-6-methoxy-nicotininaldehyde with the appropriate aldehyde.

Table HH Example No.

Chemical name

6-ethoxy-4- (5- (6 - ((6methoxy-5methylpyridin-3 yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2yl) pyrazole [1,5а] pyridine -3carbonitrile

6-ethoxy-4- (5- (6 - ((5fluoropyridin-3 yl) methyl) -3,6diazabicyclo [3.1.1] heptan-3-yl) pyrazin-2yl) pyrazolo [1,5а] pyridine -3carbonitrile

MS apci (m / z)

497.2 (M + H)

471.2 (M + H)

Example 561.

(R) -6-ethoxy-4- (6- (7-ethyl-2,7-diazaspiro [4.5] decan-2-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3carbonitrile.

This compound was prepared using a method similar to that described in the synthesis of (K) -6-ethoxy-4 (6- (7-methyl-2,7-diα-aspiro [4.5] decan-2-yl) pyridin-3-yl) pyrαzolo [1 , 5-a] pyridine-3-carbonitrile (Example 528), replacing formaldehyde with acetaldehyde. The crude product was purified by reverse phase chromatography (5 to 45% ACN in water with 0.1% TFA), then converted to the free base with NaHCO ₃ (sat.) To give the title product as a solid (3 , 9 mg, 29% yield). MS (apci) m / z = 431.3 (M + H).

- 351 035568

Conventional abbreviations:

18-crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane ACN Acetonitrile Ason Acetic acid (±) -BINAP 2,2'-bis (diphenylphosphino) -1,1'-binaphthalene Bis (pinacolato) dibor 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) BF ₃ "Et ₂ O Boron trifluoride diethylether Vos tert-butyl carboxylate group Boc anhydride di-tert-butyl dicarbonate n-BuLi n-butyllithium or 1-butyllithium s-BuOH Sec-butanol or 2-butanol tert-BuOH tert-butanol or 2-methylpropan-2-ol Cui Copper (I) iodide Cu (OAc) ₂ Copper diacetate (P) d day, days DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DCE 1,2-dichloroethane DXM Dichloromethane DIAD Diisopropylazodicarboxylate DIEA Ν, Ν-diisopropylethylamine CI water Deionized water dioxane 1,4-dioxane DMA Ν, Ν-dimethylacetamide DMAP 4-dim ethylaminopyridine DME 1,2-dimethoxyethane DMFA Ν, Ν-dimethylformamide DMP Periodat of Dess-Martin; 1,1,1-tris (acetyloxy) -1,1 dihydro-1,2-benziodoxol-3- (1H) -one dmso Dimethyl sulfoxide dioxane 1,4-dioxane EDC-HC1 Hydrochloride 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide Et ₂ O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol EKV. equivalent GF / F paper fiberglass filter paper GF / F 4 hour, hours HATU Hexafluorophosphate 1 - [bis (dimethylamino) methylene] -1 Η-1,2,3 triazolo [4,5-b] pyridinium 3-oxideylhexafluorophosphate 2 (7-aza-1H-benzotriazol-1-yl) -1,1 , 3,3-tetramethyluronium HBTU Hexafluorophosphate 3- [bis (dimethylamino) methylumyl] -ZIAbenzotriazole-1-oxide or 2- (1H-benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium HOAc Acetic acid iso-RgON Isopropanol g / zo-PrMgCl Isopropyl magnesium chloride KOAc Potassium acetate LCMS Liquid chromatography-mass spectrometry LiHMDS Lithium hexamethyl disil azide MeOH methanol Me ₄ N (AcO) ₃ BH Tetramethylammonium triacetoxyborohydride min minute, minutes

- 352 035568

MsCl m etansul fonilchl ory d MSH o- (mesitylsulfonyl) hydroxylamine MTBE Methyl tert-butyl ether NCS N-chlorosuccinimide NBS N-bromosuccinimide NIS N-iodosuccinimide NaBH (AcO) ₃ Sodium triacetoxyborohydride NH ₄ OAc Ammonium acetate 10% Pd / C Palladium 10 wt.% (Dry basis), activated carbon, wet, Degussa type Pd (PPh ₃ ) ₄ Tetrakis (triphenylphosphine) palladium (0) Pd ₂ (dba) ₃ tris (dibenzylideneacetone) dipalladium (0) PdCh / dppfJ'CHiCb 1,1'-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane complex Pd ₂ (dba) ₃ * CHCl ₃ tris (dibenzylideneacetone) dipalladium (0) chloroform complex PdCl ₂ (PPh ₃ ) ₂ bis (triphenylphosphine) palladium (II) dichloride PPh ₃ triphenylphosphine Pl-HCO ₃ resin Stratospheres MP-NSOZ PPTS pyridinium p-toluenesulfonate PS filter phase separator Biotage® "Isolute®" PS filter phase separator filter paper Whatman® PVDF disc (0.45 μm) polyvinylidene difluoride membrane with pore size 0.45 μm Ph.D. room temperature TBAF Tetra-n-butylammonium fluoride TEA triethylamine Tf-O-Tf trifluoromethanesulfonic anhydride TFK Trifluoroacetic acid THF tetrahydrofuran TMSCN Trim ethyl sil il cyanide d Triphosgene (bis (trichloromethyl) carbonate TsCl 4-toluenesulfonyl chloride X-Phos dicyclohexyl (2 ', 4', 6'-triisopropyl- [1, G-biphenyl] -2-yl) phosphine

CLAIM

Claims (22)

CLAIM 1. The compound of formula I No. \ / \ Β · ₀ ΛΧζ4 _χ! kJ II <A x ¹ irx, ( ^D / I and its pharmaceutically acceptable salts and solvates, where X ¹ , X ² , X ³ and X ⁴ independently represent CH, CF, CCH ₃ or N, where zero, one or two of X ¹ , X ² , X ³ and X ⁴ are N; A is H, CN, Cl, CH ₃ -, CH ₃ CH ₂ -, cyclopropyl, —CH2 CN, or —CH (CN) CH ₃ ; B represents: (a) hydrogen, (b) A-A-alkyl optionally substituted with 1-3 fluorine atoms, (c) hydroxy-A-A-alkyl, where the alkyl moiety is optionally substituted with 1-3 fluorine atoms or A-A-cycloalkylidene ring , (d) dihydroxy-A-A-alkyl, where the alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring, (e) (A-A-alkoxy ^ -A-alkyl optionally substituted with 1 to 3 fluorine atoms, (f) ^ ^ K ^ -A-alkyl, wherein said alkyl moiety is optionally substituted with OH and where R ¹ and R ^{2 are} independently H or A-A-alkyl (optionally substituted with 1-3 fluorine atoms); (g) het-Ar-A-alkyl, where het-Ar ¹ is a 5-6 membered heteroaryl ring containing 1 to 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected A-A-alkyl substituents; (h) (A-A-cycloalkyl ^ -A-alkyl, wherein said cycloalkyl is optionally substituted with OH, (i) (het-Cyc ^a ) C ₁ -C ₃ -alkyl, (j) het-Cyca; (k) A-A-cycloalkyl, wherein said cycloalkyl is optionally substituted with OH, - 353 035568 (l) (C ₁ -C ₄ alkyl) C (= O) _O-C1-C6 alkyl, wherein each C1-C ₄ -alkyl and C 1 C ₆ alkyl moiety are optionally and independently substituted with 1-3 fluorine atoms, or (m) (R ¹ R ² N) C (= O) C1-C6 alkyl, where R ¹ and R ^{2 are} independently H or C1-C6 alkyl (optionally substituted by 1-3 fluorine atoms); het Sus represents ^a 4-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O, and optionally substituted by one or more substituents independently selected from OH, _C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), hydroxy _C1-C6 alkyl, C1-C ₆ -alkoxy, _(C1-C6 alkyl) C (= O) _(C1-C6 alkoxy) C1-C ₆ - alkyl and fluorine, or where het-Cyca is substituted with oxo; ring D is (i) a saturated 4-7 membered heterocyclic ring containing two ring nitrogen atoms, (ii) a saturated 7-9 membered bridged heterocyclic ring containing two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring containing two ring nitrogen atoms, where each of said rings is optionally substituted with (a ) one to four groups independently selected from halogen, OH, _C1-C3 alkyl, which is optionally substituted with 1-3 fluorine atoms or _{C1-C3-alkoxy,} which is optionally substituted with 1-3 fluorine atoms, (b) a cycloalkylidene a C ₃ -C ₆ ring or (c) an oxo group; E represents: (a) hydrogen, (b) _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms, (c) _(C1-C6 alkoxy) _C1-C6 alkyl optionally substituted with 1-3 fluorine atoms, ( d) _(C1-C6 alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted with 1-3 fluorine atoms or a substituent R ^g R ^h N, where R ^g and R ^h independently represent h or C1-C ₆ -alkyl, (e) (hydroxy-C ₂ -C ₆ -alkyl) C (= O) -, optionally substituted with 1-3 fluorine atoms, (f) (C1-C ₆ -alkoxy) C (= O) - , (g) (C ₃ -C ₆ -cycloalkyl) C (= O) -, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C ₆ -alkyl, C1-C ₆ -alkoxy, OH and ( _C1-C6 alkoxy) _C1-C6 alkyl or said cycloalkyl substituted 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O, (h) Ar ^1, C ₁ -C ₆ - alkyl-, (i) Ar ¹ (C1-C6-alkyl) C (= O) -, where said alkyl fragment is optionally substituted with OH, hydroxy-C1-C6-alkyl-, C1-C6-alkoxy, R ^m R ⁿ N - or R ^m R ⁿ N-CH2-, where each R ^m and R ⁿ independently represents H or C1-C ₆ -alkyl, (j) het-Ag2S1-C6-alkyl, wherein the alkyl moiety is optionally substituted with 1-3 fluorine atoms, (k) het-Ar ² (P ₁ -C ₆ -alkyl) C (= O) -, wherein said alkyl moiety is optionally substituted with OH, hydroxy-C1-C ₆ -alkyl or C1-C ₆ -alkoxy, (l) het-Lg ² C (= O) - , (m) het-Cus1C (= O) -, (n) het-Cus ¹ C ₁ -C ₆ -alkyl-, (o) R ³ R ⁴ NC (= O) -, (p) Ar1N (R ³ ) C (= O) -, (q) het-LI4 (K ³ ) C (= O) -, (d) (C1-C ₆ -alkyl ^ O ₂ -, where the alkyl fragment is optionally substituted by 1-3 fluorine atoms , (s) Ar1SO2-, (t) het-ArXO ₂ -. (u) No. (C1-C ₆ -alkyl) pyridinonyl, (v) Ar1C (= O) -, (w) Ar1O-C (= O) -, (x) (C ₃ -C ₆ -cycloalkyl) (C1 -C ₆ -alkyl) C (= O) -, (y) (C ₃ -C ₆ -cycloalkyl) (C1-C ₆ -alkyl ^ O ₂ -, where the alkyl moiety is optionally substituted by 1-3 fluorine atoms, (z ) LrXC ^ Cb-alkyl ^ Og-, (aa) het-Cus ¹ -O-C (= O) -, (bb) het-Cus1CH ₂ C (= O) -, (cc) het-Lu ² or ( dd) C ₃ -C ₆ cycloalkyl; Lg ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluorine atoms), C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms), R ^e R ^f N-, where R ^e and R ^f independently represent H or C1-C6-alkyl, (KK ^ CgCb-alkoxy-, where R ^p and R ^q independently represent H or C1-C6 -alkyl, and (het-Lg ^a ) C1-C6-alkyl-, where het-Lg ^a is a 5-6-membered 354 035568 heteroaryl ring containing 1-2 ring nitrogen atoms, or Ar ¹ is a phenyl ring fused with a 5-6 membered heterocyclic ring containing 1-2 ring heteroatoms independently selected from N and O; het-Ar ² is a 5-6 membered heteroaryl ring containing 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl ring containing 1-3 ring nitrogen atoms, where het -Ar ^{2 is} optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6-alkyl (optionally substituted with 1-3 fluorine atoms), QQ- ^ kokch (optionally substituted with 1-3 fluorine atoms), (C1-C6 alkoxy) C1-C6-alkyl- (optionally substituted with 1-3 fluorine atoms), R ^e R ^f N-, where R ^e and R ^f independently represent H or ^ - ^ - alkyl, OH, (QQ- ^ kokc ^ QQ- ^ kokch- and C3-C ₆ -cycloalkyl; het-Cyc ¹ is a 4-6 membered saturated heterocyclic ring containing 1-2 ring heteroatoms independently selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from ^ - ^ - alkoxy and halogen; R ³ is H or ^ - ^ - alkyl and R ⁴ is C ₁ -C ₆ alkyl. 2. A compound according to claim 1, wherein ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, said ring being optionally substituted with (a) one - four groups independently selected from halogen, OH, C1-C3 alkyl, which is optionally substituted by 1-3 fluorine atoms, or ^ - ^ - alkoxy, which is optionally substituted by 1-3 fluorine atoms, (b) C ₃ -C ₆ -cycloalkylidene ring or (c) oxo. 3. A compound according to claim 2, wherein the ring D is where the wavy line indicates the point of attachment of the ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the point of attachment to the group E. 4. A compound according to claim 3, wherein the ring D is 5. A compound according to any one of claims 1 to 4, characterized in that B is hydroxy-C ₂ -C ₆ alkyl, wherein the alkyl moiety is optionally substituted with a C ₃ -C ₆ cycloalkylidene ring. 6. A compound according to any one of claims _{1 to 4} , wherein B is (het-Cyc ^a ) C ₁ -C ₃ alkyl. 7. A compound according to any one of claims 1-6, characterized in that X ¹ is N and X ² , X ³ and X ⁴ are CH. 8. A compound according to any one of claims 1 to 7, wherein A is CN. 9. A compound which is or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9, which is 11. The compound, which is - 355 035568 or a pharmaceutically acceptable salt thereof. 12. A compound which is or a pharmaceutically acceptable salt thereof. 13. A compound which is or a pharmaceutically acceptable salt thereof. 14. A compound which is or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 in admixture with a pharmaceutically acceptable diluent or carrier. 16. A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 14 in admixture with a pharmaceutically acceptable diluent or carrier. 17. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer associated with RET. 18. Use according to claim 17, characterized in that said cancer is associated with dysregulation of the expression or activity of the RET and / or RET protein kinase gene. 19. Use according to any one of claims 17, 18, characterized in that the cancer associated with RET is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer , refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell renal cell carcinoma, intestinal mucosal ganglioneuromatosis and gastrointestinal tract cervical cancer. 20. Use according to claim 19, characterized in that the lung cancer is RET fusion lung cancer or the cancer is medullary thyroid cancer. 21. Use according to claim 19, wherein the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiole cell lung cancer or lung adenocarcinoma. 22. Use according to any one of claims 17-21, characterized in that the medicament is formulated for oral administration.