EA039324B1 - 5,6-fused-bicyclic compounds and compositions for the treatment of parasitic diseases - Google Patents

Abstract

The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:and therapeutic uses thereof. The invention further provides a pharmaceutical composition.

Description

and ways of their therapeutic application. The invention further provides a pharmaceutical composition.

Cross-reference to related applications

This application claims the benefit of U.S. Provisional Application No. 62/513211 filed May 31, 2017 and U.S. Provisional Application No. 62/581919 filed November 6, 2017; each of which is incorporated by reference herein in its entirety.

The field of technology to which the invention belongs

The present invention relates to compounds that have antiparasitic activity against protozoa of the kinetoplastid class.

Background of the invention

Leishmaniasis is a disease caused by protozoan parasites belonging to the genus Leishmania and transmitted by the bites of certain mosquito species. There are four main forms of leishmaniasis. Cutaneous leishmaniasis is the most common form of leishmaniasis. Visceral leishmaniasis, the most dangerous form in which parasites migrate to vital organs, is caused by the parasite Leishmania donovani and is potentially fatal if left untreated. It affects up to 12 million people worldwide, with 1.5-2 million new cases each year. The incidence of visceral leishmaniasis is estimated at 500,000 new cases and causes 60,000 deaths each year.

The two main treatments for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimonate (Glucantim®). Sodium stibogluconate has been used for about 70 years and drug resistance is an increasing problem. In addition, the treatment is relatively long and painful and may cause unwanted side effects. The current treatment of choice is amphotericin (AmBisome®). Other alternative treatments are miltefosine (Impavido®) and paromomycin.

Amphotericin (AmBisome) is expensive and requires intravenous administration. Paromomycin provides intramuscular injections for 3 weeks; The big problem is adherence to the treatment regimen. Miltefosine is an oral drug and has been shown to be more effective and better tolerated than other drugs. However, there are problems associated with the use of miltefosine, which are caused by its teratogenicity and pharmacokinetics. Miltefosine was shown to be much more slowly eliminated from the body and could still be detected five months after the end of treatment. The presence of sub-therapeutic levels of miltefosine in the blood more than five months after treatment may favor the selection of resistant parasites; moreover, it is necessary to reconsider measures regarding the prevention of teratogenic risks of miltefosine. There are currently no vaccines that are routinely administered.

Chagas disease, also called American trypanosomiasis, is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. T. cruzi is commonly transmitted to humans and other mammals by blood-sucking kissing bugs from the subfamily Triatominae (family Reduviida). Every year, an estimated 10 to 15 million people around the world become infected with Chagas disease, most of whom do not know they are infected. Every year, 14,000 people die as a result of the disease. More people die from Chagas disease in Central and South America than from any other parasitic disease, including malaria. The CDC estimates that there are more than 300,000 people living in the United States of America who are infected with Trypanosoma cruzi.

The symptoms of Chagas disease change as the infection progresses. In the early, acute stage, symptoms are mild and usually cause no more than local swelling at the site of infection. The initial acute phase is susceptible to antiparasitic treatments with a cure rate of 60-90%. After 4-8 weeks in individuals with active infection, Chagas disease enters the chronic phase, which is asymptomatic for 60-80% of individuals with chronic infection during their lifetime. However, the remaining 20-40% of infected people will develop severe and sometimes life-threatening medical problems throughout their lives.

Treatment for Chagas disease focuses on eradicating the parasite and controlling the signs and symptoms. The drugs currently available for treatment during the acute phase of Chagas disease are benznidazole and nifurtimox. Once Chagas disease enters the chronic phase, drugs are no longer effective in curing the disease. Instead, treatment depends on specific signs and symptoms. However, problems with these currently used therapies include their various side effects, duration of treatment, and the need for medical supervision during treatment. There is already resistance to two first-line drugs. The antifungal agent amphotericin b has been proposed as a second-line drug, but it is

- 1 039324 horn-bearing and relatively toxic. There is no vaccine for Chagas disease.

Human African trypanosomiasis (HAT), also known as African sleeping sickness, is a vector-borne parasitic disease caused by the protozoan Trypanosoma brucei. There are two subtypes that infect humans: T/b. gambiense and T/b. rhodesiense, with the former responsible for over 95% of known cases and the latter responsible for the remaining known cases. The parasites are transmitted to humans through the bite of the tsetse fly (Glossina genus) that has been infected by humans or by animals that carry parasites that are pathogenic to humans. Approximately 48,000 people died from sleeping sickness in 2008. As a result of efforts to prevent and eradicate the tsetse fly population, public health organizations have been successful in controlling the spread of the disease; fewer than 10,000 new cases were reported in 2009 according to WHO data, a significant decrease from an estimated 300,000 new cases in 1998.

The symptoms of African trypanosomiasis occur in two stages. In the first stage, known as the hemolymphatic phase, trypanosomes proliferate in the subcutaneous tissue, blood, and lymph. The hemolymphatic phase is characterized by bouts of fever, headaches, joint pain, and itching. In the second stage, the neurological phase, the parasites pass through the blood-brain barrier and infect the central nervous system. At this stage, more obvious signs and symptoms of the disease appear (eg, behavioral changes, confusion, sensory disturbances, and impaired coordination). The disruption of the sleep cycle, from which the disease gets its name, is an important feature of the second stage of the disease. Without treatment, the disease is inevitably fatal, with progressive mental impairment leading to coma, systemic organ failure, and death.

Four medicines are registered for the treatment of sleeping sickness. The protocol depends on the stage of the disease. Currently, the standard treatment for the first stage of the disease involves intravenous or intramuscular administration of pentamidine (in the case of T.b. gambiense) or intravenous administration of suramin (in the case of T.b. rhodesiense). The current standard treatment for stage 2 disease is intravenous melarsoprol or intravenous melarsoprol in combination with oral nifurtimox, intravenous eflornithine alone, or eflornithine in combination with nifurtimox. All medicines have unwanted or potentially dangerous side effects. For example, 3-10% of patients injected with melarsoprol (Arsobal®) developed reactive encephalopathy (convulsions, progressive coma or psychotic reactions) and 10-70% of such cases result in death.

Thus, there is still a need for new and better treatments and therapies for leishmaniasis, Chagas disease and HAT.

Brief description of the invention

In certain aspects, this document provides a compound of formula (I) or subformulas thereof

or a pharmaceutically acceptable salt or stereoisomer thereof;

where ring A is phenyl or pyridinyl;

R ¹ is selected from (a) C _1-6 alkyl which is unsubstituted or substituted with 1-3 substituents independently selected from halogen and C _3-6 cycloalkyl;

(b) C 1 _-4 alkoxy which is unsubstituted or substituted with C _1-4 haloalkyl;

(c) -NR ^5a R ^5b where R ^5a and R ^5b are independently hydrogen, _C1-4 alkyl or C _1-4 haloalkyl;

or R ^5a and R ^5b together with the nitrogen atom to which they are both attached form a 4-7 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S as ring atoms;

wherein the 4-7 membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents independently selected from halogen, C _1-4 alkyl and C _1-4 alkoxy; or two substituents on the same or different ring atoms of a 4-7 membered heterocycloalkyl together with the atoms to which they are attached form a spiro-, bridged or fused ring B attached to a 4-7 membered heterocycloalkyl;

where ring B is C _3-6 cycloalkyl or 3-7 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms;

or -NR ^5a R ^5b is -N(CD ₃ ) ₂ ;

- 2 039324 (d) monocyclic C _3-6 cycloalkyl, C _3-6 cycloalkenyl or spiropentyl; each of which is unsubstituted or substituted with 1-3 substituents independently selected from halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, and C _1-4 alkoxy;

(e) phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms; each unsubstituted or substituted with 1-2 substituents independently selected from halogen, cyano, C _1-4 αalkyl, C _1-4 haloalkyl, di-C _1-4 alkylamino-C _1-4 alkyl, CD ₃ , C _{1 -4} alkoxyC _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy and C _3-6 cycloalkyl;

R ² and R ⁷ are independently hydrogen or C _1-4 alkyl;

R ³ is hydrogen or halogen and n is 0 or 1; and

R ⁴ is selected from (a) hydrogen;

(b) halogen;

(c) C _1-6 haloalkyl or C _1-6 alkyl which is unsubstituted or substituted by C _3-6 cycloalkyl;

(d) -NR ^6a R ^6b where R ^6a is hydrogen or C1-4 alkyl; R ^6b is hydrogen, C 1-4 alkoxycarbonyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, or C _1-4 alkyl which is unsubstituted or substituted with C _1-4 alkoxy; or

R ^6a and R ^6b together with the nitrogen atom to which they are both attached form a 4-7 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms;

while 4-7-membered heterocycloalkyl is not substituted or substituted by 1-2 substituents independently selected from halogen, cyano, hydroxyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyC _1-4 alkyl, C _{1 -4} alkoxy, oxo, 1,1-dioxo, -C(O)-OR ⁷ or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O and S; or two substituents on the same or different ring atoms of a 4-7 membered heterocycloalkyl together with the atoms to which they are attached form a spiro-, bridged or fused ring C attached to a 4-7 membered heterocycloalkyl;

where ring C is selected from C _3-6 cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms; and it is independently substituted or substituted with 1-2 substituents independently selected from halo and oxo;

(e) C _3-6 cycloalkyl;

(f) a 4-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms; and it is unsubstituted or substituted by -C(O)OR ⁸ or -C(O)R ⁸ where R ⁸ is C _1-4 alkyl and phenylC _1-4 alkyl which is unsubstituted or substituted by 1-2 substituents representing halogen; and (g) a 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms; which is unsubstituted or substituted with 1-2 substituents independently selected from halogen, C _1-4 alkyl, C _1-4 hydroxyalkyl and C _3-6 cycloalkyl.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or subformulas thereof, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

The compounds of formula (I) or subformulas thereof, in free form or in the form of a pharmaceutically acceptable salt, may be useful as a therapy for a disease or condition in which a beneficial effect can be observed by inhibiting the growth and proliferation of parasites of the kinetoplastid class. In one aspect, the present invention provides a compound of formula (I) or subformulas thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in the treatment, prevention, inhibition, amelioration, or elimination of the pathology and/or symptom cluster of a disease caused by a parasite of the kinetoplastid class.

In another aspect, the present invention provides the use of a compound selected from formula (I) or subformulas thereof, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease caused by a parasite of the kinetoplastid class in a subject. Parasites of the kinetoplastid class include, without limitation, parasites of the genus Leishmania, for example Leishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major; or parasites of the genus Trypanosoma, such as Trypanosoma cruzi and Trypanosoma brucei. Accordingly, the compounds of the present invention may be useful in the treatment of an indication selected from leishmaniasis, Chagas disease (also referred to as American trypanosomiasis), more specifically Chagas disease caused by the protozoan Trypanosoma cruzi; and human African trypanosomiasis, more specifically human African trypanosomiasis caused by the protozoan Trypanosoma brucei.

Unless otherwise indicated, the term compounds of the present invention means compounds of formula I and its subformulas, salts of the compounds, hydrates or solvates of compounds, salts, as well as all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds (in

- 3 039324 including those substituted with deuterium). The compounds of the present invention further provide polymorphs of the compounds of formula (I) (or subformulas thereof) and their salts.

Detailed description of the invention

Definitions.

As used herein, terms in the singular form and similar terms used in the context of the present invention (in particular, in the context of the claims) should be construed as covering both the singular form and the plural form, unless otherwise indicated in this document. or there is no clear contradiction with the context.

As used herein, the term C _1-6 alkyl means a straight or branched chain hydrocarbon radical, consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, containing from one to six carbon atoms, and which is attached to the rest of the molecule through a single bond . The term C _1-4 alkyl should be interpreted accordingly. As used herein, the term n-alkyl means a straight chain (straight chain) alkyl radical as defined herein. Examples of C _1-6 alkyl include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl (-CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (-CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (-C (CH ₃ ) ₃ ), n-pentyl, isopentyl (-(CH ₂ ) ₂ CH (CH ₃ ) ₂ ), neopentyl (-CH ₂ C (CH ₃ ) ₃ ), tert- pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 2-pentanyl (-CH(CH ₃ )(CH ₂ ) ₂ CH ₃ ), n-hexyl, and the like.

As used herein, the term C _1-4 alkylamino means a radical of the formula -NH-R ^a , where R ^a is a C _1-4 alkyl radical as defined above.

As used herein, the term di-(C _1-4 alkyl)amino means a radical of the formula -N(R ^a )-R ^a , where each R ^a is a C _1-4 alkyl radical which may be the same or different as defined above.

As used herein, the term C _1-6 alkoxy means a radical of the formula -OR _a , where R _a is a C _1-6 alkyl radical as generally defined above. Examples of C _1-6 alkoxy include, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

As used herein, the term C _1-4 alkoxyC _1-4 alkyl means a radical of the formula -R ^a -OR ^a , where each R ^a is independently a C _1-6 alkyl radical as defined above. The oxygen atom may be bonded to any carbon atom in any alkyl radical. Examples of C _1-4 alkoxyC _1-4 alkyl include, without limitation, methoxymethyl, methoxyethyl, ethoxyethyl, 1ethoxypropyl, and 2-methoxybutyl.

As used herein, the term C _1-6 alkoxycarbonyl means a radical of the formula -C(=O)-OR ^a , where R ^a is a C _1-6 alkyl radical as defined above.

Aryl as used herein means a 6- to 14-membered monocyclic or polycyclic aromatic assembly of rings where all ring atoms are carbon atoms. Typically, aryl is a 6-membered monocyclic, 10-12-membered bicyclic or 14-membered fused tricyclic aromatic ring system. CHaryl and CX-Y aryl as used herein describe an aryl group where X and Y indicate the number of carbon atoms in the ring system. C _6-14 aryls include, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl.

An internally bridged ring or bridged rings as used herein means a polycyclic ring system where ring atoms that are common to two rings are not directly bonded to each other. One or more rings of the ring system may include C _3-6 cycloalkyl or 4-6 membered heterocyclic rings containing heteroatoms selected from N, O and S as ring atoms. Non-limiting examples of ^N1 ' internally bridged rings include adamantanyl, azabicyclo[3.2.1]oct-3-en-3-yl, ^z , and the like.

As used herein, the term cyano means the * radical.

The term cycloalkyl means a non-aromatic carbocyclic ring which is a fully hydrogenated ring, including mono-, bi- or polycyclic, fused, bridged or spiro ring systems. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1,1,1]pentanyl, cyclohexyl, norbornyl, and cubanyl.

The term fused ring as used herein means an assembly of multiple rings where the rings constituting the ring assembly are bonded such that the ring atoms that are common to the two rings are directly bonded to each other. Fused ring assemblies can be saturated, partially saturated, aromatic, carbocyclic, heterocyclic, and the like. Non-limiting examples of conventional fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, quinoline, and the like.

Halogen or halide means bromine, chlorine, fluorine or iodine; preferably fluorine, chlorine or bromine.

As used herein, C _1-6 haloalkyl means a C _1-6 alkyl radical as defined above which is substituted by one or more halogen radicals.

- 4 039324 as defined above. Examples of C _1-6 haloalkyl include, without limitation, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutane -2-yl.

The term heteroaryl means aromatic moieties containing at least one heteroatom (eg, oxygen, sulfur, nitrogen, or combinations thereof) in a 5-10 membered aromatic ring system. Examples of heteroaryl include, without limitation, pyrrolyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzopyranilyl , benzothiophenyl, benzimidazolyl, benzoxazolyl and 1Hbenzo[b][1,2,3]triazolyl. The heteroaromatic fragment may consist of a single ring or a fused ring system. A typical single heteroaryl ring is a 5-6 membered ring containing one to four heteroatoms independently selected from N, O, and S, and a typical fused heteroaryl ring system is a 9-10 membered ring system containing one to four heteroatoms, independently selected from N, O, and S. The fused heteroaryl ring system may consist of two heteroaryl rings fused together, or a heteroaryl fused to an aryl (eg, phenyl).

As used herein, the term heteroatoms means nitrogen (N), oxygen (O), or sulfur (S) atoms. Unless otherwise noted, any heteroatom with unfilled valences is assumed to have sufficient hydrogen atoms to fill the valences, and if the heteroatom is a sulfur atom, it may be unoxidized (S) or oxidized to S(O) or S(O) ₂ .

The term hydroxyl or hydroxy as used herein means the -OH radical.

Heterocycloalkyl means cycloalkyl as defined in this application, provided that one or more of the indicated carbon atoms in the ring is replaced by a moiety selected from -O-, -N=, -NH-, -S-, -S(O)- and -S(O) ₂ -. Examples of 3-8 membered heterocycloalkyl include, without limitation, oxiranyl, aziridinyl, azetidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl-1,1-dioxide, oxazolidinyl, thiazolidinyl, pyrrolidinyl, pyrrolidinyl-2-one, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, hexahydropyrimidinyl, 1,4-dioxa-8azaspiro[4.5]dec-8-yl, thiomorpholinyl, sulfanomorpholinyl, sulfonomorpholinyl and octahydropyrrolo[3,2-b]pyrrolyl.

The term oxo as used herein means the divalent radical =O.

The term spiro as used herein includes C _3-6 cycloalkyl or 4-6 membered heterocyclic rings containing one or two heteroatoms selected from N, O and S as ring members, where the spiro ring is fused to one carbon atom of a non-aromatic ring, which makes the carbon atom common to both rings a spirocyclic center. The spiro ring may optionally be substituted, as defined, for example, with halogen, hydroxyl, or C _1-4 alkyl. Illustrative examples of spiro groups are

where the dashed bonds in each structure represent the bonds of the non-aromatic ring with which the spirocyclic group shares one atom.

As used herein, the expression "substituted" means that at least one hydrogen atom is replaced by a group other than hydrogen, provided that the normal valences are maintained, and that the substitution results in the formation of a stable compound. If the substituent is oxo (i.e. =O), then 2 hydrogen atoms on the atom are replaced. In cases where nitrogen atoms (e.g. amines) are present in the compounds of the present invention, they can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to give other compounds of the present invention.

A person skilled in the art will appreciate that, for example, a ketone group (-CH-C(=O)-) in a molecule can be tautomerized to its enol form (-C=C(OH)-). Thus, the present invention is intended to cover all possible tautomers, even if the structure depicts only one of them.

If any variable occurs more than once in any constituent or compound formula, its definition in each occurrence is independent of its definition in every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be unsubstituted or substituted with no more than three R groups, and in each case R is selected regardless of the definition of R. The notation X- as used herein *” stands for

- 5 039324 point of attachment of X to another part of the molecule.

The term IC50 as used herein means the molar concentration of an inhibitor that provides 50% of the inhibitory effect.

The term EC ₅₀ as used herein means the molar concentration of an inhibitor or modulator that provides 50% effectiveness.

As used herein, the term "pharmaceutical composition" means a compound of the present invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier in a suitable form for topical or parenteral administration.

As used herein, the term pharmaceutically acceptable carrier means a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffer agents, emulsifiers, absorption inhibitors, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, coloring agents, and combinations thereof, as will be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ^Ed . Pharmaceutical Press, 2013, pp. 1049-1070).

As used herein, the terms inhibit, inhibition, or inhibitory mean a reduction or amelioration of a given condition, symptom, or disorder, or disease, or a significant reduction in baseline activity in relation to a biological activity or process.

As used herein, the term prevent, preventing or preventing any disease or disorder means prophylactically treating the disease or disorder or delaying the onset or progression of the disease or disorder.

As used herein, the term subject means primates (eg, humans, males or females), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "therapeutically effective amount of a compound of the present invention" means an amount of a compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity, or lessening the severity of symptoms, alleviating conditions, slowing or halting the progression of a disease, or preventing development of the disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that, when administered to a subject, is effective in (1) at least partially alleviating, suppressing, preventing and/or reducing the severity of a condition or disorder or disease associated with proliferation of a parasite of the kinetoplastid class; or (2) reducing or suppressing the proliferation of a parasite of the kinetoplastid class.

As used herein, the term treat, treat, or treat any disease or disorder means alleviating or reducing the severity of the disease or disorder (ie, slowing or stopping the progression of the disease or at least one of its clinical symptoms); or a decrease or decrease in at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be perceived by the patient.

Embodiments of the invention

The present invention relates to compounds that have antiparasitic activity against protozoa of the kinetoplastid class. In particular, it relates to compounds which inhibit the growth of kinetoplastid class parasite cells by inhibiting the parasitic proteasome and are therefore useful as a therapeutic agent for leishmaniasis, Chagas disease and African sleeping sickness.

Various (listed) embodiments of the present invention are described in this document. The features described in each embodiment can be combined with other features described to provide additional embodiments of the present invention.

Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the Summary of the Invention.

Embodiment 2 The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

Embodiment 3 A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl.

Embodiment 4 A compound according to any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from -(CH2) ₁ . ₃ CF ₃ , -(CH ₂ )-CH(CH ₃ )-CF ₃ , -(CH ₂ )C(CH ₃ ) ₃ , -O(CH ₂ ) ₂ CF ₃ , -(CH ₂ ) ₀ _ ₂ - cyclopropyl, -(CH ₂ ) ₀ _ ₂ -cyclobutyl, -NHCH3, -N(CH ₃ ) ₂ , -N(CD ₃ ) ₂ ,

- 6 039324 rV

-N(CH3)(CH2CH ₃ ), -N(CH ₃ )(CH2CF ₃ ), ^u

Embodiment 5 A compound according to any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein R ¹ is azetidinyl that is unsubstituted or substituted with 1-2 substituents independently selected from halo and C1. ₄ alkyl; or two substituents on the same atom of the azetidinyl ring, together with the ring atom to which they are both attached, form spirocyclopropyl or spirotetrahydrofuranyl attached to the azetidinyl ring.

Embodiment 6. A compound according to any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from

Embodiment 7 A compound according to any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein R ³ is halogen and n is 1.

Embodiment 8 A compound according to Embodiment 7, or a pharmaceutically acceptable salt thereof, wherein R ³ is fluorine.

Embodiment 9 A compound according to any of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein ^R4 is selected from hydrogen, chlorine, bromine, methyl, isopropyl, -(CH2)1-2CH(CH3)2, -( CH2)o-1C(CH3)3, -C(CH3)2CH ₂ CH3, -CH(CH3)(CH2)1-2CH3, -CH2-cyclobutyl, -(CH2)o-iCF3, -NH-(CH2) o-iCH3, -N-(CD3)2, -N(CH3)2, -NH-CH-(CH3)2, -NH-(CH2)-CH-(CH3)2, -NHC(O)OCH( CH3)2, -NH(CH2)2OCH3,

- 7 039324

Embodiment 10. The compound according to any of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -NR ^6a R ^6b ;

R ^6a is hydrogen or C1. ₄ alkyl;

R ^6b is hydrogen, C _1-4 alkoxycarbonyl, or C _1-4 alkyl which is unsubstituted or substituted with C _1-4 alkoxy; or R ^6a and R ^6b together with the nitrogen atom to which they are both attached form a 46-membered heterocycloalkyl, optionally containing 1-2 additional heteroatoms, independently

- 8 039324 selected from N, O and S, as ring atoms;

wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents independently selected from halogen, cyano, hydroxyl, C1. ₄ alkyl, C ₁ . ₄ haloalkyl, C ₁ . ₄ alkoxyC ₁ . ₄ alkyl, C _1-4 alkoxy and oxo; or two substituents on the same or different ring atoms of a 4-6 membered heterocycloalkyl together with the atoms to which they are attached form a spiro-, bridged or fused ring C attached to a 4-6 membered heterocycloalkyl; where ring C is selected from C ₃ . ₆ cycloalkyl and 3-5 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms; and wherein ring C is independently substituted or substituted with 1-2 substituents independently selected from halo and oxo.

Embodiment 11. A compound according to any of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from

Embodiment 12 A compound according to any of Embodiments 1-3, or a pharmaceutically acceptable salt thereof;

where R ¹ is azetidinyl which is unsubstituted or substituted with 1-2 substituents independently selected from halo and C1. ₄ alkyl; or two substituents on the same ring atom of azetidinyl together with the ring atom to which they are both attached form spirocyclopropyl or spirotetrahydrofuranyl attached to the azetidinyl ring;

R ² is hydrogen or C1. ₄ alkyl;

R ³ is selected from halogen and n is 1; and

R ⁴ is -NR ^6a R ^6b where R ^6a is hydrogen or C1.4 alkyl; R ^6b is hydrogen, C1.4alkoxycarbonyl or C1. ₄ alkyl which is unsubstituted or substituted by C1. ₄ alkoxy; or R ^6a and R ^6b together with the nitrogen atom to which they are both attached form a 4-6 membered heterocycloalkyl optionally containing 1-2 additional heteroatoms independently selected from N, O and S as ring atoms;

wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents independently selected from halogen, cyano, hydroxyl, C1. ₄ alkyl, C1. ₄ haloalkyl, C ₁ . ₄ alkoxyC ₁ . ₄ alkyl, C _1-4 alkoxy and oxo; or two substituents on the same or different ring atoms of a 4-6 membered heterocycloalkyl together with the atoms to which they are attached form a spiro-, bridged or fused ring C attached to a 4-6 membered heterocycloalkyl;

where ring C is selected from C ₃ . ₆ cycloalkyl; 3-5-membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms; and wherein ring C is independently substituted or substituted with 1-2 substituents independently selected from halo and oxo.

Embodiment 13 A compound according to any of Embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from

Embodiment 14 A compound according to any of Embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from

Embodiment 16 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 15, wherein the compound is characterized by formula (I-B)

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Embodiment 17 A compound or pharmaceutically acceptable salt thereof according to Embodiment 15 or 16, wherein Ring A is phenyl.

Embodiment 18 A compound or pharmaceutically acceptable salt thereof according to Embodiment 15 or 16, wherein Ring A is pyridinyl.

Embodiment 19 A compound or pharmaceutically acceptable salt thereof according to any of Embodiments 15-18 wherein X is -C(O)-.

Embodiment 20 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Embodiments 15-19 wherein R ¹ is azetidinyl which is unsubstituted or substituted with 1-2 substituents independently selected from halo and C _{1- 4} alkyl; or two substituents on the same ring atom of azetidinyl, together with the ring atom to which they are both attached, form spirocyclopropyl or spirotetrahydrofuranyl attached to the azetidinyl ring.

Embodiment 21 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 20, wherein R ¹ is

Ej ^Z

Embodiment 22 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 20, wherein R ¹ is

^FZ

Embodiment 23 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 20 wherein R ¹ is rN ^z

F

Embodiment 24 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Embodiments 15-23 wherein R ³ is selected from halo or C _1-4 alkyl and n is 1.

Embodiment 25 A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Embodiment 24, wherein R ³ is halogen.

Embodiment 26 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 25, wherein R ³ is fluoro.

Embodiment 27 A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of Embodiments 15-26, wherein R ⁴ is -NR ^6a R ^6b ; where R ^6a represents hydrogen or C1-4alkyl; and R ^6b is hydrogen or C 1-4 alkyl which is unsubstituted or substituted with C _1-4 alkoxy or C _1-4 alkoxycarbonyl; or where R ^6a and R ^6b together with the nitrogen atom to which they are both attached form a 4-6 membered heterocycloalkyl optionally containing 1-2 additional heteroatoms independently selected from N, O and S as ring atoms;

wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted by 1-2 substituents independently selected from halogen, cyano, hydroxyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyC _1-4 alkyl, C _{1 -4} alkoxy and oxo; or two substituents on the same or different ring atoms of a 4-6 membered heterocycloalkyl together with the atoms to which they are attached form a spiro-, bridged or fused ring C attached to a 4-6 membered heterocycloalkyl;

where ring C is selected from C _3-6 cycloalkyl; 3-5-membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms; and 5-membered heteroaryl containing 1-3 heteroatoms independently selected from N or O as ring atoms; and ring C is unsubstituted or substituted with 1-2 substituents independently selected from halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, and oxo.

Embodiment 28 A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 15-27, wherein R ⁴ is selected from

Embodiment 29 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 15, wherein the compound is characterized by formula (ID)

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where R ¹ is selected from (a) -NR ^5a R ^5b where R ^5a and R ^5b together with the nitrogen atom to which they are both attached form a 4-5 membered heterocycloalkyl that is unsubstituted or substituted with 1-2 substituents independently selected from halogen and C _1-4 alkyl; and (b) a monocyclic 5-membered heteroaryl containing 1-2 heteroatoms independently selected from N and O as ring atoms, and each of which is unsubstituted or substituted with 1-2 substituents independently selected from halogen and C _1-4 alkyl;

R ³ is halo or C _1-4 alkyl and n is 0 or 1;

R ⁴ is selected from (a) -NR ^6a R ^6b where R ^6a and R ^6b together with the nitrogen atom to which they are both attached form a 4 or 5 membered heterocycloalkyl which is unsubstituted or substituted with 1-2 substituents independently selected from halogen, hydroxyl and C _1-4 alkyl; or 2 substituents on the same or different ring atoms of a 4- or 5-membered heterocycloalkyl, together with the atoms to which they are attached, form a C spiro ring attached to a 4-5 membered heterocycloalkyl, where ring C is C _3-6 cycloalkyl; and (b) a 6-membered heteroaryl containing 1-2 nitrogen atoms as ring atoms, which is unsubstituted or substituted with 1-2 substituents independently selected from halogen and C _1-4 alkyl.

Embodiment 30. The compound according to Embodiment 29, wherein R ¹ is selected from

F

F1—N—N

YG FJ, I.

Embodiment 31 A compound of formula (ID) or a pharmaceutically acceptable salt thereof according to one of Embodiments 29 or 30, wherein R ³ is fluorine or chlorine and n is 1.

Embodiment 32 A compound of formula (ID) or a pharmaceutically acceptable salt thereof according to any of Embodiments 29-31 wherein R ⁴ is selected from /-F _g p—N— ¹ J—J

Jis'* V i ^U "=? ^Z , , and

Embodiment 33 A compound of formula (ID) or a pharmaceutically acceptable salt thereof according to any of Embodiments 29-31 wherein R ⁴ is selected from

Option implementation 34. The compound of formula (I) or its pharmaceutically acceptable salt, selected from the table. one.

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Table 1

one X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -2,4-d umethyl-1,3 -oxazole-5-carboxamide 2 X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 3 X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} azetidine-1-carboxamide four (ZK)-3-Fluoro-X-{4-fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } pyrrolidine-1-carboxamide 5 3,3-Difluoro-M-{4-fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } azetidine-1-carboxamide 6 3-Fluoro-M-{4-fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}azetidine-1-carboxamide 7 M-{4-Fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide eight 3,3-Difluoro-M-!4-fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 9 X-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 3,3-difluoroazetidine-1-carboxamide ten X-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} azetidin-1-carboxamide And 5-Fluoro-X-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 12 X-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropanecarboxamide 13 2-Cyclopropyl-T4-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl}acetamide fourteen 3-Fluoro-X-{4-fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide fifteen T4-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 16 M-{4-Fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-d imethyl-1, 3-oxazole-5-carboxamide 17 M-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-2,4-

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dimethyl-1,3-oxazole-5-carboxamide eighteen M-(3-{5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 19 T4-(3-{5-Cyclohexyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide twenty M-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 21 N-[3-[5-(2,2-Dimethyl propyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 22 T4-(3-{5-tert-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 23 3-Fluoro-M-{4-fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl}azetidine-1-carboxamide 24 3-Fluoro-T4-{4-fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 25 T4-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 26 M-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}3-fluoroazetidine-1-carboxamide 27 3-Fluoro-T4-{4-fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 28 3-Fluoro-N-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 29 M-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetide in-1-carboxamide thirty N-(3-[5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetide in-1-carboxamide 31 M-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetide in-1-carboxamide 32 N-J 3-[5-(2,2-Dimethyl propyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3,3-difluoroazetidine-1-carboxamide 33 Ν-(3-{5-τρ et-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetide in-1-carboxamide 34 3,3-Difluoro-M-{4-fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2-

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yl]phenyl}azetidine-1-carboxamide 35 3,3 - Difluoro-N-{4-fluoro-3-[5-(2-methyl-butan-2-yl)-2H-pyrazolo[3,4b]pyridin-2-yl]phenyl}azetidine-1 -carboxamide 36 M-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3,3-difluoroazetide in-1-carboxamide 37 M-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 3,3-difluoroazetidine-1-carboxamide 38 3,3-Difluoro-M-{4-fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl}azetidine-1-carboxamide 39 3,3-Difluoro-M-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 40 M-{4-Fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 41 (3K)-3-Fluoro-M-{4-fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} pyrrolidine-1-carboxamide 42 (3K)-M-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)3-fluoropyrrolidine-1-carboxamide 43 (3R)-N-(3-i 5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)3-fluoropyrrolide in-1-carboxamide 44 (3K)-M-(3-{5-Cyclohexyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)3-fluoropyrrolide in-1-carboxamide 45 (3K)-M-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoropyrrolide in-1-carboxamide 46 (3K)-M-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 47 (3R)-N-(3-i 5-tert-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoropyrrolide in-1-carboxamide 48 (3K)-3-Fluoro-M-{4-fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } pyrrolide in- 1-carboxamide 49 (3K)-3-Fluoro-T4-{4-fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } pyrrolidine-1-carboxamide fifty (ZZH)-M-[3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}3-fluoropyrrolide in-1-carboxamide 51 (3K)-M-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-

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fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 52 (3K)-3-Fluoro-X-{4-fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} pyrrolidine-1-carboxamide 53 (3K)-3-Fluoro-T4-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} pyrrolidine-1-carboxamide 54 M-{4-Fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 55 T4-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan2-carboxamide 56 X-(3-{5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan2-carboxamide 57 M-(3-{5-Cyclohexyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan2-carboxamide 58 3-Fluoro-X-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}azetidine-1-carboxamide 59 X-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} furan-2-carboxamide 60 N-[4-Fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 61 T4-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}furan2-carboxamide 62 X-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} furan-2-carboxamide 63 M-{4-Fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 64 M-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 65 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5methylpyrazin-2-carboxamide 66 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3methylcyclopentan-1-carboxamide 67 5-Fluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 68 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2-

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methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxamide M 2-Cyclopropyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2- yl]phenyl}acetamide ΊΟ 3,5-Difluoro-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} pyride in-2-carboxamide 71 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3- (trifluoromethyl)cyclopentane-1-carboxamide 7? M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,5- dimethylfuran-3-carboxamide 73 N-[4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4methyl-1,3-oxazol-5-carboxamide 74 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,5dimethyl-1,3-oxazol-4 -carboxamide 7S 2-Cyclopropyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2- yl] phenyl}-1,3-oxazole-5-carboxamide 76 2-Cyclopropyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2- yl] phenyl} -4-methyl-1,3-oxazole-5-carboxamide 77 14-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2methyloxolane-2-carboxamide 78 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4methyl-2-(trifluoromethyl)-1,3 -oxazole-5-carboxamide 7Q 2-[(tert-Butoxy)methyl]-K-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}-4-methyl-1,3-oxazol-5-carboxamide M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2- o V yl]phenyl}oxane-2-carboxamide 81 ^{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4,5dimethyl-1,3-oxazol-2- carboxamide 82 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 83 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2methyl-1,3-oxazol-5-carboxamide 84 5-Cyano-M-[4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 85 ^{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2-

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methyl-1,3-oxazole-4-carboxamide 86 6-Chloro-3-fluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 87 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyrazine-2-carboxamide 88 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}oxolane-2-carboxamide 89 5-Chloro-2-fluoro-N-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} benzamide 90 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropanecarboxamide 91 Ν-(3-ί 5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl [-4fluorophenyl)azetidine-1-carboxamide 92 N-ί 3-(5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 93 X-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)azetidine-1-carboxamide 94 N-{3-(5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 95 X-{4-Fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} azetidine-1-carboxamide 96 T4-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} azetidine-1-carboxamide 97 X-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 98 X-{4-Fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 99 X-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 100 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 101 X-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-2,4dimethyl-1,3-oxazole-5-carboxamide 102 N-{ 3-(5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-

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fluorophenyl}-2,4-dimethyl-1,3-oxazole-5-carboxamide 103 N-(3-{5-tert-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-2,4dimethyl-1,3-oxazole-5-carboxamide 104 X-{4-Fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } -2,4-d imethyl-1,3 -oxazole-5-carboxamide 105 T4-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-2,4dimethyl-1,3-oxazol-5- carboxamide 106 X-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 2,4-d imethyl-1, 3-oxazole-5-carboxamide 107 T4-{4-Fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,4dimethyl-1,3-oxazol-5-carboxamide 108 M-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-d imethyl-1, 3-oxazole-5-carboxamide 109 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5methylfuran-2-carboxamide ON M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5methoxyfuran-2-carboxamide 111 5-[(Dimethylamino)methyl]-T4-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}furan-2-carboxamide 112 5-Cyano-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide FROM 5-Fluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 114 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4,5dimethylfuran-2-carboxamide 115 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3methylfuran-2-carboxamide 116 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-1benzofuran-2-carboxamide 117 3,3-Difluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl}-1-methyl cyclobutan-1 -car boxamide 118 3,3-Difluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclobutan-1-carboxamide 119 Methyl-8-({4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2-

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yl]phenyl}carbamoyl)cu ban-1-carboxylate 120 Methyl-3-({4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}carbamoyl)bicyclo[1.1.1]pentan-1 -carboxylate 121 3-Fluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} cyclobutan-1-carboxamide 122 M-{4-Fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} furan-2-carb oxamide 123 Propan-2-yl-K-{2-[2-fluoro-5-(furan-2-amido)phenyl]-2H-pyrazolo[3,4- b] pyridin-5-yl} carbamate 124 3,3-Difluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 125 N-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetide in-1-carboxamide 126 M-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 127 (3K)-N-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoropyrrolide in-1-carboxamide 128 M-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-2,4-dimethyl1,3-oxazole-5-carboxamide 129 M-(3-|5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)azetidine-1carboxamide 130 X-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan-2carboxamide 131 3-Fluoro-X-{4-fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 132 3-Fluoro-X-{4-fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 133 (3K)-R-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 134 (3K)-3-Fluoro-N-{4-fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin2-yl] phenyl } pyrroleide in-1 -carboxamide 135 (3K)-3-Fluoro-N-{4-fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyrrolidine-1-carboxamide 136 Propan-2-yl-M-[2-(2-fluoro-5-{[(ZK)-3-fluoropyrrolidine-1-

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carbonyl]amino}phenyl)-2H-pyrazolo[3,4-b]pyridin-5-yl]carbamate 137 M-{4-Fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} azetidine-1-carboxamide 138 Propan-2-yl-M-(2-{5-[(azetidine-1-carbonyl)amino]-2-fluorophenyl}-2Hpyrazolo[3,4-b]pyridin-5-yl)carbamate 139 M-{4-Fluoro-3-[5-(methylamino)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 140 T4-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} furan-2-carboxamide 141 M-{4-Fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 142 1-{4-Fluoro-3-[5-(methylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3methylurea 143 1-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3,3dimethylurea 144 M-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 3,3-difluoroazetidine-1-carboxamide 145 3,3-Difluoro-M-{4-fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 146 Propan-2-yl-M-(2-{5-[(3,3-difluoroazetidine-1-carbonyl)amino]-2fluorophenyl}-2H-pyrazolo[3,4-b]pyridin-5-yl)carbamate 147 M-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 148 3-Fluoro-M-{4-fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} azetidine-1-carboxamide 149 (ZI)-A-[3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 150 (ZI)-3-Fluoro-A-{4-fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyrrolidine-1-carboxamide 151 M-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} furan-2-carboxamide 152 3-Fluoro-N-[4-fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 153 A-!4-Fluoro-3-[5-(methylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,4-

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dimethyl-1,3-oxazole-5-carboxamide 154 M-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 2,4-d imethyl-1, 3-oxazole-5-carboxamide 155 X-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 2,4-d imethyl-1, 3-oxazole-5-carboxamide 156 3-Fluoro-N-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 157 X-{4-Fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-d imethyl-1, 3-oxazole-5-carboxamide 158 M-{4-Fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-d imethyl-1, 3-oxazole-5-carboxamide 159 Propan-2-yl-M-{2-[5-(dimethyl-1,3-oxazol-5-amido)-2-fluorophenyl]-2Hpyrazolo[3,4-b]pyridin-5-yl}carbamate 160 M-{4-Fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} azetidine-1-carboxamide 161 3,3-Difluoro-K-{4-fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl}azetidine-1-carboxamide 162 (ZK)-3-Fluoro-M-{4-fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}pyrrolidin-1-carboxamide 163 M-{4-Fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 164 ^{4-Fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 165 3,3-Difluoro-X-{4-fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 166 3,3-Difluoro-K-{4-fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl}azetidine-1-carboxamide 167 PM-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 168 Propan-2-yl-M-(2-{2-fluoro-5-[(3-fluoroazetidine-1-carbonyl)amino]phenyl }2H-pyrazolo[3,4-b]pyridin-5-yl)carbamate 169 M-[4-Fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl J-2,4dimethyl-1,3-oxazol-5 -carboxamide 170 M-)3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-

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fluorophenyl}azetidine-1-carboxamide 171 3-Fluoro-N-[4-fluoro-3-(5-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 172 3-Φτορ-Ν-(4-φτορ-3-ί 5-[(18.48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2Hpyrazolo[3,4-b] pyridin-2-yl}phenyl)azetidine-1-carboxamide 173 4,4,4-Trifluoro-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} butanamide 174 3,3,3-Trifluoropropyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4b]pyridin-2-yl]phenyl}carbamate 175 M-{4-Fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } -2,4-d imethyl-1,3 -oxazole-5-carboxamide 176 N-{4-Φτop-3-[5-(2,2,2-τpiφtoroethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 177 N-(3-{5-[(2S, 68)-2,6-Dimethylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-2yl}-4-fluorophenyl)-3-fluoroazetidine- 1-carboxamide 178 b1-{3-[5-(1,1-Dioxo-thiomorpholino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 179 3-Fluoro-M-{4-fluoro-3-[5-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } azetidine-1-carboxamide 180 3-Φτορ-Ν-[4-φτορ-3-(5-{5H,6H,7H,8H-imidazo[1,2-а]pyrazin-7-yl}-2Hpyrazolo[3,4-b]pyridine- 2-yl)phenyl]azetidine-1-carboxamide 181 3-Fluoro-M-{4-fluoro-3-[5-(3-hydroxyazetidin-1-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } azetidine-1-carboxamide 182 3-Fluoro-M-{4-fluoro-3-[5-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 183 3-Fluoro-M-[4-fluoro-3-(5-[2-oxa-6-azaspiro[3.4]octan-6-yl}-2H-pyrazolo[3,4- b] pyridin-2-yl)phenyl]azetidine-1-carboxamide 184 3 -Φτορ-Ν-[4-φτορ-3 -(5- { 8-oxa-3 -azabicyclo [3.2.1] octan-3 -yl } -2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 185 3-Fluoro-M-(4-fluoro-3-{5-[(2-methoxyethyl)amino]-2H-pyrazolo[3,4-b]pyridine- 2-yl } phenyl)azetide in-1-carboxamide 186 3-Fluoro-M-[4-fluoro-3-(5-{5H,6H,7H,8H-[1,2,4]triazolo[4,3-а]pyrazin-7-yl}- 2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl]azetidine-1-carboxamide 187 3-Fluoro-M-{4-fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine-

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2-yl]phenyl}azetidine-1-carboxamide 188 M-{3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 189 3-Fluoro-M-]4-fluoro-3-[5-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 190 X-(3-{5-[(2K,68)-2,6-Dimethylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-2yl} -4-fluorophenyl)-3-fluoroazetidine- 1-carboxamide 191 3-Fluoro-N-[4-fluoro-3-(5-{6-oxa-1-azaspiro[3.3]heptan-1-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 192 3-Fluoro-M-(4-fluoro-3-{5-[3-(methoxymethyl)azetidin-1-yl]-2H-pyrazolo[3,4- b] pyridin-2-yl } phenyl)azetidine-1-carboxamide 193 N-[3-(5-{5-Azaspiro[2.3]hexan-5-yl [-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 194 M-(3-{5-[(ZK,4K)-3,4-Difluoropyrrolidin-1-yl]-2H-pyrazolo[3,4-b]pyridin-2yl} -4-fluorophenyl)-3-fluoroazetidine- 1-carboxamide 195 (3K)-3-Fluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyrrole in-1 -carboxamide 196 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 197 3-Fluoro-M-[4-fluoro-3-(5-{2-oxa-5-azabicyclo[2.2.2]octan-5-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 198 3-Fluoro-M-(4-fluoro-3-{5-[(2-methylpropyl)amino]-2H-pyrazolo[3,4-b]pyridin2-yl } phenyl)azetide in-1-carboxamide 199 M-!3-[5-(Ethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 200 3-Φτορ-Ν-(4-φτορ-3-[5-[(propan-2-yl)amino]-2H-pyrazolo[3,4-b]pyridin-2yl} phenyl)azetide in-1-carboxamide 201 3-Φτορ-Ν-[4-φτορ-3-(5-{1-oxa-6-azaspiro[3.3]heptan-6-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)φenyl] azetidine-l-κapboκcamamide 202 3-Fluoro-M-[4-fluoro-3-(5-{6-oxa-2-azaspiro[3.4]octan-2-yl}-2H-pyrazolo[3,4- b] pyridin-2-yl)phenyl]azetidine-1-carboxamide 203 3-Fluoro-N-[4-fluoro-3-(5-{7-oxa-2-azaspiro[3.5]nonan-2-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 204 X-[3-(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2H-pyrazolo[3,4-

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b]pyridin-2-yl)-4-fluorophenyl]-3-fluoroazetidine-1-carboxamide 205 3-Fluoro-X-{4-fluoro-3-[5-(3-methoxyazetidin-1-yl)-2H-pyrazolo[3,4b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 206 5-Cyano-X-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 207 2-Ethoxy-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclopropan-1-carboxamide 208 2,2-Difluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} cyclopropan-1-carboxamide 209 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-1(trifluoromethyl)cyclopropan-1-carboxamide 210 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } ring butanecarboxamide 211 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2methylcyclopropan-1-carboxamide 212 3,3,3-Trifluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } propanamide 213 4,4,4-Trifluoro-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -3-methyl butanamide 214 5,5,5-Trifluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } pentanamide 215 3-Cyclopropyl-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } propanamide 216 2-Cyclobutyl-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} acetamide 217 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3,3dimethylbutanamide 218 M-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclobut-1-en-1-carboxamide 219 1-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3,3bis( ^2H3 )methylurea 220 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5azaspiro[2.4]heptan-5-carboxamide 221 (3K)-X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2-

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yl] phenyl } -3-methyl pyrrole ide in-1-carboxamide 222 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5azaspiro[2.3]hexane-5-carboxamide 223 (1K,58)-M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}-3-azabicyclo[3.1.0 ]hexane-3-carboxamide 224 3-Ethyl-1-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -3-methyl urea 225 (3K)-X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}-3-methoxypyrrolidine-1-carboxamide 226 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2azaspiro[3.3]heptan-2-carboxamide 227 1-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3methyl-3-(2,2,2- trifluoroethyl)urea 228 1-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3,3- dimethylurea 229 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-1,4diazabicyclo[3.2.2] nonan-4 -carboxamide 230 N-(3-{5-[(2R,68)-2,6-Dimethylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-2yl}-4-fluorophenyl)-3-fluoroazetidine- 1-carboxamide 231 3-Fluoro-X-[4-fluoro-3-(5-{6-oxa-1-azaspiro[3.3]heptan-1-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 232 3-Φτορ-Ν-(4-φτορ-3-ί 5-[3-(methoxymethyl)azetidin-1-yl]-2H-pyrazolo[3,4- b] pyridin-2-yl } phenyl)azetidine-1-carboxamide 233 Ν-[3-(5-ί 5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 234 M-(3-{5-[(3K,4K)-3,4-Difluoropyrrolidin-1-yl]-2H-pyrazolo[3,4-b]pyridin-2yl}-4-fluorophenyl)-3-fluoroazetidine- 1-carboxamide 235 3 -Φτορ-Ν-[4-φτορ-3 -(5- { 3-oxa-8-azabicycle o [3.2.1] octan-8-yl } -2Hpyrazolo[3,4-b]pyridin-2-yl )phenyl]azetidine-1-carboxamide 236 1-(2-{2-Fluoro-5-[(3-fluoroazetidine-1-carbonyl)amino]phenyl}-2H-pyrazolo[3,4- b]pyridin-5-yl)piperidine-4-carboxylic acid 237 3-Fluoro-X-(4-fluoro-3-{5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2Hpyrazolo[3,4-b]pyridin-2-yl}phenyl )azetidine-1-carboxamide 238 3-Fluoro-X-(4-fluoro-3-{5-[4-(oxetan-3-yl)piperidin-1-yl]-2H-pyrazolo[3,4-

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b] pyridin-2-yl } phenyl)azetidine-1-carboxamide 239 3-Fluoro-M-[4-fluoro-3-(5-[2-thia-6-azaspiro[3.3]heptan-6-yl}-2H-pyrazolo[3,4- b] pyridin-2-yl)phenyl]azetidine-1-carboxamide 240 3-Fluoro-X-[4-fluoro-3-(5-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 241 X-[3-(5-{5-Azaspiro[2.4]heptan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 242 X-[3-(5-{5-Azaspiro[2.4]heptan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-5-azaspiro[2,4] heptane-5-carboxamide 243 X-[3-(5-{2-Azaspiro[3.3]heptan-2-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 244 3-Fluoro-X-[4-fluoro-3-(5-{8-oxa-2-azaspiro[4.5]decan-2-yl}-2H-pyrazolo[3,4- b] pyridin-2-yl)phenyl]azetidine-1-carboxamide 245 3-Fluoro-X-[4-fluoro-3-(5-{6-oxo-2,5-diazaspiro[3.4]octan-2-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 246 M-[4-Fluoro-3-(5-{6-oxa-2-azaspiro[3.4]octan-2-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)phenyl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide 247 tert-Butyl-2-(2-{5-[(azetidine-1-carbonyl)amino]-2-fluorophenyl}-2Hpyrazolo[3,4-b]pyridin-5-yl)pyrrolidine-1-carboxylate 248 3-Fluoro-X-[4-fluoro-3-(5-{2-oxa-7-azaspiro[3.5]nonan-7-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 249 X-{3-[5-(Cyclopropylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 250 Ν-(4-Φτορ-3-ί 5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2H-pyrazolo[3,4- b] pyridin-2-yl } phenyl)azetidine-1-carboxamide 251 3-Fluoro-X-{4-fluoro-3-[5-(3-hydroxy-3-methylazetidin-1-yl)-2Hpyrazol o[3,4-b]pyridine in-2-yl]phenyl }azetidine -1 -carboxamide 252 3,3-Difluoro-X-(4-fluoro-3-{5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2Hpyrazolo[3,4-b]pyridin-2-yl }phenyl)azetidine-1-carboxamide 253 (3K)-3-Fluoro-X-(4-fluoro-3-{5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2Hpyrazole o[3,4-b]pyridine -2-yl } phenyl) pyrrolidine-1-carboxamide 254 N-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-5azaspiro[2.3]hexane-5-carboxamide 255 X-{3-[5-(3,3-Dimethylazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-

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fluorophenyl}-3-fluoroazetidine-1-carboxamide 256 (18.2K)-2-Fluoro-X-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}cyclopropan-1- carboxamide 257 N-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]azetidine-1-carboxamide 258 R-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3,3-difluoroazetidine-1- carboxamide 259 (3K)-X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2yl)-4-fluorophenyl]-3-fluoropyrrolidine- 1-carboxamide 260 M-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-5azaspiro[2.3]hexane-5-carboxamide 261 M-[3-(5-{1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)-4-fluorophenyl]-3-fluoroazetidine-1-carboxamide 262 M-{3-[5-(3,3-Difluoropyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 263 3-Fluoro-X-[4-fluoro-3-(5-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 264 N-{3-[5-(Azetidin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 265 3-Φτορ-Ν-(4-φτορ-3-[5-[3-(trifluoromethyl)azetidin-1-yl]-2Н-pyrazolo[3,4- b] pyridin-2-yl } phenyl)azetidine-1-carboxamide 266 M-[3-[5-(3-Cyanoazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 267 M-{3-[5-(1-Acetylazetidin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 268 (18.2K)-M-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-2-fluorocyclopropane- 1-carboxamide 269 (1K,28)-2-Fluoro-X-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl} cyclopropan-1 - carboxamide 270 3-Fluoro-X-{4-fluoro-3-[5-(piperazin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 271 (1K,28)-X-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-2-fluorocyclopropane- 1-carboxamide 272 (1K,28)-X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridine-2-

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yl)-4-fluorophenyl]-2-fluorocyclopropane-1-carboxamide 777 (18.2K)-2-Fluoro-Ni-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine- Z/J 2-yl]phenyl}cyclopropan-1-carboxamide 974 Ν-(4-Φτορ-3-ί 5-[3-(trifluoromethyl)azetidin-1-yl]-2H-pyrazolo[3,4- b] pyridin-2-yl } phenyl)azetidine-1-carboxamide ?7S (ZK)-3-Fluoro-X-(4-fluoro-3-{5-[3-(trifluoromethyl)azetidin-1-yl]-2H- z / J pyrazolo[3,4-b] pyride in-2-yl } phenyl) pyrrolidine-1-carboxamide 776 N-(3-{5-Chloro-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3- z / and fluorazetidine-1-carboxamide 777 X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2- yl]phenyl}-4-(hydroxymethyl)-2-methyl-1,3-oxazole-5-carboxamide 77" M-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2- yl ] phenyl } -2-( ^2H3 )methyl-4-methyl-1,3-oxazole-5-carboxamide 77Q X-(4-Fluoro-3-{5-[3-(trifluoromethyl)azetidin-1-yl]-2H-pyrazolo[3,4- Z / y b]pyridin-2-yl}phenyl)-2,4-dimethyl-1,3-oxazole-5-carboxamide 7RO X-{2-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2- ZOU yl]pyridin-4-yl}azetidine-1-carboxamide qqi 3,3-Difluoro-X-{2-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine-2- Zo 1 yl]pyridin-4-yl }azetidine-1-carboxamide 7R7 M-[2-(5-!5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridine-2- ZoZ yl)pyridin-4-yl]azetidine-1-carboxamide 7R7 M-{4-Chloro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3- ZoJ fluorazetidine-1-carboxamide 7R4 X-{4-Chloro-3-[5-(3,3-difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2- ZO4 yl]phenyl } azetidine-1-carboxamide 7R5 X-{4-Chloro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2- ZOJ yl]phenyl } azetidine-1-carboxamide 7R6 X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4- ZOU chlorophenyl]azetidine-1-carboxamide 7R7 X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridine-2- ZO / yl)phenyl]azetidine-1-carboxamide 7's X-{4-Fluoro-3-[5-(oxan-2-yl)-2H-pyrazolo[3,4-b]pyridine-2- Zoo yl]phenyl } azetidine-1-carboxamide 289 T4-{3-[5-(1,4-Dioxan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-

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fluorophenyl}azetidine-1-carboxamide 290 T4-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 291 3-Fluoro-N-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}azetidine-1-carboxamide 292 M-{4-Fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl}azetidine-1-carboxamide 293 3-Fluoro-T4-{4-fluoro-3-[5-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 294 3-Fluoro-N-{4-fluoro-3-[5-(pyrazin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 295 3-Φτορ-Ν-ί4-φτορ-3-[5-(Ι H-imidazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} azetidine-1-carboxamide 296 T4-{3-[5-(1-Benzylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 297 3-Fluoro-T4-{4-fluoro-3-[5-(1H-pyrazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} azetidine-1-carboxamide 298 T4-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 299 T4-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3,3-difluoroazetidine-1-carboxamide 300 (3K)-M-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]- 4-fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 301 3-Fluoro-K-{4-fluoro-3-[5-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } azetidine-1-carboxamide 302 (ZI)-3-Fluoro-M-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } pyrrolidine-1-carboxamide 303 3,3-Difluoro-M-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } azetidine-1-carboxamide 304 3-Fluoro-M-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4- b] pyridin-2-yl]phenyl } azetidine-1-carboxamide 305 3-Fluoro-M-[4-fluoro-3-(5-{1-[(4-fluorophenyl)methyl]piperidin-4-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 306 Ν-(3-{5-[bis( ² H3)methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-

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fluorophenyl)azetidine-1-carboxamide 307 T4-(3-{5-[bis( ^2H3 )methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)-3,3-difluoroazetidine-1-carboxamide 308 (3R)-N-(3-i 5-[bis( ^2H3 )methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)-3-fluoropyrrolidine-1-carboxamide 309 3,3-Difluoro-T4-{4-fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4- b] pyride in-2-yl]-phenyl}-azetidine-1-carboxamide 310 X-[3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3,3-difluoroazetidine-1-carboxamide 311 3-Fluoro-M-(4-fluoro-3-{2H-pyrazolo[3,4-b]pyridin-2-yl}phenyl)azetidine-1carboxamide 312 3-Fluoro-M-{4-fluoro-3-[5-(3-methylpyrazin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}azetidine-1-carboxamide 313 ^{4-Fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 314 N-(3-[5-[bis( ^2H3 )methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)-3-fluoroazetidine-1-carboxamide 315 X-[3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} azetidine-1-carboxamide 316 (3I)-X-[3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 317 (ZI)-3-Fluoro-X-!4-fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4- b] pyride in-2-yl]phenyl } pyrrolidine-1-carboxamide 318 3-Φτορ-Ν-(4-φτορ-3-{5-methyl-2H-pyrazolo[3,4-b]pyridin-2yl}phenyl)azetide in-1-carboxamide 319 3-Fluoro-M-{4-fluoro-3-[5-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 320 M-{4-Fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 321 3-Fluoro-X-{4-fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 322 (3K)-3-Fluoro-1X-{4-fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } pyrroleide in-1-carboxamide 323 3-Φτορ-Ν-{4-φτορ-3-[5-(1 H-imidazol-1-yl)-2H-pyrazolo[3,4-b]pyridine-2-

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yl]phenyl}azetidine-1-carboxamide 324 3,3-Difluoro-N-{4-fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl}azetidine-1-carboxamide 325 PM-{3-[5-(1-Cyclopropyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-3-fluoroazetidine-1-carboxamide 326 M-)3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}cyclopropanecarboxamide 327 M-{4-Fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropanecarboxamide 328 3-Fluoro-X-{4-fluoro-3-[5-(4-methyl-1H-imidazol-1-yl)-2H-pyrazolo[3,4- b] pyride in-2-yl]phenyl } azetidine-1-carboxamide 329 3-Fluoro-M-{4-fluoro-3-[5-(5-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}azetidine-1-carboxamide 330 X[-{4-Fluoro-3-[5-(5-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } azetidine-1-carboxamide 331 M-)3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} cyclopropanecarboxamide 332 M-{4-Fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropanecarboxamide 333 M-)3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} cyclopropanecarboxamide 334 ^{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}-2-(hydroxymethyl)-4-methyl-1, 3-oxazole-5-carboxamide 335 X-(4-Fluoro-3-{5-[3-(hydroxymethyl)pyridin-2-yl]-2H-pyrazolo[3,4- b]pyridin-2-yl}phenyl)-2,4-dimethyl-1,3-oxazole-5-carboxamide 336 M-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } pyrroleide in-1-carboxamide 337 PM-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl] pyrrolidine-1-carboxamide 338 M-)3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} pyrrolidine-1-carboxamide 339 (1Sh28)-M-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-2-fluorocyclopropan-1 - carboxamide 340 (3R)-N-(2-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl }pyridin-4-yl)-3-

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fluoropyrrolide in-1-carboxamide 341 M-{2-[5-(Pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]pyridin-4- yl}azetidine-1-carboxamide 342 3-Fluoro-M-{2-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]pyridin-4- yl}azetidine-1-carboxamide 343 N-{3-(5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 344 M-(3-[5-(Pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}azetidine-1carboxamide 345 M-[4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyrazine-2-carboxamide 346 M-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } spiro [2.2] pentan-1-carboxamide 347 M-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}3,3-dimethylcyclobut-1-eu-1 - carboxamide 348 1-Cyano-M-(4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclopropane-1-carboxamide 349 (1 S,2S)-2-Φτop-N-ί4-φτop-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine2-yl] phenyl} cyclopropan-1 -carboxamide 350 N-(4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -3,3-dimethyl ring but-1 - en-1-carboxamide 351 M-(4-Fluoro-3-(5-isopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)-2,4dimethyloxazole-5-carboxamide 352 Y1-(4-Fluoro-3-(5-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)-2,4dimethyloxazole-5-carboxamide 353 3,3 - Difluoro-N-(4-fluoro-3 - (5-phenyl-2H-pyrazolo [3,4-b] pyride in-2yl)phenyl)azetidine-1-carboxamide

Embodiment 35 A compound of formula (I) or a pharmaceutically acceptable salt thereof according to Embodiment 34, wherein said compound is selected from compounds 1-76, 7879, 81-87, 89-115, 117-118, and 121-353 from Table . one.

Embodiment 36. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-35 and at least one excipient.

Embodiment 37. A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any of Embodiments 1-35 or a pharmaceutical composition based on them according to Embodiment 36 and one or more therapeutically active agents.

Embodiment 38 A compound according to any of Embodiments 1-35 or a pharmaceutical composition according to Embodiment 36 for use in therapy.

Embodiment 39 A compound according to any one of Embodiments 1-35 or a pharmaceutical composition according to Embodiment 36 for use in the treatment of a disease selected from leishmaniasis, forms of Chagas disease and human African trypanosomiasis.

Embodiment 40. The use of a compound according to any of Embodiments 1-35 or a pharmaceutical composition according to Embodiment 36 in the manufacture of a medicament for the treatment of a disease selected from leishmaniasis, forms of Chagas disease, and human African trypanosomiasis.

Embodiment 41. A method of inhibiting the growth and proliferation of a kinetoplastid parasite in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-35.

Embodiment 42 Method for Treating a Disorder or Disease Caused by a Parasite

- 32 039324 of the kinetoplastid class, which provides for the introduction to a subject in need of it, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with any of embodiments 1-35 and optionally in combination with a second agent; where the disease is selected from leishmaniasis, forms of Chagas disease and human African trypanosomiasis.

Embodiment 43. The method according to Embodiment 42, wherein said disease is leishmaniasis selected from visceral leishmaniasis and cutaneous leishmaniasis.

Embodiment 44. The method of Embodiment 43 wherein said second agent is selected from stibogluconate, meglumine antimonate, amphotericin, miltefosine, and paromomycin.

Embodiment 45. The method of Embodiment 42, wherein said disease is Chagas disease; and wherein said second agent is selected from benznidazole, nifurtimox and amphotericin.

Embodiment 46. The method of Embodiment 42, wherein said disease is human African trypanosomiasis; and wherein said second agent is pentamidine, suramin, melarsoprol, eflornithine and nifurtimox.

Depending on the choice of starting materials and procedures, the compounds may be in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers or as a mixture of stereoisomers such as racemates and mixtures of diastereoisomers, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers, and optically pure forms. Optically active (R)- and (S)-stereoisomers can be obtained using chiral synthons or chiral reagents or isolated using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in the cis or trans configuration. It is also intended to include all tautomeric forms.

As used herein, the terms salt or salts mean an acid addition or base addition salt of a compound of the present invention. Salts include, in particular, pharmaceutically acceptable salts. The term pharmaceutically acceptable salts means salts which retain the biological efficacy and properties of the compounds of the present invention and which are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or the like.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium and metal salts from Groups I-XII of the Periodic Table of the Elements. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; in particular, suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

In another aspect, the present invention provides compounds of formula (I) or its subformulas in the form of a salt, which is acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride /hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucat , naphthoate, napsilate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrophosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate triphenate, trifluoroacetate, or xinafoate.

In another aspect, the present invention provides compounds of formula (I) or subforms thereof

- 33 039324 mule in the form of sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salts.

Any formula given in this document includes unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted using the formulas given herein, except that one or more atoms are replaced by an atom characterized by the selected atomic mass or mass number. Isotopes that can be included in the compounds of the present invention include, for example, isotopes of hydrogen.

In addition, the incorporation of certain isotopes, particularly deuterium (i.e., ² H or D), may confer certain therapeutic benefits due to higher metabolic resistance, such as increased in vivo half-life, or reduced dosage required, or improved therapeutic index, or portability. It is understood that deuterium is considered in this context as a substituent of the compound of formula (I). The deuterium concentration can be determined from the isotopic enrichment factor. As used herein, the term isotopic enrichment factor means the ratio of the abundance of an isotope to the natural abundance of said isotope. When a substituent in a compound of the present invention is indicated as deuterium, that compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (introduction of 52.5% deuterium at each designated deuterium atom), at least 4000 (introduction of 60% deuterium), at least 4500 (feeding 67.5% deuterium), at least 5000 (feeding 75% deuterium), at least 5500 (feeding 82.5% deuterium), at least 6000 (feeding 90% deuterium) , at least 6333.3 (introduction of 95% deuterium), at least 6466.7 (introduction of 97% deuterium), at least 6600 (introduction of 99% deuterium), or at least 6633.3 (introduction of 99.5% deuterium). It should be understood that the term isotopic enrichment factor can be used with respect to any isotope in the same manner as described for deuterium.

Other examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F ³¹ P , ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, respectively. However, it should be understood that the present invention includes compounds in which one or more of any of the above isotopes is included, including, for example, radioactive isotopes such as ³ H and ¹⁴ C, or compounds in which non-radioactive isotopes are present, such as ² H and ¹³ C. Such isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C), studies of reaction kinetic parameters (for example, using ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including analyzes of the distribution of the drug or substrate in tissues, or in radiation therapy of patients. In particular, ¹⁸ F or a labeled compound may be particularly useful for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparation methods, using an appropriate isotopically labeled reagent instead of an unlabeled reagent, previously used.

Any asymmetric atom (eg carbon or the like) of the compound(s) of the present invention may be in racemic or enantiomerically enriched form, eg in the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom is characterized by at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least at least 95% enantiomeric excess or at least 99% enantiomeric excess in the (R)- or ^-configuration. Substituents on atoms with unsaturated double bonds may, if possible, be in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein, a compound of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, e.g., substantially pure geometric (cis or trans) stereoisomers, diastereoisomers, optical isomers. (antipodes), racemates or mixtures thereof.

Any resulting mixtures of stereoisomers may be separated, on the basis of the physicochemical differences of the constituents, into pure or substantially pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.

Any resulting racemates of end products or intermediates can be separated into optical antipodes by known methods, for example by separating their diastereomeric salts obtained with an optically active acid or base, and you

- 34 039324 divisions of an optically active acidic or basic compound. In particular, the basic fragment can thus be used to separate the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O '-p-toluotartaric acid, mandelic acid, malic acid or camphor-10sulfonic acid. Racemic products can also be separated by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Pharmacology and applicability

In one aspect, the present invention relates to small molecular weight compounds of formula (I) that target the proteasome of kinetoplastid parasites and are useful as a therapeutic agent; in particular for the prevention and treatment of diseases and conditions caused by infection with parasites of the kinetoplastid class. The activity of a compound of the present invention can be assessed using the in vitro and in vivo methods described in the Biological Assays section below. Obviously, the analyzes illustrate the present invention without limiting in any way the scope of the present invention.

Thus, as a further aspect, the present invention provides the use of a compound of formula (I), or subformulas thereof, or a pharmaceutically acceptable salt or stereoisomer thereof, as a therapeutic agent for a disease or condition in which a beneficial effect can be observed by inhibiting the growth and proliferation of parasites. kinetoplastid class; and in the manufacture of a medicament, for example, for the treatment of a disease caused by the growth and proliferation of a parasite of the kinetoplastid class. In one embodiment, the disease to be treated is selected from leishmaniasis, Chagas disease, and human African trypanosomiasis. In another embodiment, the disease being treated is leishmaniasis caused by a parasite, including, but not limited to, Leishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major. In one embodiment, the disease being treated is visceral leishmaniasis. In another embodiment, the disease being treated is cutaneous leishmaniasis. In another embodiment, the disease being treated is Chagas disease caused by Trypanosoma cruzi. In yet another embodiment, the disease to be treated is human African trypanosomiasis caused by Trypanosoma brucei, Trypanosoma brucei gambiense, or Trypanosoma brucei rhodesiense.

According to the above, the present invention further provides a method for preventing or treating leishmaniasis, Chagas disease or human African trypanosomiasis in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound selected from formula (I) or subformulas thereof, its pharmaceutically acceptable salt or its stereoisomer. The required dose will vary depending on the route of administration, the particular condition being treated and the desired effect.

Pharmaceutical compositions, dosage and administration.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In an additional embodiment, the composition contains at least two such pharmaceutically acceptable carriers as described herein. The pharmaceutical composition may be formulated for specific routes of administration such as oral administration, parenteral administration (eg by injection, infusion, transdermal or topical administration) and rectal administration. Topical administration may also refer to inhalation or intranasal administration. Pharmaceutical compositions of the present invention may be formulated in solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be either coated or enteric coated according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of

a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; also in the case of tablets

c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) disintegrants, for example types of starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

- 35 039324

e) absorbents, colors, flavors and sweeteners. The pharmaceutical composition or combination of the present invention may be presented in a single dosage of about 1-1000 mg of active ingredient(s) for a subject weighing about 50-70 kg, or about 1-500 mg, or about 1-250 mg , or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of the active ingredients. A therapeutically effective dose of a compound, pharmaceutical composition, or combinations thereof will depend upon the type of subject, body weight, age, and individual condition, disorder, or disease being treated, or their severity. A skilled physician, clinician, or veterinarian can easily determine the effective amount of each of the active ingredients needed to prevent, treat, or inhibit the progression of a disorder or disease.

The above dosage parameters are evident in in vitro and in vivo tests using predominantly mammals, eg mice, rats, dogs, non-human apes or isolated organs, tissues and preparations thereof. The compounds of the present invention can be administered in vitro as solutions, eg aqueous solutions, and in vivo either enterally or parenterally, preferably intravenously, eg as a suspension or aqueous solution. The in vitro dosage may range from about 10 ^-3 to 10 ^-9 molar concentration. A therapeutically effective amount in vivo, depending on the route of administration, may be in the range of about 0.1-500 mg/kg or about 1-100 mg/kg.

The compounds of the present invention may be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). The compound of the present invention can be administered either simultaneously with one or more other therapeutic agents, or before or after their administration. The compound of the present invention can be administered separately from other agents, by the same or different route of administration, or together with them in the same pharmaceutical composition. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present invention.

Products presented as a combination preparation include a composition containing a compound of formula (I) or subformulas thereof, a pharmaceutically acceptable salt or stereoisomer thereof, and other therapeutic agent(s) together in the same pharmaceutical composition, or a compound formula (I) and other(s) therapeutic(therapeutic) agent(s) in a separate form, for example, in the form of a kit. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or subformulas thereof, a pharmaceutically acceptable salt or stereoisomer thereof, and other therapeutic agent(s). Optionally, the pharmaceutical composition may contain a pharmaceutically acceptable carrier as described above. In another embodiment, the present invention provides a product containing a compound of formula (I) and at least one other therapeutic agent in the form of a combined preparation for simultaneous, separate or sequential use in therapy.

In one embodiment, the present invention provides a kit containing two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or its subformula, its pharmaceutically acceptable salt or its stereoisomer. In one embodiment, the kit contains means for keeping said compositions separate, such as a container, a split bottle, or a split foil pouch. An example of such a kit is a blister pack, typically used for packaging tablets, capsules, and the like. The kit of the present invention can be used to administer various dosage forms, for example, for oral and parenteral use, to administer separate compositions at different intervals between doses, or to titrate individual compositions against each other. In order to facilitate adherence to a treatment regimen, the kit of the present invention typically contains instructions for administration.

In the combination therapies of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the present invention and another therapeutic agent can be combined in combination therapy (i) before the combined product reaches the physicians (eg, in the case of a kit containing the compound of the present invention and another therapeutic agent); (ii) by physicians themselves (or under the supervision of a physician) shortly before administration; (iii) in the patients themselves, for example, during sequential administration of a compound of the present invention and another therapeutic agent.

Accordingly, the present invention provides the use of a compound of formula (I) for the treatment of a disease or condition due to the growth and proliferation of a parasite of the kinetoplastid class, wherein the drug is formulated to be administered with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment

- 36 039324 diseases or conditions caused by the growth and proliferation of a parasite of the kinetoplastid class, where the drug is administered with a compound of formula (I).

The present invention also provides the use of a compound of formula (I) for the treatment of a disease or condition due to the growth and proliferation of a parasite of the kinetoplastid class, where the patient has previously (eg, within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of a disease or condition due to the growth and proliferation of a parasite of the kinetoplastid class, where the patient has previously (eg, within 24 hours) been treated with a compound of formula (I).

In one embodiment, the other leishmaniasis therapeutic agent is selected from stibogluconate, meglumine antimonate, amphotericin, miltefosine, and paromomycin. In one embodiment, another therapeutic agent for Chagas disease is selected from benznidazole, nifurtimox and/or amphotericin. In another embodiment, another therapeutic agent for human African trypanosomiasis is selected from pentamidine, suramin, melarsoprol, eflornithine, and/or nifurtimox. When the compounds of the present invention are administered in combination with other therapies, the dosages of the co-administered compounds will, of course, vary depending on the type of co-administered drug, the particular drug used, the condition being treated, etc.

Getting connections

Compounds of the present invention can be obtained using a number of methods known to a person skilled in the field of organic synthesis, taking into account the methods, reaction schemes and examples presented in this document. For illustrative purposes, the reaction schemes depicted below provide possible routes for the synthesis of the compounds of the present invention, as well as key 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 present invention. Although specific starting materials and reagents are depicted in the schemes and discussed below, they can be replaced with other starting materials and reagents to provide different derivatives and/or reaction conditions. In addition, many of the compounds obtained by the methods described below can be further modified in accordance with the present invention using conventional chemical techniques well known to those skilled in the art. All of the methods described herein may be performed in any suitable order, unless otherwise noted or clearly inconsistent with the context.

Compounds of formula (I) can be prepared as generally illustrated in Schemes 1-3 below, where R ¹ , R ² , R ³ , R ⁴ and n are defined in the Brief Description of the Invention.

Compounds of formula (I) can be prepared as generally illustrated in Scheme 1-3 below, wherein X is chlorine, bromine or trifluoromethyl; and R ¹ , R ² , R ³ , R ⁴ and n are defined in the Brief Description of the Invention.

Scheme 1

Alternatively, a compound of formula (I) may be prepared from intermediate (Id) following the procedures in Scheme 2.

- 37 039324

Scheme 2

Alternatively, a compound of formula (I) may be prepared from intermediate (1e) following the procedures in Scheme 3.

Scheme 3

The present invention further includes any variant of the methods of the present invention in which an intermediate product obtained in any of its stages is used as a starting material and the remaining stages are carried out, or in which the starting materials are obtained in situ under the reaction conditions, or in which the components of the reaction mixture used in the form of their salts or optically pure substance. The compounds of the present invention and intermediates can also be converted into each other according to methods well known to those skilled in the art.

Examples

The Examples section of this document merely explains the present invention and does not limit the scope of the present invention as claimed in any form.

Temperature values are given in degrees Celsius. Unless otherwise indicated, all evaporation operations are carried out under reduced pressure, typically from about 15 to 100 mmHg. (= 20-133 mbar). The structure of end products, intermediates and starting materials is confirmed using standard analytical methods, eg microanalysis and spectroscopic characterization, eg MS, IR, NMR.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are either commercially available or can be obtained by organic synthetic methods known to one of ordinary skill in the art. (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Also, the compounds of the present invention can be obtained by organic synthesis methods known to the person of ordinary skill in the art, as shown in the following examples. If necessary, traditional protecting groups are used to protect reactive functional groups in accordance with standard practice, for example, see nW. Greene and P.G.M. Wuts in Protecting Groups in Organic Synthesis, John Wiley and Sons, 1991.

Unless otherwise noted, starting materials are generally available from non-exclusive commercial sources such as Aldrich Chemicals (Milwaukee, WI), TCI Fine Chemicals (Japan), Shanghai Chemhere Co., Ltd. (Shanghai, China), Aurora Fine Chemicals LLC (San Diego, California), FCH Group (Ukraine), Lancaster Synthesis, Inc. (Wyndham, New Hampshire), Acros Organics (Fair Lawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, New Jersey), AstraZeneca Pharmaceuticals (London, England), Chembridge Corporation (USA), Matrix Scientific (USA), Conier Chem & Pharm Co., Ltd (China), Enamine Ltd (Ukraine), CombiBlocks, Inc. (San Diego, USA), Oakwood Products, Inc. (USA), Apollo Scientific Ltd. (Great Britain), Alichem LLC. (USA), Rieke Metals (USA), Silicycle Inc (Canada) and Ukrorgsyntez Ltd (Latvia); or are readily obtainable using methods well known to those skilled in the art (e.g., obtained using methods generally described in Louis F. Fieser and Mary Fie

- 38 039324 ser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), Larock, RC, Comprehensive Organic Transformations, 2nd ^-ed ., Wiley-VCH Weinheim, Germany (1999) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including additions (also available via the Beilstein online database).

Abbreviations.

The abbreviations used in this document are defined as follows: 1x means once, 2x means twice, 3x means thrice, °C means degrees Celsius, aq. means aqueous solution, Col means column, eq. means equivalent or equivalents, g means grams or grams, mg means milligram or milligrams, l means liter or liters, ml means milliliter or milliliters, μl means microliter or microliters, n.a. means normal, M means molar, µM means micromolar, nM means nanomolar, mole means mole or moles, mmol means millimoles or millimoles, min means minute or minutes, h means hour or hours, k.t. means room temperature, ON means overnight, atm means atmosphere, psi means psi, conc. means concentrated, aq. means aqueous solution, sat. or sat. means saturated, MW means molecular weight, mw or μwave means microwave, m.p. means melting point, Wt means weight, MS or Mass Spec means Mass Spectrometry, ESI means Electrospray Ionization Mass Spectrometry, HR means High Resolution, HRMS means High Resolution Mass Spectrometry, LCMS means Liquid Chromatography with Mass Spectrometry, HPLC means High Pressure Liquid Chromatography , RP HPLC means reverse phase HPLC, TLC or tlc means thin layer chromatography, NMR means nuclear magnetic resonance spectroscopy, nOe means nuclear Overhauser spectroscopy, 1H means proton, δ means delta, s means singlet, d means doublet, t means triplet , q is a quartet, m is a multiplet, br is wide, Hz is hertz, ee is enantiomeric excess, and α, β, R, r, S, s, E, and Z are stereochemical terms known to those skilled in the art.

The following abbreviations, as used in this document below, have their respective meanings:

- 39 039324

AIBN azobisisobutyronitrile

Bn benzyl

Vos tert-butoxy carbonyl

Vos ₂ O di-tert-butyl and carbonate

Wee butyl

Cs ₂ CO ₃ anhydrous cesium carbonate

SHC1 ₃ chloroform

DAST diethylaminosulfur trifluoride

DBA dibenzylideneacetone

DBU 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine

DCM dichloromethane

DIEA N, N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethyl sulfoxide

DPP diphenylphosphine

DPPA diphenylphosphoryl azide

Dppf 1,1'-bis(diphenylphosphino)ferrocene

EA ethyl acetate

Eq. equivalent

Et ethyl

Et ₂ O diethyl ether

EtOH ethanol

EtOAc ethyl acetate

FA formic acid

HATU 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HC1 hydrochloric acid z Bu isobutyl zPr isopropyl

KO As potassium acetate

LiAlH ₄ lithium aluminum hydride

Me methyl wCPBA 3-chloroperoxybenzoic acid

MeCN acetonitrile

MnO ₂ manganese dioxide

N ₂ nitrogen

NaBH ₄ sodium borohydride

NaHCO ₃ sodium bicarbonate

Na ₂ SO ₄ sodium sulfate

NBS A-bromosuccinimide

Ph phenyl

PPh ₃ triphenylphosphine

Ph ₃ P=O triphenylphosphine oxide

R _f retention factor

room temperature (°C)

SFC supercritical fluid chromatography /-Vi or Vi ¹ tert-butyl

ТЗР® propanephosphonic acid anhydride

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

Tgos 2,2,2-trichloroethyl

- 40 039324

LCMS.

Method 1.

System for UPLC Acquity Waters:

Acquity binary gradient control system with degasser.

Acquity column compartment set to 50°C.

Diode array detector Acquity.

Automatic dispenser HTS Pal Leap Technologies.

Chemiluminescent Nitrogen Detector (CLND) Antek.

Waters 3100 mass spectrometer.

Column for HPLC: Syncronis C18 30x2.1 mm Thermo.

Mobile phase: (A) 95% H ₂ O/5% MeOH/IPA (75/25, v/v) + 0.05% formic acid, (B) MeOH/IPA (75/25, v/v) vol.) + 0.035% formic acid.

Gradient: 0.4 ml/min, initial 2% B over 1.0 min, rise to 95% B over 2.5 min, up to time 4.0 min, return to 2% B up to time 4.25 min and until the end of the cycle at time 5.0.

Scanning at MS: 150 to 1000 amu for 1 s.

Diode array detector: 190 nm - 400 nm.

Method 2.

System for UPLC Acquity Waters:

Acquity binary gradient control system with degasser.

Acquity column compartment set to 50°C.

Diode array detector Acquity.

Acquity ELSD.

Automatic dispenser HTS Pal Leap Technologies.

Mass detector Waters Qda.

HPLC column: Acquity C18 1.7 µm, 2.1x30 mm, Waters.

Mobile phase: (A) H ₂ O+0.05% TFA and (B) acetonitrile+0.05% TFA.

Gradient: 1 ml/min, initial 5% B over 0.1 min, rise to 95% B over 1.5 min, hold to time 1.6 min, then to 100% B at time 1.7 and return to 5% B until time 1.9 min and until the end of the cycle at time 2.25.

Scanning at MS: 160 to 1000 amu for 0.4 s.

Diode array detector: 214 nm - 400 nm.

NMR. Proton spectra were recorded on a Bruker AVANCE II 400 MHz with a 5 mm QNP cryoprobe or a Bruker AVANCE III 500 MHz with a 5 mm QNP probe, unless otherwise noted. Chemical shifts are given in ppm relative to dimethyl sulfoxide (δ 2.50), chloroform (δ 7.26), methanol (δ 3.34) or dichloromethane (δ 5.32). A small amount of dry sample (2-5 mg) was dissolved in a suitable deuterated solvent (1 ml).

Intermediate 1. 3-(5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluoroaniline (I-1) F _ΝΗ2 , EtOH, 85°С

about

Br

H

¹⁾ o ₂ n

Stage B

2) Toluene, HE reversed

NaN ₃ , DMF ^Br °C

Stage A

Step A. Stir the reaction mixture of NaN ₃ (8 g, 122.5 mmol, 1 eq.), 5-bromo-2fluoropyridine-3-carbaldehyde (25 g, 122.5 mmol, 1 eq.) in DMF (250 ml) at 70° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (500 ml) and poured into ice water (500 ml). The aqueous layer was separated and extracted with ethyl acetate (500 ml x 6). The combined organic layers were washed with brine (300 ml x 3), dried over sodium sulfate and concentrated. The residue was triturated with Et ₂ O (100 ml) to give compound I-1a as a yellow solid.

¹ H NMR: (400 MHz, DMSO-d ₆ ) δ ppm 10.26-10.46 (m, 1H), 10.12 (d, J=1.51 Hz, 1H), 8.64 (d, J=1.51 Hz, 1H).

In order to safely handle low molecular weight azides, this reaction was carried out in several batches and pooled for use in step B.

Step B. Stir the reaction mixture of compound 1-1a (30 g, 132.1 mmol, 1 eq.) and 2-fluoro5-nitroaniline (20.6 g, 132.1 mmol, 1 eq.) in EtOH (500 ml) at 85°C for 4 hours under N2 atmosphere. Re

- 41 039324 the stock mixture was concentrated in vacuo. Toluene (700 mL) was added to the crude material and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated and the material was purified by silica gel chromatography eluting with 0 to 50% EtOH in DCM. The resulting material was triturated with EtOH (100 ml) to give Compound 1-1b as a yellow solid.

¹ H NMR: (400 MHz, DMSO-d6) δ ppm 9.04 (d, J=2.26 Hz, 1H), 8.85 (dd, J=6.53, 3.01 Hz, 1H), 8.79 (d, J=2.26 Hz, 1H), 8.60-8.71 (m, 1H), 8.47 (dt, J=9.03, 3.39 Hz, 1H), 7 .92 (dd, J=10.54, 9.29 Hz, 1H).

Step C. Stir the reaction mixture of compound 1-1b (25 g, 74.2 mmol, 1 eq.), diiodozinc (9.5 g, 29.7 mmol, 0.4 eq.) and Raney Ni (50 g, 583 .6 mmol, 7.9 eq.) in THF (500 ml) at 20° C. for 12 h under H ₂ at 15 psi. The reaction mixture was diluted with MeOH (450 ml), filtered and the filter cake was washed with MeOH (200 ml x 3). The filtrate was concentrated and triturated with water (500 ml), dried in vacuo to give compound I-1 as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.81 (br d, J=1.51 Hz, 1H), 8.71 (br d, J=1.76 Hz, 1H), 8, 58 (br d, J=1.76 Hz, 1H), 7.10-7.41 (m, 2H), 6.56-6.85 (m, 1H), 5.45 (br s, 2H) .

Intermediate 2 2,2,2-Trichloroethyl-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl)carbamate (I-2)

To a solution of compound I-1 (5 g, 16.3 mmol, 1 eq.) in EtOH (150 ml) was added a saturated aqueous solution of NaHCO ₃ (150 ml). The reaction mixture was cooled to 0° C. followed by the dropwise addition of 2,2,2-trichloroethylcarbonyl chloride (6.9 g, 32.6 mmol, 2 eq.). The mixture was stirred at 0° C. for 2 h and then stirred at 25° C. for 20 h. The solid was collected by filtration and washed with water (150 ml) and ethyl acetate (20 ml) to give compound I-2 as a yellow solid substances.

¹ H NMR (400 MHz, DMSO-d6), δ ppm, 10.57 (br s, 1H), 8.92 (d, J=2.51 Hz, 1H), 8.76 (d, J=2 .26 Hz, 1H), 8.63 (d, J=2.51 Hz, 1H), 8.27 (br d, J=4.52 Hz, 1H), 7.62-7.67 (m, 1H), 7.55-7.61 (m, 1H), 4.99 (s, 2H).

Intermediate 3 N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)-3,3-difluoroazetidine-1-carboxamide (I-3) (also connection 125)

To a solution of compound I-2 (2 g, 4.14 mmol, 1 eq.) and 3,3-difluoroazetidine-HCl (1.1 g, 8.3 mmol, 2 eq.) in DMSO (15 ml) was added DMAP (25.3 mg, 207 µmol, 0.05 eq.) and DIEA (1.1 g, 8.3 mmol, 1.45 ml, 2 eq.). The mixture was stirred at 60° C. for 15 hours. The product was precipitated by adding 60 ml of water and 10 ml of ethyl acetate and collected by filtration. The filter cake was washed with 40 ml of water and 10 ml of ethyl acetate, and the resulting solid was dried under reduced pressure to give compound 1-3 as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ), δ ppm, 9.25 (s, 1H), 8.91 (br s, 1H), 8.76 (br s, 1H), 8.63 (br s, 1H), 8.25 (br s, 1H), 7.69 (br s, 1H), 7.51 (br t, J=10.16 Hz, 1H), 4.41 (br t, J =12.67 Hz, 4H).

Intermediate 4 N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)-3fluoroazetidine-1-carboxamide (I-4) (also compound 126 )

DMAP (25.3 mg, 207 µmol, 0.05 eq.) and DIEA (1.07 g, 8.28 mmol, 1.45 ml, 2 eq.). The mixture was stirred at 60° C. for 15 hours. The product was precipitated by adding 60 ml of water and 10 ml of ethyl acetate and collected by filtration. The filter cake was washed with 40 ml of water and 10 ml of ethyl acetate, and the resulting solid was dried under reduced pressure to obtain compound I-4 as a solid.

¹ H NMR (400 MHz, DMSO-d ₆ ), δ ppm, 8.98 (s, 1H), 8.90 (d, J=2.51 Hz, 1H), 8.76 (d, J=2 .51 Hz, 1H),

- 42 039324

8.63 (d, J=2.51 Hz, 1H), 8.24 (dd, J=7.03, 2.76 Hz, 1H), 7.67-7.74 (m, 1H), 7 .49 (dd, J=11.17, 9.16 Hz, 1H), 5.29-5.51 (m, 1H), 4.25-4.39 (m, 2H), 3.96-4 .10 (m, 2H).

Intermediate 5 (R)-N-(3-(5-bromo-2H-n-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)-3fluoropyrrolidine-1-carboxamide (I-5) (also connection 127)

Intermediate I-5 was prepared in a similar manner as Intermediate I-3 using (R)-3-fluoropyrrolidine-HCl as starting material.

1H NMR (400 MHz, DMSO-d ₆ ), δ ppm, 8.90 (d, J=2.26 Hz, 1H), 8.76 (d, J=2.51 Hz, 1H), 8.66 (s, 1H), 8.63 (d, J=2.26 Hz, 1H), 8.27 (dd, J=7.03, 2.76 Hz, 1H), 7.71-7.77 ( m, 1H), 7.48 (dd, J=11.17, 9.16 Hz, 1H),

5.28-5.48 (m, 1H), 3.40-3.78 (m, 4H), 2.01-2.27 (m, 2H).

Intermediate 6 N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)azetidine-1-carboxamide I-6 (also compound 129)

DMAP (20.3 mg, 166 µmol, 0.05 eq.) and DIEA (857 mg, 6.63 mmol, 2 eq.). The mixture was stirred at 60°C for 15 hours. The product was precipitated by adding 60 ml of water and 10 ml of ethyl acetate and collected by filtration. The filter cake was washed with 40 ml of water and 10 ml of ethyl acetate, and the resulting solid was dried under reduced pressure. The resulting solid was triturated with 10 ml of ethyl acetate to give compound I-6 as a yellow solid.

1 H NMR (400 MHz, DMSO-d ₆ ), δ ppm, 8.89 (d, J=2.01 Hz, 1H), 8.70-8.80 (m, 2H), 8.62 (d, J=2.26 Hz, 1H), 8.25 (dd, J=6.90, 2.38 Hz, 1H), 7.72 (br d, J=9.03 Hz, 1H), 7.46 (br t, J=10.16 Hz, 1H), 3.98 (br t, J=7.53 Hz, 4H), 2.20 (quint, J=7.59 Hz, 2H).

Intermediate 7 N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)-2,4dimethyloxazole-5-carboxamide (I-7) (also connection 128)

To a solution of compound I-1 (1 g, 3.3 mmol, 1 eq.) and 2,4-dimethyloxazole-5-carboxylic acid (552.1 mg, 3.9 mmol, 1.2 eq.) in DMF ( 15 ml) was added HATU (1.5 g, 3.9 mmol, 1.2 eq.) and DIEA (632 mg, 4.9 mmol, 854 μl, 1.50 eq.). The mixture was stirred at 25° C. for 13 hours. Saturated aqueous NaHCO ₃ (40 ml) was added to the reaction mixture and the solid was collected by filtration. The filter cake was washed with water (30 ml) and ethyl acetate (10 ml). The resulting solid was triturated in water (20 ml) to give Compound I-7 as a brown solid.

1H NMR (400 MHz, DMSO-d6), δ ppm, 10.53 (s, 1H), 8.94 (d, J=2.51 Hz, 1H), 8.77 (d, J=2.26 Hz, 1H), 8.64 (d, J=2.26 Hz, 1H), 8.58 (dd, J=7.15, 2.64 Hz, 1H), 7.89-7.97 (m , 1H), 7.59 (dd, J=11.17, 9.16 Hz, 1H), 2.52-2.53 (s, 3H), 2.40 (s, 3H).

Intermediate 8 N-(3-(5-bromo-2H-n-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)furan2-carboxamide (I-8) (also compound 130)

Intermediate I-8 was prepared in a similar manner as Intermediate I-7 using furan-2-carboxylic acid as starting material.

1H NMR (400 MHz, DMSO-d ₆ ), δ ppm, 10.58 (br s, 1H), 8.94 (d, J=2.26 Hz, 1H), 8.77 (d, J=2 .26 Hz, 1H), 8.64 (d, J=2.26 Hz, 1H), 8.53 (dd, J=7.03, 2.51 Hz, 1H), 7.92-8.02 (m, 2H), 7.60 (dd, J=11.04, 9.29 Hz, 1H), 7.40 (d, J=3.26 Hz, 1H), 6.74 (dd, J= 3.26, 1.51 Hz, 1H).

- 43 039324

Intermediate 9 4-Fluoro-3-(5-isopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl)aniline (I-9)

Step A To a solution of intermediate I-1 (4 g, 13.0 mmol, 1 eq.) in THF (60 ml) and H ₂ O (9 ml) was added Cs ₂ CO ₃ (12.7 g, 39. 1 mmol, 3 eq.), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (531.8 mg, 651.2 µmol, 0.05 eq.) and trifluoro(prop-1-en-2-yl)borate potassium (2.2 g, 14.7 mmol, 1.1 eq.). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with petroleum ether:EtOH=1:2) to give compound I-9a as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.00 (d, J=2.26 Hz, 1H), 8.78 (d, J=2.38 Hz, 1H), 8.23 ( d, J=2.26Hz, 1H), 7.09-7.29(m, 2H), 6.68(dt, J=8.88, 3.34Hz, 1H), 5.64(s , 1H), 5.44 (s, 2H), 5.22 (s, 1H), 2.18 (s, 3H), M+H=269.1.

Step B To a solution of intermediate I-9a (3.4 g, 12.7 mmol, 1 eq.) in EtOH (216 ml) was added 20% Pd(OH) ₂ /C (5.3 g, 7.60 mmol, 0.6 eq.) and the mixture was stirred at 25° C. for 4 h under H2 at 15 psi. The reaction mixture was filtered through celite and the filter cake was washed with ethanol (30 ml). The filtrate was concentrated, the resulting residue was dissolved in EtOAc (10 ml) and 4M HCl in EtOH (2 ml) was added. The solid was collected by filtration and dried in vacuo to give the HCl salt of compound I-9 as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.10 (d, J=2.26 Hz, 1H), 8.90 (d, J=2.01 Hz, 1H), 8.47 (br d, J=1.63 Hz, 1H), 8.07 (br dd, J=6.46, 2.45 Hz, 1H), 7.72 (br dd, J=10.85, 9.10 Hz , 1H), 7.58 (dt, J=8.50, 3.28 Hz, 1H), 3.07-3.25 (m, 1H), 1.32 (d, J=6.78 Hz, 6H), M+H=271.1.

Intermediate 10 (2-(2-Fluoro-5-(3-fluoroazetidine-1-carboxamido)phenyl)-2Hpyrazolo[3,4-b]pyridin-5-yl)boronic acid (I-10)

4,4,4',4',5,5,5',5'-octamethyl-2 ,2'-bi(1,3,2-dioxaborolane) (223.9 mg, 881.9 µmol, 1.2 eq.), Pd(dppf)Cl ₂ (53.8 mg, 73.5 µmol, 0 .1 eq.) and KOAc (144.3 mg, 1.5 mmol, 2 eq.). The mixture was stirred at 100° C. for 16 hours. The reaction mixture was concentrated and the residue was washed with EtOAc (5 ml), water (5 ml) and dried under reduced pressure to obtain compound I-10 as a black solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (br s, 2H), 8.70 (br s, 1H), 8.45 (br s, 1H), 8.24 (br s, 1H ), 7.69 (br s, 1H), 7.56 (br s, 1H), 7.50 (br s, 1H), 6.59 (br s, 1H), 5.25-5.56 ( m, 1H), 4.33 (br s, 2H), 3.90-4.13 (m, 2H), M+H=374.2.

Intermediate 11 4-Fluoro-3-(5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl)aniline I-11

ZnBr

Compound I-1 (947 mg, 3.1 mmol) and Pd(Ph ₃ P) ₄ (178 mg, 0.15 mmol) were combined in a flask and placed under a nitrogen atmosphere. 0.5M pyridin-2-ylzinc(II) bromide in THF (24.7 ml, 12.3 mmol) was added and the reaction mixture was heated to 65° C. for 4 hours. The reaction mixture was quenched with water and concentrated. Not

- 44 039324 the purified material was purified by flash chromatography on a C18 column eluting with 10 to 80% acetonitrile in water to give compound I-11 as a pale yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J=2.3 Hz, 1H), 8.93 (dd, J=3.4, 2.4 Hz, 2H), 8, 73 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.12 (dt, J=8.0, 1.0 Hz, 1H), 7.95 (td, J= 7.7, 1.8 Hz, 1H), 7.46-7.40 (m, 1H), 7.26-7.16 (m, 2H), 6.69 (ddd, J=8.9, 3.9, 2.9 Hz, 1H), 5.46(s, 2H).

Intermediate 12 2-(5-Amino-2-fluorophenyl)-N,N-dimethyl-2H-pyrazolo[3,4b]pyridine-5-amine (I-12)

Stir the reaction mixture of N-methylmethanamine (4.4 g, 98.7 mmol, 5 ml, 50.5 eq.), I-1 (0.6 g, 1.9 mmol, 1 eq.), L-proline ( 22.5 mg, 195.4 µmol, 0.1 eq.), CuI (37.2 mg, 195.4 µmol, 0.1 eq.) and

K2CO3 (540 mg, 3.9 mmol, 2 eq.) in DMSO (5 ml) at 90°C for 12 h. The reaction mixture was quenched with 10% aqueous NH4OH (20 ml) and extracted with ethyl acetate (25 ml x 4) . The combined ethyl acetate layers were washed with brine (15 ml x 3), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate and 20% DCM in petroleum ether to give I-12 as a yellow solid.

¹ H NMR: (400 MHz, DMSO-d ₆ ) δ ppm 8.68 (br s, 1H), 8.48 (br s, 1H), 7.16 (br s, 3H), 6.63 (br s, 1H), 5.38 (br s, 2H), 2.95 (br s, 6H). M+H=391.1.

Intermediate 13 2,2,2-Trichloroethyl-(3-(5-(dimethylamino)-2H-pyrazolo[3,4b]pyridin-2-yl)-4-fluorophenyl)carbamate (I-13)

CI^CI

A-J. Ij. I. .___ ₄ 'N NII O

N.--N. _ _Ν M3

The synthesis of I-13 is described in example 9.

Intermediate 14 (R)-N-(3-(5-(3,6-dihydro-2H-niran-4-yl)-2H-pyrazolo[3,4b]pyridine-2-yl)-4-fluorophenyl )-3-fluoropyrroludin-1-carboxamide (I-14)

F

The synthesis of I-14 is described in example 18.

Intermediate 15 N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridine-2-ul)-4-fluorophenyl)-5azaspiro[2.3]hexane-5-carboxamide I-15 (also connection 254)

Intermediate I-15 (Compound 254) was prepared in a similar manner as Intermediate I-3 using 5-azaspiro[2.3]hexane hemi-oxalate as starting material.

¹ H NMR (400 MHz, DMSO-d6), δ ppm, 8.90 (d, J=2.45 Hz, 1H), 8.85 (s, 1H), 8.74-8.78 (m, 1H), 8.61-8.65 (m, 1H), 8.26 (dd, J=7.09, 2.69 Hz, 1H), 7.69-7.76 (m, 1H), 7 .47 (dd, J=11.25, 9.29 Hz, 1H), 4.05 (s, 4H), 0.66 (s, 4H).

Method 1: RT=2.95 min; M+H=416.0, 418.0.

Intermediate 16

Intermediate I-16 was prepared in a similar manner as Intermediate I-1, with

- 45 039324 using 5-chloro-2-fluoronicotinaldehyde as starting material.

A-NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J=2.26 Hz, 1H), 8.67 (d, J=2.51 Hz, 1H), 8.44 (d , J=2.51 Hz, 1H), 7.12-7.28 (m, 2H), 6.61-6.75 (m, 1H), 5.44 (br s, 2H).

Intermediate 17 2-(5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)pyridin-4-amine (I-17)

Ν^ί

Λ Λ _U U NH _? \,-Α —Ν 1-17

Intermediate I-17 was prepared in a similar manner as Intermediate I-1 using 4-nitropyridine-2-amine as starting material in step B.

1H NMR (400 MHz, DMSO) δ ppm 9.19 (br s, 1H), 8.73 (br s, 1H), 8.59 (br s, 1H), 8.01 (br d, J=5 .27 Hz, 1H), 7.42 (br s, 1H), 6.54-6.74 (m, 3H).

Intermediate 18

Intermediate I-18 was prepared in a similar manner as Intermediate I-1 using 2-chloro-5-nitroaniline as starting material in step B. M+H=325.0.

Intermediate 19 3-(5-Bromo-2H-pyrαzolo[3,4-b]pyridin-2-yl)αniline (I-19)

Intermediate I-19 was prepared in a similar manner as Intermediate I-1 using 3-nitroaniline as starting material in Step B.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 1H), 8.69 (d, J=2.44 Hz, 1H), 8.56 (d, J=2.45 Hz, 1H), 7.31 (t, J=2.08 Hz, 1H), 7.12-7.26 (m, 2H), 6.61-6.72 (m, 1H), 5.56 (br s, 2H).

Intermediate yl)pyridin-4-yl)carbamate (I-20)

20. 2,2,2-Trichloroethyl-(2-(5-bromo-2H-pyrazolo[3,4-b]pyridine-2-

The synthesis of I-20 is described in example 21.

Intermediate 21 3-(2-(5-Bromo-2H-n-pyrazolo[3,4-b]pyridin-2-yl)pyridin-4-yl)-1,1dimethylurea (I-21)

The synthesis of I-21 is described in example 21.

Intermediate 22 N-(2-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)pyridin-4-yl)-3,3difluoroazetidine-1-carboxamide (I-22)

The synthesis of I-22 is described in example 22.

- 46 039324

Intermediate 23 4-Fluoro-3-(5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl)aniline (I-23)

Intermediate I-23 was prepared in a similar manner as Intermediate I-1 using 2-fluoro-5-(trifluoromethyl)nicotinaldehyde as a starting material.

1H NMR (400 MHz, DMSO), δ ppm, 9.06 (d, J=2.01 Hz, 1H), 8.98 (d, J=2.26 Hz, 1H), 8.85 (s, 1H), 7.167.30 (m, 2H), 6.72 (dt, J=8.91, 3.33 Hz, 1H), 5.48 (s, 2H).

Intermediate 24 N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)cyclopropanecarboxamide (I-24)

Intermediate I-24 was prepared in a similar manner as Intermediate I-7 using cyclopropanecarboxylic acid as starting material.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.90 (d, J=2.38 Hz, 1H), 8.75 (d, J=2.38 Hz, 1H), 8.62 ( d, J=2.38 Hz, 1H), 8.38 (dd, J=7.03, 2.51 Hz, 1H), 8.25-8.30 (m, 1H), 7.66-7 .75 (m, 1H), 7.53 (dd, J=11.17, 9.16 Hz, 1H), 1.72-1.83 (m, 1H), 0.83 (d, J=6 .15 Hz, 4H).

Intermediate 25

Step A. Stir the reaction mixture of I-1 (10 g, 32.6 mmol, 1 eq.) and Boc ₂ O (21.3 g, 97.7 mmol, 22.4 ml, 3 eq.) in THF (100 ml) at 76° C. for 12 hours. The reaction mixture was concentrated and the residue was triturated with petroleum ether (100 ml) to obtain I-25a as a brown solid. M+H=408.9.

Step B. Stir the reaction mixture of I-25α (0.5 g, 1.2 mmol, 1 eq.), 1H-pyrazole (126 mg, 1.8 mmol, 1.5 eq.), CuI (35 mg, 184 .5 µmol, 0.15 eq.), Quinolin-8-ol (27 mg, 184.5 µmol, 31.9 µl, 0.15 eq.) and K ₂ CO ₃ (221 mg, 1.6 mmol, 1.3 eq.) in DMSO (5 ml) at 120°C for 12 hours. The reaction mixture was poured into 20 ml of water, extracted with DCM (20 ml x 3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to give I25b as a black solid. M+H=395.3.

Step C. Stir the reaction mixture of I-25b (0.4 g, 1.0 mmol, 1 eq.) in HCl/dioxane (10 ml) at 25°C for 12 hours. The reaction mixture was concentrated and purified by preparative HPLC. (Phenomenex Gemini 150 x 25 mm x 10 µm; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; V%: 18 to 48%, 12 min) to give I-25 as a yellow solid.

1H NMR (400 MHz, DMSO) δ ppm 9.28 (d, J=2.69 Hz, 1H), 8.90 (d, J=2.45 Hz, 1H), 8.61 (dd, J= 10.64, 2.57 Hz, 2H), 7.84 (d, J=1.47 Hz, 1H), 7.14-7.31 (m, 2H), 6.66-6.75 (m , 1H), 6.57-6.65 (m, 1H), 5.45 (s, 2H).

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Intermediate 26 4-Fluoro-3-(5-(4-methyl-1H-imidazol-1-yl)-2H-pyrazolo[3,4b]pyridin-2-yl)aniline (I-26)

Intermediate I-26 was prepared in a similar manner as Intermediate I-25 using 4-methyl-1H-imidazole as starting material in step B.

1 H NMR: (400 MHz, DMSO) δ ppm 9.00 (d, J=2.69 Hz, 1H), 8.89 (d, J=2.20 Hz, 1H), 8.37-8.49 (m, 1H), 8.20 (s, 1H), 7.53 (s, 1H), 7.13-7.30 (m, 3H), 6.61-6.80 (m, 1H), 5.45(s, 2H), 2.21(s, 3H).

Intermediate 27 N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl)pyrrolidine-1-carboxamide (I-27)

Intermediate I-27 was prepared in a similar manner as Intermediate I-3 using pyrrolidine as starting material.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.89 (d, J=2.26 Hz, 1H), 8.75 (d, J=2.26 Hz, 1H), 8.62 ( d, J=2.51 Hz, 1H), 8.51 (s, 1H), 8.28 (dd, J=7.03, 2.51 Hz, 1H), 7.74 (dt, J=9 .10, 3.48 Hz, 1H), 7.46 (dd, J=11.29, 9.29 Hz, 1H), 3.39 (br s, 4H), 1.87 (br t, J= 6.40 Hz, 4H).

Intermediate 28 4-Fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl)aniline I-28

Intermediate I-28 was prepared in a similar manner as Intermediate I-11 using (3-methylpyridin-2-yl)zinc(II) bromide as starting material.

1H NMR (400 MHz, DMSO-d ₆ ) 8.89 (dd, J=8.2, 2.4 Hz, 2H), 8.56 (dd, J=4.6, 1.7 Hz, 1H) , 8.47 (d, J=2.2 Hz, 1H), 7.80 (ddd, J=7.7, 1.7, 0.8 Hz, 1H), 7.40-7.32 (m , 1H), 7.24-7.14 (m, 2H), 6.69 (ddd, J=9.0, 3.9, 2.8 Hz, 1H), 5.46 (s, 2H), 2.44(s, 3H).

Intermediate 29

Pd ₂ (dba) ₃ , Xantphos,t-BuONa dioxane, 85°C, 1 h

Stage A l-25a

l-29a

Stage B

HC1 in dioxane

1-29

Step A. Degassed a mixture of I-25α (100 mg, 245.6 µmol, 1 eq.), 3-(trifluoromethyl)azetidine (48 mg, 294.7 µmol, 1.2 eq., HCl), NaOBu-t ( 2M, 368.3 µl, 3 eq.), XantPhos (28 mg, 49.11 µmol, 0.2 eq.) and Pd ₂ (dba) ₃ (22 mg, 24.6 µmol, 0.1 eq.) in dioxane (2 ml) and then stirred at 80° C. for 1 h under N2 atmosphere. The mixture was quenched and the pH adjusted to 7 with 1M HOAc. The mixture was purified by silica gel chromatography (petroleum ether/ethyl acetate=1/1) to give I-29a as a yellow solid. M+H=452.3.

Stage B. This stage was carried out in a similar manner as for I-25, stage C, to obtain I-29.

1H NMR (400 MHz, DMSO) δ ppm 8.49 (d, J=2.45 Hz, 1H), 8.29 (d, J=2.81 Hz, 1H), 7.09-7.22 ( m, 2H), 7.02 (d, J=2.69 Hz, 1H), 6.63 (dt, J=8.74, 3.33 Hz, 1H), 5.38 (s, 2H), 4.07-4.23 (m, 2H), 3.98 (dd, J=7.95, 5.38

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Hz, 2H), 3.66-3.83 (m, 1H).

Intermediate 30 1-carboxylate (I-30)

The synthesis of I-30 is described in Example 24.

intermediate connection

31. trans-N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl)-2-fluorocyclopropane-1-carboxamide (I-31)

To a solution of I-1 (2.5 g, 8.1 mmol, 1 eq.) and trans-2-fluorocyclopropanecarboxylic acid (1.0 g, 9.8 mmol, 1.2 eq.) in DMF (20 ml) HATU (3.7 g, 9.8 mmol, 1.2 eq.) and DIEA (1.6 g, 12.2 mmol, 2.1 ml, 1.5 eq.) were added. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with saturated NaHCO ₃ solution (50 ml) and with 100 ml brine (50 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was triturated in tert-butyl methyl ether (20 ml) and collected by filtration to give I-31 as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 8.91 (d, J=2.51 Hz, 1H), 8.75 (d, J=2.26 Hz , 1H), 8.62 (d, J=2.26 Hz, 1H), 8.36 (dd, J=7.03, 2.51 Hz, 1H), 7.60-7.74 (m, 1H), 7.55 (dd, J=11.17, 9.16 Hz, 1H), 4.70-5.12 (m, 1H), 2.89 (s, 1H), 2.23-2 .41 (m, 1H), 1.46-1.66 (m, 1H).

Intermediate 32 4-(Methoxymethyl)-2-methyloxazole-5-carboxylic acid (I-32)

I x Θ θ θ _ο XX UOH, ο-Λ

NBS, acetamide, 60°С

Step A 1-32a Step B ^1-32

Step A: Combine acetamide (1.7 g, 28.6 mmol, 4 eq) and 2-hydroxy-N,N,N-trimethylethane-1-aminium chloride (1 g, 7.2 mmol, 1 eq) and heat up to 60°С within 30 min. NBS (2.5 g, 14.3 mmol, 2 eq.) and methyl 4-methoxy-3-oxobutanoate (2.1 g, 14.3 mmol, 2 eq.) were added to the reaction mixture and heated to 60° C for 1 hour. The reaction mixture was purified by preparative TLC eluting with 50% ethyl acetate in petroleum ether to give I-32a as a light yellow oil.

¹ H NMR: (400 MHz, CDC^) δ ppm 4.66 (s, 2H), 3.94 (s, 3H), 3.47 (s, 3H), 2.55 (s, 3H).

Step B A mixture of I-32a (60 mg, 324.01 µmol, 1 eq.) and LiOH H ₂ O (27.2 mg, 648.0 µmol, 2 eq.) in THF (1 ml), MeOH ( 1 ml) and H ₂ O (0.5 ml) at 25°C for 16 hours under N2 atmosphere. The reaction mixture was concentrated in vacuo to give 60 mg of lithium salt I-32 as a yellow solid.

Intermediate 33 N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl)phenyl)-4-(methoxymethyl)-2 -methyloxazole-5-carboxamide (I-33)

The synthesis of I-33 is described in example 28.

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Intermediate 34 4-Methyl-2-(methyl-d3)oxazole-5-carboxylic acid (I-34)

Stage A Stage B

1-3 4a

NaOH THF/H ₂ O

Stage C

BUT

1-34

Step A To a solution of methyl 3-oxobutanoate (900 mg, 7.7 mmol, 833 μl, 1 eq.) in toluene (15 ml) was added 2,2,2-trideuteroacetamide (962 mg, 15.5 mmol, 2 eq.) and TsOH (13.3 mg, 77.5 µmol, 0.01 eq.). The mixture was stirred at 120° C. for 12 hours. The mixture was concentrated in vacuo to give a residue which was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate 30:1 to 10:1 gradient to give I-34a as white solid.

1 H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (br s, 1H), 5.02 (s, 1H), 3.63 (s, 3H), 2.29 (s, 3H).

Step B. To a solution of I-34a (250 mg, 1.6 mmol, 1 eq.) in DCE (8 ml) was added (diacetoxyiodine)benzene (654 mg, 2.0 mmol, 1.3 eq.) and BF ₃ -Et ₂ O (443 mg, 3.1 mmol, 385 μl, 2 eq.). The mixture was stirred at 90° C. for 2 hours. The mixture was concentrated in vacuo to give a residue which was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate 30:1 to 10:1 gradient to give I-34b as white solid.

¹ H NMR: (400 MHz, DMSO-d ₆ ) δ ppm 3.81 (s, 3H), 2.33 (s, 3H).

Step C To a solution of I-34b (100 mg, 632 µmol, 1 eq.) in THF (1 ml) and H ₂ O (1 ml) was added 15% aqueous NaOH solution (1 ml). The mixture was stirred at 70° C. for 2 hours. The pH was adjusted to 5 by adding aqueous HCl (1M) and a white solid formed. The suspension was filtered and the filter cake was washed with H ₂ O (5 ml). The filter cake was dried under reduced pressure to give I-34 as a white solid.

1 H NMR: (400 MHz, DMSO-d ₆ ) δ ppm 13.30 (brs, 1H), 2.32 (s, 3H).

Intermediate 35 2-(tert-Butoxymethyl)-N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl) -4-methyloxazole-5-carboxamide (I-35)

The synthesis of I-35 is described in example 29.

Intermediate 36 4-Fluoro-3-(5-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)aniline (I-36)

F PhB(OH) ₂ , F

Pd(dppf)CI ₂ -DCM, Fe, CaCI ₂ , EtOH 'N \= y NaHCOs, DME, N \ H ₂ O, heating heating NO ₂

I b Stage A l-36a Stage B

Step A. A 100 ml capped tube containing I-1b (500 mg, 1.483 mmol) and phenylboronic acid (181 mg, 1.483 mmol) in DME:H2O (8:2) (15 ml) was purged with gaseous argon for 15 min. NaHCO ₃ (249 mg, 2.966 mmol) and Pd(dppf)Cl2DCM (61 mg, 0.074 mmol) were added and the reaction mixture was stirred at 80°C for 1 h. The reaction mixture was diluted with water, extracted with EtOH (100 ml x 2 ). The combined organic layers were washed 1x with water (150 ml) and 1x with brine (100 ml) and then dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel chromatography eluting with 25% EtOH in n-hexane to give I-36a.

¹ H NMR (300 MHz, CDCl ₃ ): δ 9.32-9.29 (m, 1H), 9.10 (s, 1H), 8.69 (s, 1H), 8.34-8.29 (m, 1H), 8.23 (s, 1H), 7.65 (d, J=6.9 Hz, 2H), 7.55-7.41 (m, 4H); M+H=335.2.

Step B. To a flask containing I-36a (150 mg, 0.449 mmol) in EtOH:H ₂ O (8:2) (20 ml) was added iron powder (370 mg, 6.730 mmol) and CaCl ₂ (995 mg, 8.973 mmol) and the reaction mixture was stirred at 65°C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (100 ml x 2). The combined organic layers were washed 1x with water (100 ml) and 1x with brine (100 ml) and then dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by washing with n-pentane to give I-36.

1H NMR (300 MHz, CDCl ₃ ): δ 9.04 (s, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 7.70-7.40 (m, 6H) , 7.20-7.00 (m, 1H), 6.75-6.60 (m, 1H); M+H=305.30.

Example 1 N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)-2,4dimethyloxazol-5- carboxamide (compound 1)

To a mixture of I-7 (30 mg, 0.070 mmol) and Siliacat DPP-Pd 0.25 mmol/g (0.014 g, 3.52 μmol, 0.05 eq.) was added 0.5 ml of anhydrous THF. The reaction mixture was placed under a nitrogen atmosphere and (3-methylpyridin-2-yl)zinc(II) bromide (0.5 M in THF, 0.56 ml, 0.28 mmol, 4 eq.) was added and the reaction mixture was stirred at 65° C during the night. The reaction mixture was quenched with 0.2 ml of water and purified by preparative HPLC (Waters Atlantis T3 C18 column 19 x 50 mm x 10 µm) eluting with 20 to 80% acetonitrile (0.035% TFA) in water (0.05% TFA) to give compound 1.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.90 (dd, J=13.2, 2.3 Hz, 2H), 8.59-8.43 (m, 3H), 7.97- 7.81 (m, 2H), 7.55-7.35 (m, 2H), 2.56 (s, 3H), 2.48-2.45 (m, 6H).

Method 1: RT=2.69 min; M+H=443.1.

Compounds 16, 17, 101, 102, 103, 104, 105, 106, 107 and 108 were synthesized according to the protocol described above using the corresponding zinc(II) bromides.

Example 2 N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)furan-2carboxamide (compound 2)

Compound 2 was prepared in a similar manner as compound 1 using I-8 as starting material.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.92 (d, J=2.4 Hz, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.55-8, 45 (m, 3H), 7.96 (m, 1H), 7.87 (m, 1H), 7.78 (m, 1H), 7.52-7.39 (m, 2H), 7.32 (m, 1H), 6.68 (m, 1H), 2.46 (s, 3H).

Method 2: RT=0.89 min; M+H=414.3.

Compounds 54, 55, 56, 57, 59, 60, 61, 62, 63 and 64 were synthesized according to the protocol described above using the corresponding zinc(H) bromides.

Example 3 N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine1-carboxamide (compound 3)

Compound 3 was prepared in a similar manner as compound 1 using I-6 as starting material.

- 51 039324 ¹ H NMR (400 MHz, methanol-d4) δ 8.89-8.84 (m, 2H), 8.52 (m, 1H), 8.48 (m, 1H), 8.18 ( m, 1H), 7.86 (m, 1H), 7.67 (m, 1H), 7.44-7.32 (m, 2H), 4.18-4.06 (m, 4H), 2 .46 (s, 3H), 2.41-2.26 (m, 2H).

Method 1: RT=2.41 min; M+H=403.3.

Compound 99 was synthesized according to the protocol described above using the appropriate zinc(II) bromide.

Example 4 (R)-3-fluoro-N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2 yl)phenyl) pyrrolidine-1-carboxamide (compound 4)

Compound 4 was prepared in a similar manner as compound 1 using 1-5 as starting material.

¹ H NMR (400 MHz, methanol-OO δ 8.87 (dd, J=4.7, 2.3 Hz, 2H), 8.52 (m, 1H), 8.49 (m, 1H), 8 .19 (m, 1H), 7.86 (m, 1H), 7.67 (m, 1H), 7.45-7.34 (m, 2H), 5.42-5.25 (m, 1H ), 3.85-3.55 (m, 4H), 2.46 (s, 3H), 2.39-2.19 (m, 2H).

Method 1: RT=2.41 min; M+H=435.3.

Compounds 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 and 53 were synthesized according to the protocol described above using the corresponding zinc(II) bromides.

Example 5 3,3-Difluoro-N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl)phenyl)azetidine-1 -carboxamide (compound 5)

Compound 5 was prepared in a similar manner as compound 1 using I-3 as starting material.

¹ H NMR (400 MHz, methanol-bD δ 8.88 (dd, J=5.4, 2.3 Hz, 2H), 8.52 (m, 1H), 8.48 (m, 1H), 8 .22 (m, 1H), 7.86 (m, 1H), 7.69 (m, 1H), 7.45-7.36 (m, 2H), 4.44 (m, 4H), 2, 46 (s, 3H).

Method 2: RT=0.76 min; M+H=439.1.

Example 6 3-Fluoro-N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1 -carboxamide (compound 6)

Compound 6 was prepared in a similar manner as compound 1 using I-4 as starting material.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.94 (dd, J=16.9, 2.3 Hz, 2H), 8.57 (ddd, J= 4.8, 1.7, 0.7 Hz, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.28 (dd, J=7.0, 2.7 Hz, 1H ), 7.80 (ddd, J=7.7, 1.7, 0.8 Hz, 1H), 7.72 (ddd, J=9.1, 4.1, 2.7 Hz, 1H), 7.49 (dd, J=11.2, 9.1 Hz, 1H), 7.37 (dd, J=7.7, 4.7 Hz, 1H), 5.41 (dtt, J=57, 5, 6.1, 3.1 Hz, 1H), 4.34 (dddd, J=21.7, 10.4, 6.0, 1.4 Hz, 2H), 4.04 (dddd, J= 24.9, 10.4, 3.1, 1.4 Hz, 2H), 2.44 (s, 3H).

Method 1: RT=2.39 min; M+H=421.1.

Compounds 14, 15, 18, 19, 20, 21, 23, 24, 25, 26, 27 and 28 were synthesized according to the protocol described above using the corresponding zinc(II) bromides.

Compound 318 was synthesized according to the protocol described above using dimethylzinc.

Example 7 N-(4-fluoro-3-(5-isobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1-carboxamide (compound 7)

Compound 7 was prepared in a similar manner as compound 1 using I-6 and isobutylzinc(II) bromide as starting materials.

¹ H NMR (400 MHz, methanol-bd) δ 8.66 (d, J=2.4 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.12 (m, 1H), 8.07(m, 1H), 7.64(m, 1H), 7.34(m, 1H), 4.19-4.01(m, 4H), 2.67(m, 2H ), 2.41-2.24 (m, 2H), 1.97 (m, 1H), 0.99 (m,

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6H).

Method 1: RT=3.11 min; M+H=368.3.

Compounds 91, 93, 94, 95, 96, 97 and 98 were synthesized according to the protocol described above using the corresponding zinc(II) bromides.

Example 8 3,3-Difluoro-N-(4-fluoro-3-(5-isobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine1-carboxamide (compound 8) ^F

Compound 8 was prepared in a similar manner as compound 1 using 1-3 and isobutylzinc(II) bromide as starting materials.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.59 (d, J=2.5 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.06 (m, 1H), 7.97(m, 1H), 7.56(m, 1H), 7.30-7.24(m, 1H), 4.33(m, 4H), 2.57(m, 2H ), 1.92-1.81 (m, 1H), 0.89 (m, 6H).

Method 2: RT=1.09 min. M+H=404.1.

Compounds 29, 30, 31, 32, 33, 34, 35, 36, 37 and 38 were synthesized according to the protocol described above using the corresponding zinc(II) bromides.

Example 9 N-(3-(5-(dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)-3,3-difluoroazetidine-1-carboxamide (compound 9)

Step A. To a solution of I-12 (0.5 g, 1.8 mmol, 1 eq.) in ethyl acetate (5 ml) and saturated aqueous NaHCO ₃ (5 ml) was added 2,2,2-trichloroethylcarbonyl chloride (585, 7 mg, 2.8 mmol, 370.7 μl, 1.5 eq.) at 0°C and the reaction mixture was stirred at 0°C for 1 h. The reaction mixture was extracted with EtOH (30 ml x 3) and combined the organics were dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with 20% EtOH and 20% DCM in petroleum ether to give I-13 as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br s, 1H), 8.71 (d, J=2.93 Hz, 1H), 8.57 (d, J=2.69 Hz, 1H), 8.25 (br d, J=5.14 Hz, 1H), 7.44-7.64 (m, 2H), 7.16 (d, J=2.69 Hz, 1H) , 4.99 (s, 2H), 2.96 (s, 6H).

Step B. Stir the reaction mixture of I-13 (60 mg, 134.3 µmol, 1 eq.), 3,3 difluoroazetidine-HCl (25 mg, 268.6 µmol, 2 eq.), DIEA (34.6 mg, 268 .6 µmol, 46.7 µl, 2 eq.), DMAP (1.6 mg, 13.4 µmol, 0.1 eq.) in DMSO (1 ml) at 60°C for 12 h and at 70° C for a further 12 hours. The reaction mixture was purified by preparative HPLC, column: Phenomenex Gemini C18 250 x 50 mm x 10 μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; In %: 25 to 55%, 12 min to give 9 as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (s, 1H), 8.70 (d, J=3.01 Hz, 1H), 8.55 (d, J=2.76 Hz, 1H), 8.20 (dd, J=6.90, 2.64 Hz, 1H), 7.56-7.78 (m, 1H), 7.45 (dd, J=11.42, 9, 16 Hz, 1H), 7.15 (d, J=3.01 Hz, 1H), 4.41 (t, J=12.67 Hz, 4H), 2.95 (s, 6H).

Method 1: RT=2.84 min; M+H=391.1.

Connections 100, 124, 133, 142, 143, 156, 167, 170 322, 323, 324 and 328 were synthesized according to the protocol described above using intermediates I-9, I-12, I-16, I-23, I-25 or I-26 and the appropriate amine.

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Example 10 N-(3-(5-(azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)azetidine-1-carboxamide (compound 10)

A mixture of I-6 (80 mg, 205 µmol, 1 eq.), azetidine (17.6 mg, 307.5 µmol, 20.7 µl, 1.5 eq.), NaOt-Bu (2M in THF, 307 .5 µl, 3 eq.), XantPhos (23.7 mg, 41 µmol, 0.20 eq.) and Pd ₂ (dba) ₃ (18.8 mg,

20.5 µmol, 0.10 eq.) in dioxane (3 ml) with argon and heated to 90° C. for 4 h. 250 χ 50 mm χ 10 µm, mobile phase: [water (0.05% ammonium hydroxide v/v) acetonitrile]; V%: 28 to 58%, 12 min) to give 10 as a yellow solid.

¹ H NMR (400 MHz, methanol-d4), δ ppm, 8.42 (d, J=2.51 Hz, 1H), 8.22 (d, J=2.76 Hz, 1H), 8.05 (dd, J=6.78, 2.76Hz, 1H), 7.58-7.62 (m, 1H), 7.30 (dd, J=11.04, 9.16Hz, 1H), 7.01 (d, J=2.64 Hz, 1H), 4.10 (t, J=7.65 Hz, 4H), 3.99 (t, J=7.22 Hz, 4H), 2. 41-2.49 (m, 2H), 2.27-2.35 (m, 2H).

Method 1: RT=2.80 min; M+H=367.1.

Compounds 40, 58, 92, 122, 131, 132, 134, 135, 137, 141, 144, 145, 147, 149, 151, 155, 157, 158, 161, 163, 171, 172, 177, 178, 179 , 180, 181, 183, 184, 185, 186, 190, 191, 192, 193, 194, 197, 198, 199, 200, 201, 202, 203, 204, 205, 230, 231, 232, 234, 235 . 303, 306, 307, 308, 314, 326, 327, 338 and 339 were synthesized according to the protocol described above using the appropriate intermediates I-3, I-4, I-5, I-6, I- 7, I-8, I-24, I-27 or I-31 and the corresponding amines.

Compound 242 was isolated in addition to compound 241 using the above reaction conditions. Similarly, compound 246 was isolated in addition to compound 202 using the above reaction conditions.

Compound 270 was synthesized using the protocol described above using Vospiperidine, after which the Boc group was removed using TFA in DCM at a ratio of 0.36:1, followed by neutralization to pH 7 with Et ₃ N and then purification using preparative HPLC (column: Phenomenex Synergi C18 150x25x10 µm; mobile phase: [water (0.225% FA)-acetonitrile]; V%: 3 to 30%, 10 min) to give compound 270.

Example 11 4,4,4-Trifluoro-N-(4-fluoro-3-(5-isopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)butanamide (compound 173)

To a solution of I-9 (25 mg, 0.092 mmol) in DMF (1.5 ml) and DIEA (0.040 ml, 0.23 mmol) was added 4,4,4 trifluorobutanoyl chloride (14.9 mg, 0.092 mmol) and the reaction mixture was stirred for 12 hours at room temperature. The crude reaction mixture was purified directly on a 15 g C18 flash column eluting with 20 to 90% acetonitrile in water to give compound 173 as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.81 (d, J=2.7 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H ), 8.36 (dd, J=7.0, 2.7Hz, 1H), 8.05 (dd, J=2.3, 0.8Hz, 1H), 7.68 (ddd, J= 9.1, 4.2, 2.7 Hz, 1H), 7.54 (dd, J=11.2, 9.0 Hz, 1H), 3.08 (pd, J=6.9, 0, 8 Hz, 1H), 2.72-2.55 (m, 4H), 1.30 (d, J=6.9 Hz, 6H).

Method 1: RT=3.19 min; M+H=395.2.

Compound 174 was synthesized according to the protocol described above, using the appropriate chloroformate instead of the acid chloride.

Example 12 N-(4-fluoro-3-(5-isopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)pyrazine-2carboxamide (compound 87)

- 54 039324

Pyrazine-2-carboxylic acid (16.5 mg, 0.13 mmol) was added to the flask followed by I-9 (30 mg, 0.11 mmol) dissolved in 0.25 ml DMF. A solution of DIEA (0.058 ml, 0.33 mmol) and HATU (50.6 mg, 0.13 mmol) in 0.25 ml DMF was added to the reaction mixture and the resulting mixture was stirred overnight. The reaction mixture was filtered through a 0.2 µm syringe filter and the material was purified by preparative HPLC (Waters Atlantis T3 C18 column 19 x 50 mm x 10 µm) eluting with 20 to 80% acetonitrile (0.035% TFA) in water (0.05 % TFA) to give compound 87.

Ή NMR (400 MHz, methanol^) δ 9.36 (m, 1H), 8.84 (m, 1H), 8.76 (m, 1H), 8.72 (m, 1H), 8.66 ( m, 1H), 8.57 (m, 1H), 8.13 (m, 1H), 7.99 (m, 1H), 7.46 (m, 1H), 3.13 (m, 1H), 1.38 (2s, 6H).

Method 1: RT=3.05 min; M+H=377.3.

Connections 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 , 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 196, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 261 , 262 and 351 were synthesized according to the protocol described above using the corresponding carboxylic acids.

Compounds 139, 140, 153, 154, 279, 330 and 352 were synthesized according to the protocol described above using I-12, I-29 or I-36 and the corresponding carboxylic acids.

Compound 278 was synthesized according to the protocol described above using I-28 and I-34 as starting materials.

Example 13 3-Fluoro-N-(4-fluoro-3-(5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1 -carboxamide (compound 152)

To a solution of I-10 (106 mg, 285.6 µmol, 1 eq.) in dioxane (1 ml) was added 1,1,1-trifluoro-2-iodoethane (119.9 mg, 571.10 µmol, 56.03 µl, 2 eq.), Pd ₂ (dba) ₃ (13.1 mg, 14.3 µmol, 0.05 eq.), XantPhos (28.1 mg, 48.5 µmol, 0.2 eq.) and Cs ₂ CO ₃ (372.15 mg, 1.1 mmol, 4 eq.) under N ₂ atmosphere. After 1 min, water (92.6 mg, 5.1 mmol, 92.6 μl, 18 eq.) was added and the mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (30 ml) and the organic layer was washed with water (10 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , DCM: methanol=10:1) and further purified by preparative HPLC (column: Phenomenex Gemini C18 250 x 50 mm x 10 μm; mobile phase: [water (0.05% hydroxide ammonium v/v)-acetonitrile] B%: 28% to 58%, 12 min) to give compound 152 as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6), δ ppm, 8.98 (s, 1H), 8.95 (d, J=2.51 Hz, 1H), 8.69 (d, J=2, 01 Hz, 1H), 8.33 (d, J=1.76 Hz, 1H), 8.24 (dd, J=6.90, 2.63 Hz, 1H), 7.67-7.74 ( m, 1H), 7.48 (dd, J=11.29, 9.29 Hz, 1H), 5.30-5.52 (m, 1H), 4.26-4.39 (m, 2H) , 3.97-4.09 (m, 2H), 3.87 (q, J=11.71 Hz, 2H).

Method 1: RT=2.76 min; M+H=412.2.

Compounds 162, 164, 166, 175 and 176 were synthesized according to the protocol described above using the appropriate boronic acid prepared from intermediates I-3, I5, I-6, I-7 or I-8 prepared in a similar manner. like I-10.

Example 14 Isopropyl-(2-(2-fluoro-5-(3-fluoroazetidine-1-carboxamido)phenyl)-2H-pyrazolo[3,4b]pyridin-5-yl)carbamate (compound 168)

In a mixture of I-4 (120 mg, 294 µmol, 1 eq.), isopropyl carbamate (45.5 mg, 441 µmol, 1.5 eq.) and CS ₂ CO ₃ (287.3 mg, 881.9 µmol, 3 eq.) in dioxane (3 ml) were added XantPhos (34.0 mg, 58.8 µmol, 0.20 eq.) and Pd ₂ (dba) ₃ (26.9 mg, 29.4 µmol, 0.10 eq. .) in an argon atmosphere. The mixture was heated to 90° C. and stirred for 4 hours. The mixture was quenched by adding 1M HOAc and purified by preparative HPLC (column: Boston pH-1ex 150 x 25 10 µm; mobile phase: [water (0.225% formic acid) acetonitrile ]; V%: 33 to 63%, 10 min followed by further purification on a Phenomenex Gemini C18 250 x 50 mm x 10 µm column; mobile phase: [water (0.05% ammonium hydroxide v/v)

- 55 039324 acetonitrile]; B%: 28 to 58%, 12 min). Compound 168 was obtained as a yellow solid.

1H NMR (400 MHz, methanol-AD δ ppm, 8.64 (br d, J=2.26 Hz, 1H), 8.61 (br d, J=2.64 Hz, 1H), 8.44 ( br s, 1H), 8.10 (dd, J=6.71, 2.70 Hz, 1H), 7.60-7.67 (m, 1H), 7.33 (dd, J=10.92 , 9.16 Hz, 1H), 5.25-5.47 (m, 1H), 5.01 (dt, J=12.52, 6.23 Hz, 1H), 4.32-4.43 ( m, 2H), 4.07-4.19 (m, 2H), 1.33 (d, J=6.27 Hz, 6H).

Method 1: RT=2.88 min; M+H=431.1.

Compounds 123, 136, 138, 146 and 159 were synthesized according to the protocol described above using the appropriate intermediates I-3, I-5, I-6, I-7 or I-8.

Example 15 3-Fluoro-N-(4-fluoro-3-(5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1 -carboxamide (compound 187)

Pd(dppf)Cl ₂ (18.6 mg, 25.5 µmol, 0.1 eq.) , Na ₂ CO ₃ (81 mg, 763.8 µmol, 3 eq.) and 2-bromo-3-fluoropyridine (89.5 mg, 509.2 µmol, 2 eq.). The mixture was stirred at 90° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Boston Green ODS 150 χ 30 5 µm; mobile phase: [water (0.225% FA)-acetonitrile]); B %: 35 to 65%, 10 min) to give compound 187 as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 9.00-9.09 (m, 2H), 8.82 (s, 1H), 8.63 (br d, J=4.39Hz, 1H), 8.29 (dd, J=6.90, 2.51Hz, 1H), 7.93 (dd, J=10.73, 8.47Hz, 1H), 7.72 (dt, J=8.60, 3.48 Hz, 1H), 7.52-7.58 (m, 1H), 7.46-7.51 (m, 1H), 5.28- 5.55 (m, 1H), 4.25-4.44 (m, 2H), 3.93-4.14 (m, 2H).

Method 1: RT=2.74 min; M+H=425.1.

Compounds 188, 294, 295, 297, 301, 304, 312, 325, 329, 330 and 335 were synthesized according to the protocol described above using the appropriate bromides.

Example 16 5-Fluoro-N-(4-fluoro-3-(5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)furan2-carboxamide (compound eleven)

O

Dissolve I-11 (40 mg, 0.131 mmol) in 2 ml DMF. 5-fluorofuran-2-carboxylic acid (25.6 mg, 0.20 mmol), DIEA (0.058 ml, 0.33 mmol) and HATU (50.6 mg, 0.13 mmol) were added to the reaction mixture, and the resulting mixture was stirred in during the night. The reaction mixture was diluted with EtOAc and washed with 1x sat. aq. Na ₂ CO ₃ solution and 1x water. The organics were dried over Na ₂ SO ₄ and concentrated. The crude material was purified by silica gel chromatography eluting with 0 to 100% 3:1 EtOAc:EtOH in heptanes to give compound 11.

1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.49 (d, J=2.3 Hz, 1H), 9.06 (d, J=2.6 Hz, 1H ), 8.96 (d, J=2.3 Hz, 1H), 8.74 (ddd, J=4.8, 1.9, 0.9 Hz, 1H), 8.53 (dd, J= 7.0, 2.7 Hz, 1H), 8.14 (dt, J=8.0, 1.1 Hz, 1H), 8.017.91 (m, 2H), 7.62 (dd, J=11 .2, 9.1 Hz, 1H), 7.50-7.38 (m, 2H), 6.14 (dd, J=7.0, 3.7 Hz, 1H).

Method 2: RT=0.91 min; M+H=418.1.

Compounds 12, 13, 206, 218, 345, 346, 347, 348 and 349 were synthesized according to the protocol described above using the appropriate carboxylic acid.

Compound 350 was synthesized according to the protocol described above using the appropriate carboxylic acid and I-28.

Example 17 3-Fluoro-N-(4-fluoro-3-(5-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1-carboxamide (compound 182)

Into a solution of I-4 (80 mg, 196 µmol, 1 eq.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (60.3 mg, 294 µmol, 1.5 eq.) in DME (3 ml) was added Pd(dppf)Cl2 (14.34 mg, 19.6 µmol, 0.1 eq.) and

- 56 039324

Na ₂ CO ₃ (2M, 294 μl, 3 equiv.) under N2 atmosphere. The mixture was stirred at 90° C. for 20 hours. The reaction mixture was concentrated and the residue was diluted with EtOAc (30 ml). The organic layer was washed with water (10 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250 x 50 mm x 10 µm; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; V%: 18 to 48% , 12 min) to give compound 182 as a white solid.

¹ H NMR (400 MHz, DMSO-d6), δ ppm, 9.17 (d, J=2.26 Hz, 1H), 9.03 (d, J=2.51 Hz, 1H), 9.00 (s, 1H), 8.75 (d, J=2.51 Hz, 1H), 8.67-8.73 (m, 2H), 8.28 (dd, J=6.90, 2.64 Hz, 1H), 7.84-7.90 (m, 2H), 7.68-7.75 (m, 1H), 7.50 (dd, J=11.29, 9.03 Hz, 1H) , 5.30-5.52 (m, 1H), 4.27-4.40 (m, 2H), 3.97-4.10 (m, 2H).

Method 2: RT=0.58 min; M+H=407.1.

Compound 189 was synthesized according to the protocol described above using the appropriate boronic acid ester.

Example 18 (R)-3-fluoro-N-(4-fluoro-3-(5-(tetraαhydro-2H-pyran-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl)phenyl )pyrrolidine-1-carboxamide (compound 150)

Step A. To a mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (65.7 mg, 312.6 µmol , 1.1 eq.), I-5 (120 mg, 284.2 µmol, 1 eq.) and Na ₂ CO ₃ (2M, 426.3 μl, 3 eq.) in DME (3 ml) and water ( 0.5 ml) in an argon atmosphere was added Pd(dppf)Cl ₂ (20.8 mg, 28.4 μmol, 0.1 eq.). The mixture was heated to 90° C. for 4 hours. The mixture was purified by preparative TLC eluting with 90% EtOH in petroleum ether to give I-14 as a white solid. M+H=426.2.

Step B To a mixture of I-14 (85 mg, 199.8 µmol, 1 eq.) in methanol (10 ml) was added Pd/C (30 mg, 10% purity). The suspension was degassed under vacuum and purged several times with H ₂ . The mixture was stirred under H ₂ (15 psi) at 10° C. for 1 hour. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 x 30 5 μm; mobile phase: [water (0.225% FA)-α-cetonitrile]; B%: 27 to 51%, 10 min) to give compound 150 as yellow solid.

¹ H NMR (400 MHz, methanol-d4), δ ppm, 9.15 ((d, J=2.01 Hz, 1H)), 8.98 (s, 1H), 8.85 (d, J= 1.88 Hz, 1H), 8.33 (dd, J=6.78, 9.16 Hz, 1H), 7.61-7.65 (m, 1H), 7.42 (dd, J=11 .04, 9.16 Hz, 1H), 5.28-5.41 (m, 1H), 4.11-4.14 (m, 2H), 3.57-3.85 (m, 6H), 3.14-3.20 (m, 1H), 2.11-2.32 (m, 2H), 1.91-1.97 (m, 4H).

Method 1: RT=2.60 min; M+H=428.2.

Compounds 148, 160, 165, 169, 296 and 305 were synthesized according to the protocol described above using intermediates I-3, I-4, I-6 or I-7 and the appropriate boronic acid or boronic acid ester.

Compound 293 was synthesized using the protocol described above using I-4 and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate, after which the Boc group was removed using TFA in DCM at a ratio of 1:5 followed by concentration and then purification by preparative HPLC (column: Phenomenex Synergi C18 150 x 25 x 10 μm; mobile phase : [water (0.225% FA)-acetonitrile]; B%: 2 to 22%, 10 min) to give compound 293.

Example 19 N-(3-(5-(5-azaspiro[2.3]hexan-5-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)azetidine-1- carboxamide (compound 257)

A mixture of I-6 (400 mg, 1.0 mmol, 1 eq.), 5-azaspiro[2.3]hexane hemi-oxalate (128 mg, 1.0 mmol, 1 eq.), NaOBu-t (2M in THF, 1 eq.) was degassed. .5 ml, 3 equiv.) and Xphos Pd G3 (87 mg, 102.5 μmol, 0.1 equiv.) in dioxane (10 ml), placed in an argon atmosphere and heated to 90°C for 1 h. the mixture was quenched

- 57 039324 by adding a saturated solution of NH ₄ Cl (40 ml). The resulting mixture was extracted with dichloromethane (30 ml x 6) and the organic phase was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with 50% MeOH in DCM followed by purification by preparative HPLC (column: Phenomenex Synergi C18

150x25x10 microns; mobile phase: [water (0.225% FA)-acetonitrile]; In %: 30 to 60%, 10 min) to give compound 257 as a yellow solid.

1H NMR (400 MHz, DMSO) δ ppm 8.69 (s, 1H), 8.52 (d, J=2.63 Hz, 1H), 8.28 (d, J=2.76 Hz, 1H) , 8.20 (dd, J=7.03, 2.63 Hz, 1H), 7.62-7.69 (m, 1H), 7.40 (dd, J=11.29, 9.16 Hz , 1H), 6.91 (d, J=2.76 Hz, 1H), 4.01 (s, 4H), 3.97 (t, J=7.53 Hz, 4H), 2.19 (quint ., J=7.56 Hz, 2H), 0.68 (s, 4H).

Method 1: RT=2.90 min; M+H=393.2.

Compounds 233, 258, 259 and 337 were synthesized according to the protocol described above using the appropriate intermediates I-3, I-4, I-5 or I-27.

Example 20 3-Fluoro-N-(4-fluoro-3-(5-(3-(trifluoromethyl)azetidin-1-yl)-2H-n-pyrazolo[3,4-b]n-yridin-2yl)phenyl)azetidine- 1-carboxamide (compound 265)

Degassed a mixture of I-4 (3.5 g, 8.6 mmol, 1 eq.), 3-(trifluoromethyl)azetidine HCl salt (1.7 g, 10.3 mmol, 1.2 eq.), Pd ₂ (dba) ₃ (785 mg, 857.4 µmol, 0.1 eq.), XantPhos (992 mg, 1.7 mmol, 0.2 eq.) and Cs ₂ CO ₃ (8.4 g, 25.7 mmol, 3 eq.) in dioxane (60 ml) and then heated to 85° C. for 1.2 h under N 2 atmosphere. The reaction mixture was quenched with sat. NH ₄ Cl solution (400 ml) and extracted with EtOAc (300 ml x 2). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 0:1:1 to 1:5:1 MeOH/ethyl acetate/DCM to give a yellow solid which was further purified by preparative HPLC; column: Phenomenex Synergi Max-RP 250 x 80 mm x 10 µm; mobile phase: [water (0.225% FA)-acetonitrile]; V%: 30 to 60%, 35 min. The pH of the solution was adjusted to pH 7 with 20% NH ₃ in H ₂ O and the acetonitrile was removed in vacuo at 30°C. The resulting yellow solid was collected by filtration, washed with water, 100 ml x 4, and lyophilized to give Compound 265 as a yellow solid.

¹ H NMR (400 MHz, DMSO) δ ppm 8.93 (s, 1H), 8.58 (d, J=2.76 Hz, 1H), 8.32 (d, J=2.76 Hz, 1H ), 8.20 (dd, J=7.03, 2.64Hz, 1H), 7.65 (dd,J=7.34, 4.58Hz, 1H), 7.44 (dd, J= 11.17, 9.16 Hz, 1H), 7.03 (d, J=2.89 Hz, 1H), 5.29-5.51 (m, 1H), 4.24-4.38 (m , 2H), 4.18 (t, J=8.34 Hz, 2H), 3.95-4.10 (m, 4H), 3.65-3.85 (m, 1H).

Method 1: RT=2.86 min; M+H=453.1.

Compounds 274 and 275 were synthesized according to the protocol described above using the appropriate intermediates I-5 or I-6.

Example 21 N-(2-(5-(3,3-difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]niridin-2-yl)niridin-4yl)azetidine-1-carboxamide (compound 280)

F

NH C~ ^F 9 Pd2(dba)3, Xantphos, NaOBu-t (2 M in THF) F /= ^{N n} dioxane, 90°CF \= _N r

Stage C

Step A. To a solution of I-17 (2.5 g, 8.6 mmol, 1 eq.) in pyridine (30 ml) was added 2,2,2

280 trichloroethylcarbonyl chloride (3.6 g, 17.2 mmol, 2.3 ml, 2 eq.). The mixture was stirred at 30° C. for 22 hours. The reaction mixture was precipitated by adding 100 ml of water and then filtered. The filter cake was washed with 50 ml of water and dried under reduced pressure. The precipitate was then triturated in tert-butyl methyl ether (20 ml) and collected by filtration to give I-20 as a brown solid.

1H NMR (400 MHz, DMSO) δ ppm 11.08 (s, 1H), 9.32 (s, 1H), 8.77 (d, J=1.71 Hz, 1H), 8.62 (d, J=1.96

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Hz, 1H), 8.52 (d, J=1.71 Hz, 1H), 8.49 (d, J=3.91 Hz, 1H), 7.75 (dd, J=5.38, 1 .71 Hz, 1H), 5.05 (s, 2H).

Step C. To a solution of I-20 (1.2 g, 2.6 mmol, 1 eq.) and azetidine hydrochloride (482 mg, 5.2 mmol, 2 eq.) in DMSO (12 ml) was added DMAP (31 mg , 257.8 µmol, 0.10 eq.) and DIEA (666 mg, 5.2 mmol, 898.0 µl, 2 eq.). The mixture was stirred at 60° C. for 144 hours. The reaction mixture was precipitated by adding 100 ml of water and then filtered. The filter cake was washed with 50 ml of water, dried under reduced pressure to give I-21 as a brown solid.

¹ H NMR (400 MHz, DMSO) δ ppm 9.24 (s, 2H), 8.75 (d, J=2.45 Hz, 1H), 8.60 (d, J=2.20 Hz, 1H ), 8.49 (d, J=1.71 Hz, 1H), 8.35 (d, J=5.62 Hz, 1H), 7.73 (dd, J=5.75, 1.83 Hz , 1H), 4.04 (br t, J=7.58 Hz, 4H), 2.23 (quint, J=7.64 Hz, 2H).

Step C A mixture of I-21 (180 mg, 482.3 µmol, 1 eq), 3,3-difluoroazetidine (125 mg, 964.6 µmol, 2 eq, HCl), XantPhos (56 mg, 96, 5 µmol, 0.20 eq.), Pd ₂ (dba) ₃ (44 mg, 48.2 µmol, 0.10 eq.) and NaOBu-t (2M, 964.6 µl, 4 eq.) in dioxane ( 3 ml) at 90°C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography eluting with 10 to 100% petroleum ether in ethyl acetate to give 65 mg of a residue. The residue was triturated in MeOH (3 ml) and the solid was collected by filtration to give compound 280 as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.18 (s, 1H), 8.99 (s, 1H), 8.44 (d, J=1.76 Hz, 1H), 8, 36 (d, J=2.76Hz, 1H), 8.31 (d, J=5.77Hz, 1H), 7.67 (dd, J=5.52, 2.01Hz, 1H), 7.14 (d, J=2.76 Hz, 1H), 4.42 (t, J=12.17 Hz, 4H), 4.04 (t, J=7.53 Hz, 4H), 2, 16-2.29 (m, 2H).

Method 1: RT=2.76 min; M+H=386.0.

Compounds 282, 284, 286, 287 and 343 were synthesized according to the protocol described above using intermediates I-17, I-18 or I-19 and the appropriate amines.

Compound 340 was synthesized according to the protocol described in Step A and Step B using (R)-3-fluoropyrrolidine.

Example 22 connection 281)

Step A To a solution of I-20 (800 mg, 1.7 mmol, 1 eq) and 3,3-difluoroazetidine HCl salt (445 mg, 3.4 mmol, 2 eq) in DMSO (10 ml) was added DMAP (21 mg, 171.8 µmol, 0.1 eq.) and DIEA (444 mg, 3.4 mmol, 598.7 µl, 2 eq.). The mixture was stirred at 60° C. for 320 hours. The reaction mixture was precipitated by adding water (100 ml) and then filtered. The filter cake was washed with 50 ml of water, dried under reduced pressure to give I-22 as a brown solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.69 (s, 1H), 9.23-9.27 (m, 1H), 8.75 (d, J=2.45 Hz, 1H) , 8.61 (d, J=2.44 Hz, 1H), 8.47 (d, J=1.96 Hz, 1H), 8.41 (d, J=5.62 Hz, 1H), 7 .71 (dd, J=5.62, 1.96 Hz, 1H), 4.48 (t, J=12.72 Hz, 4H).

Step B. To a solution of I-22 (460 mg, 1.12 mmol, 1 eq.) and tributyl(2-pyridyl)stannane (497 mg, 1.3 mmol, 1.2 eq.) in DMF (10 ml) Pd(PPh ₃ ) ₄ (130 mg, 112.4 µmol, 0.1 eq) and CuI (21 mg, 112.4 µmol, 0.1 eq) were added. The mixture was stirred at 85° C. for 16 hours under N2. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by eluting silica gel with 10 to 100% petroleum ether in ethyl acetate to give a solid which was triturated in DCM (3 ml). The resulting solid was collected by filtration to give compound 281 as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.70 (s, 1H), 9.47 (d, J=2.20 Hz, 1H), 9.38 (s, 1H), 8.95 (d, J=2.20 Hz, 1H), 8.71-8.77 (m, 1H), 8.49 (d, J=1.71 Hz, 1H), 8.42 (d, J= 5.62 Hz, 1H), 8.12 (d, J=8.07 Hz, 1H), 7.96 (td, J=7.76, 1.83 Hz, 1H), 7.72 (dd, J=5.62, 1.96Hz, 1H), 7.39-7.47(m, 1H), 4.49(t, J=12.72Hz, 4H).

Method 1: RT=2.81 min; M+H=408.0.

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Compounds 283, 285, 309, 310, 313, 315, 317, 341, 342 and 344 were synthesized according to the protocol described above using intermediates I-1, I-17, I-18 or I-19 and correspondingly amine and the corresponding organotin substance.

Compounds 256, 332, 333 and 336 were synthesized according to the protocol described in step B using I-24, I-27 or I-31 and the appropriate organotin compounds.

Example 23 3-Fluoro-N-(4-fluoro-3-(2H-pyrazolo[3,4-b]n-iridin-2-yl)phenyl)azetidine-1-carboxamide (compound 311)

To a solution of I-4 (100 mg, 245 µmol, 1 eq.) in EtOH (2 ml) was added TEA (25 mg, 245 µmol, 34.1 µl, 1 eq.) HPd(OH) ₂ /C (34 mg , 24.5 µmol, 10% purity, 0.1 equiv.) under N2 atmosphere. The suspension was degassed and purged 3 times with H ₂ . The mixture was stirred under H ₂ (15 psi) at 25° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Luna C18 150x25x5 μm; mobile phase: [water (0.225% FA)-acetonitrile]; V%: 17 to 44%, 10 min) and lyophilized to give compound 311 as a white solid substances.

¹ H NMR (400 MHz, DMSO-d6), ppm, 8.98 (s, 1H), 8.90 (d, J=2.26 Hz, 1H), 8.72 (d, J=3.01 Hz, 1H), 8.31 (d, J=8.28 Hz, 1H), 8.25 (dd, J=7.03, 2.51 Hz, 1H), 7.66-7.73 (m , 1H), 7.43-7.51 (m, 1H), 7.20 (dd, J=8.41, 4.14 Hz, 1H), 5.29-5.51 (m, 1H), 4.24-4.39 (m, 2 H), 3.96-4.10 (m, 2 H).

Method 1: RT=2.41 min; M+H=330.1.

Example 24 N-(3-(5-(1-acetylazetidin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)-3fluoroazetidine-1-carboxamide (compound 267)

About CO ₂ H

N

Vos

400-750 nm, 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile

Vg

1,1,3,3-tetramethyl guanidine NiCI ₂ (dme),

-----------► Boc P 4,4'-di-tert-bugyl-2,2'-bipyridine DMSO, 0.10 ml/min.

1-30

Stage A

Step A Dissolve 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (394 mg, 2 mmol), I-4 (400 mg, 1 mmol), 1,1,3,3-tetramethylguanidine (226 mg, 1 .96 mmol), NiCl ₂ (dme) (22 mg, 0.1 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (26 mg, 0.1 mol) and 2.4 ,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (23mg, 0.03mmol) in DMSO (9.8mL) with heat and sonication. The solution was pumped (0.10 ml/min) through a photoreactor (reactor volume 0.9 ml; PFA tubes ID 0.04 inch, ID 0.0625 inch; irradiated area 20 cm ² ; distance to LED panel 1 cm; LED with a wavelength of 400-750 nm; brightness 8800 lm) and collected in a vial. The reaction mixture was purified by C18 flash chromatography eluting with 15% to 85% acetonitrile in water and concentrated. The material was further purified by silica gel chromatography eluting with 40 to 100% EtOAc in heptane to give I-30.

1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.71 (d, J=4.3 Hz, 1H ), 8.22 (dd, J=7.0, 2.7Hz, 1H), 7.70 (ddd, J=9.1, 4.1, 2.8Hz, 1H), 7.48 ( dd, J=11.1, 9.1 Hz, 1H), 7.13 (d, J=4.4 Hz, 1H), 5.55 (dd, J=9.0, 6.4 Hz, 1H ), 5.48-5.30 (m, 1H), 4.32 (dddd, J=21.7, 10.4, 6.0, 1.4 Hz, 2H), 4.11-3.94 (m, 6H), 1.27 (s, 9H).

Step B Dissolve I-30 (83 mg, 0.171 mmol) in DCM (1 ml) and add TFA (0.5 ml). The reaction mixture was stirred for 3 hours and concentrated, dissolved in MeOH and purified by flash chromatography on a C18 column eluting with 5 to 40% acetonitrile in water. As a result

- 60 039324 Lyophilization gave compound 264 as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 9.07-8.96 (m, 2H), 8.84 (d, J=4.3 Hz, 1H), 8.30 (dd, J=7.0, 2.7 Hz, 1H), 7.72-7.62 (m, 1H), 7.52 (dd, J=11.2, 9.1 Hz, 1H), 7.33 (dd, J=4.4, 1.2 Hz, 1H), 6.04 (s, 1H), 5.41 (dtt, J=57.4, 6.1, 3, 1 Hz, 1H), 4.40-4.25 (m, 2H), 4.27-4.16 (m, 1H), 4.10-3.94 (m, 2H), 3.90-3 .77 (m, 1H), 3.062.94 (m, 1H), 2.86 (dtd, J=11.7, 8.7, 4.4 Hz, 1H).

Method 1: RT=1.69 min; M+H=385.2.

Step C Compound 264 (20 mg, 0.052 mmol) was dissolved in DCM (volume: 1 ml) and DIEA (0.027 ml, 0.16 mmol) and acetyl chloride (5.55 μl, 0.078 mmol) were added and stirred for 60 h The reaction mixture was purified with SFC on a 250 x 21.2 mm Princeton PPU column eluting with 20 to 60% MeOH in liquid CO ₂ to give compound 267.

1H NMR (400 MHz, methanol-d4) δ 8.86 (dd, J=3.4, 2.2 Hz, 1H), 8.74 (d, J=4.4 Hz, 0.5H), 8 .67 (d, J=4.5 Hz, 0.5H), 8.17 (dd, J=6.8, 2.7 Hz, 0.5H), 8.13 (dd, J=6.8 , 2.7 Hz, 0.5H), 7.66 (dddd, J=8.8, 4.3, 2.7, 1.7 Hz, 1H), 7.37 (ddd, J=10.9 , 9.1, 3.7 Hz, 1H), 7.28 (dd, J=4.4, 0.8 Hz, 0.5H), 7.18 (dd, J=4.5, 0.9 Hz, 0.5H), 5.93 (dd, J=9.2, 5.6Hz, 0.5H), 5.73 (dd, J=9.3, 6.1Hz, 0.5H) , 5.37 (dtt, J=57.1, 6.1, 3.2 Hz, 1H), 4.48-4.32 (m, 3H), 4.244.15 (m, 2H), 4.11 (ddd, J=10.3, 3.2, 1.4 Hz, 1H), 3.05-2.91 (m, 1H), 2.34-2.21 (m, 1H), 2.03 (s, 1.5H), 1.71 (s, 1.5H).

Method 2: RT=0.66 min; M+H=427.2.

Compound 247 was synthesized according to the protocol described in step A above, using 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid as starting material.

Example 25 N-(4-fluoro-3-(5-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1-carboxamide (compound 288)

400-750nM/X

Ni(dme)CI _?

1,1,3,3-tetramethylguanidine T G ν \ /P . 2 2 t l-ll\l—& 4,4-di-tert-butyl-3,3-bipyridine lr[dF(Me)ppy] ₂ (dtbbpy)PF ₆

M DMSO, 3 hours ²⁸⁸

Dissolve I-6 (30 mg, 0.077 mmol), nickel(II) chloride complex, ethylene glycol and dimethyl ether (1.7 mg, 7.8 µmol), 1,1,3,3-tetramethylguanidine (53 mg, 0. 46 mmol), 4,4'-di-tert-butyl-3,3'bipyridine (2.1 mg, 7.7 µmol), tetrahydro-2H-pyran-2-carboxylic acid (60 mg, 0.46 mmol ) and [4,4'bis(tert-butyl)-2,2'-bipyridine]bis[3,5-difluoro-2-[5-methyl-2-pyridinyl]phenyl]iridium(III) hexafluorophosphate (3, 90 mg, 3.84 µmol) in DMSO (769 µl) with heat and sonication. The solution was added to a 0.3 ml well of a 96-well Teflon plate and irradiated for 3 h (irradiated area 20 cm ² ; distance to the LED panel 10 cm; LED wavelength 400-750 nm; brightness 7600 lm). The resulting solution was purified by preparative HPLC (Waters Atlantis T3 C18 19 x 50 mm x 10 µm column) eluting with acetonitrile (0.035% TFA) in water (0.05% TFA) to give compound 288.

1H NMR (400 MHz, methanol-d4) δ 9.03 (d, J=2.2 Hz, 1H), 8.73 (d, J=4.9 Hz, 1H), 8.19 (dd, J =6.8, 2.7 Hz, 1H), 7.63 (ddd, J=9.1, 4.2, 2.7 Hz, 1H), 7.37 (dd, J=10.9, 9 .1Hz, 1H), 7.32 (dd, J=5.0, 0.9Hz, 1H), 4.92 (ddt, J=2.7, 1.4, 0.7Hz, 1H) , 4.23 (d, J=10.3 Hz, 1H), 4.17-4.07 (m, 2H), 3.74 (td, J=11.6, 2.5 Hz, 1H), 3.37-3.32 (m, 2H), 2.33 (p, J=7.6 Hz, 2H), 2.15-1.98 (m, 2H), 1.92-1.57 ( m, 4H).

Method 2: RT=0.89 min; M+H=396.0.

Compound 289 was synthesized according to the above protocol using 1,4-dioxane-2-carboxylic acid as starting material.

Examples 26A and B. (1S,2R)-2-fluoro-N-(4-fluoro-3-(5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl)phenyl )cyclopropan-1-carboxamide or (1R,2S)-2-fluoro-N-(4-fluoro-3-(5-(pyridin-2-yl)-2Hpyrazolo[3,4-b]pyridin-2-yl )phenyl)cyclopropane-1-carboxamide (compounds 269 and 273)

trans - racemic F

Compounds 269 and 273

Compound 256 (170 mg) was separated using SFC (column: CHIRALCEL® OJ-H (250 mm x 25 mm, 10 μm); mobile phase: [CO ₂ - MeOH (0.1% NH ₃ H ₂ O)]; In%: 50%) to give compound 269 (peak 1,

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RT=5.42 min) as a yellow solid and compound 273 (peak 2, RT=6.75 min) as an off-white solid.

269 (peak 1): SFC RT: 5.42 min 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 9.48 (d, J=2.26 Hz, 1H), 9.03 (d, J=2.38Hz, 1H), 8.95 (d, J=2.26Hz, 1H), 8.74 (d, J=4.14Hz, 1H), 8. 39 (dd, J=6.96, 2.57Hz, 1H), 8.13 (d, J=8.03Hz, 1H), 7.96 (td, J=7.75, 1.69Hz , 1H), 7.65-7.74 (m, 1H), 7.57 (dd, J=11.11, 9.10 Hz, 1H), 7.42 (dd, J=7.22.5 .21 Hz, 1H), 4.78-5.06 (m, 1H), 2.26-2.35 (m, 1H), 1.49-1.66 (m, 1H), 1.24- 1.33 (m, 1H).

Method 1: RT=2.80 min; M+H=392.2.

273 (peak 2): SFC RT: 6.75 min ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.75 (s, 1H), 9.48 (d, J=2.08 Hz, 1H ), 9.03 (d, J=2.32Hz, 1H), 8.95 (d, J=2.20Hz, 1H), 8.74 (d, J=4.52Hz, 1H), 8.40 (dd, J=7.03, 2.51 Hz, 1H), 8.13 (d, J=8.07 Hz, 1H), 7.96 (td, J=7.79, 1, 77 Hz, 1H), 7.69 (dt, J=8.47, 3.53 Hz, 1H), 7.57 (dd, J=11.00, 9.17 Hz, 1H), 7.42 ( dd, J=7.09, 5.14 Hz, 1H), 4.80-5.05 (m, 1H), 2.25-2.34 (m, 1H), 1.48-1.67 ( m, 1H), 1.28 (dq, J=13.13, 6.67 Hz, 1H).

Method 1: RT=2.82 min; M+H=392.2.

Examples 27A and B. (1S,2R)-N-(3-(5-(3,3-difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl) -2-fluorocyclopropan-1-carboxamide or (1R,2S)-N-(3-(5-(3,3-difluoroazetidin-1-yl)-2Hpyrazolo[3,4-b]pyridin-2-yl)- 4-fluorophenyl)-2-fluorocyclopropane-1-carboxamide (compounds 268 and 271)

F

Compound 339 (130 mg) was separated by SFC (column: CHIRALCEL® OD-H (250 mm x 25 mm, 10 µm); mobile phase: [CO ₂ -MeOH (0.1% NH3H2O)]; V%: 50 %) to give compound 271 (peak 1, RT=4.58 min) as a yellow solid and compound 268 (peak 2, RT=8.01 min) as a yellow solid.

268 (peak 2): SFC RT: 8.01 min 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.69 (s, 1H), 8.64 (d, J=2.69 Hz, 1H) , 8.37 (d, J=2.81 Hz, 1H), 8.32 (dd, J=7.03, 2.51 Hz, 1H), 7.61-7.67 (m, 1H), 7.52 (dd, J=11.19, 9.11 Hz, 1H), 7.15 (d, J=2.81 Hz, 1H), 4.80-5.03 (m, 1H), 4 .41 (t, J=12.29 Hz, 4H), 2.24-2.33 (m, 1H), 1.46-1.67 (m, 1H), 1.27 (dd, J=13 .27, 6.54 Hz, 1H).

Method 1: RT=2.89 min; M+H=406.0.

271 (peak 1): SFC RT: 4.58 min 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.75 (s, 1H), 8.70 (d, J=2.69 Hz, 1H) , 8.43 (d, J=2.81 Hz, 1H), 8.38 (dd, J=6.97, 2.57 Hz, 1H), 7.66-7.77 (m, 1H), 7.52-7.63 (m, 1H), 7.20 (d, J=2.81 Hz, 1H), 4.85-5.08 (m, 1H), 4.47 (t, J= 12.23 Hz, 4 H), 2.27-2.39 (m, 1H), 1.52-1.72 (m, 1H), 1.33 (dq, J=13.11, 6.43 Hz, 1H).

Method 1: RT=2.89 min; M+H=406.0.

Example 28 N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)-4(hydroxymethyl)-2 -methyloxazole-5-carboxamide (compound 277)

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Step A Intermediate I-33 was prepared in a similar manner as in Example 12 using I-28 and I-32 as starting materials.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.70 (s, 1H), 9.04 (d, J=2.45 Hz, 1H), 8.95 (d, J=2.20 Hz, 1H), 8.60-8.66 (m, 2H), 8.55 (d, J=2.20 Hz, 1H), 7.89-7.96 (m, 2H), 7.62 (dd, J=11.00, 9.29 Hz, 1H), 7.44-7.52 (m, 1H), 4.64 (s, 2H), 3.31 (s, 3H), 2, 57 (s, 3H), 2.46 (s, 3H). M+H=473.0.

Step C. To a solution of I-33 (15 mg, 28.9 µmol, 1 eq., FA) in DCM (1 ml) was added dropwise BBr ₃ (14.5 mg, 57.9 µmol, 5.6 µl, 2 eq.) in DCM (0.5 ml) at -78°C. The mixture was stirred at 20° C. for 18 hours under N ₂ atmosphere. Saturated NaHCO ₃ solution (3 ml) was added and the mixture was extracted with DCM (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 µm; mobile phase: [water (0.05% ammonium hydroxide v/v) acetonitrile]; V%: 30 to 60%, 12 min) and lyophilized to give compound 277 as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (d, J=2.20 Hz, 1H), 8.94 (d, J=1.96 Hz, 1H), 8.53-8 .63 (m, 2H), 8.51 (d, J=2.20 Hz, 1H), 7.85-7.95 (m, 1H), 7.81 (br d, J=7.34 Hz , 1H), 7.55-7.67 (m, 1H), 7.37 (dd, J=7.46, 4.77 Hz, 1H), 4.69 (s, 2H), 2.55 ( s, 3H), 2.45 (s, 3H).

Method 1: RT=2.50 min; M+H=459.0.

Example 29 N-(4-fluoro-3-(5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)-2(hydroxymethyl)-4 -methyloxazole-5-carboxamide (compound 334)

he

Step A Intermediate I-35 was prepared in a similar manner as in Example 12 using I-28 and 2-(tert-butoxymethyl)-4-methyloxazole-5-carboxylic acid as starting materials.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.55-10.67 (m, 1H), 9.00 (d, J=2.45 Hz, 1H), 8.91-8.97 ( m, 1H), 8.54-8.65 (m, 2H), 8.47-8.53 (m, 1H), 7.96 (s, 1H), 7.80 (dd, J=7, 70, 0.86 Hz, 1H), 7.55-7.65 (m, 1H), 7.37 (dd, J=7.70, 4.77 Hz, 1H), 4.54 (s, 2H ), 2.69 (s, 3H), 2.44 (s, 3H), 1.24 (s, 9H).

Step B To a solution of I-35 (70 mg, 136.04 µmol, 1 eq.) in DCM (2 ml) was added TFA (0.5 ml, 6.75 mmol, 49.6 eq.). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The pH was adjusted to 7 with TEA. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 µm; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; V%: 20 to 50%, 12 min) and lyophilized to give compound 334 as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm, 10.63 (s, 1H), 9.00 (d, J=2.20 Hz, 1H), 8.94 (d, J=2, 20 Hz, 1H), 8.62 (dd, J=7.09, 2.45 Hz, 1H), 8.57 (d, J=3.67 Hz, 1H), 8.51 (d, J= 2.20 Hz, 1H), 7.91-8.01 (m, 1H), 7.81 (d, J=7.34 Hz, 1H), 7.60 (dd, J=11.00, 9 .05 Hz, 1H), 7.37 (dd, J=7.70, 4.77 Hz, 1H), 5.83 (t, J=5.99 Hz, 1H), 4.60 (d, J =6.11 Hz, 2H), 2.45 (s, 6H).

Method 1: RT=2.57 min; M+H=459.0.

Example 30 3,3-Difluoro-N-(4-fluoro-3-(5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1 -carboxamide (compound 39) with

To a solution of I-3 (3.00 g, 7.04 mmol, 1 eq.) and tributyl(2-pyridyl)stannane (3.4 g, 9.1 mmol, 1.3 eq.) in

- 63 039324

DMF (40 ml) was added with Pd(PPh ₃ ) ₄ (813 mg, 703.9 µmol, 0.1 eq.) and CuI (134 mg, 703.9 µmol, 0.1 eq.) under N2 atmosphere. The mixture was stirred at 85° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate=2:1 to 0:1 to give compound 39 as a white solid.

1H NMR (400 MHz, methanol-d ₄ ) δ 9.36 (d, J=2.3 Hz, 1H), 9.00-8.93 (m, 2H), 8.79-8.75 (m , 1H), 8.26 (dd, J=6.8, 2.7 Hz, 1H), 8.19-8.14 (m, 2H), 7.70-7.64 (m, 1H), 7.64-7.56 (m, 1H), 7.46-7.35 (m, 1H), 4.44 (td, J=12.3, 3.0 Hz, 4H).

Method 2: RT=0.99 min; M+H=425.0.

Example 31 3,3-Difluoro-N-(4-fluoro-3-(5-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl)azetidine-1carboxamide (compound 353)

F

To a stirred solution of triphosgene (23 mg, 0.079 mmol) in dry THF (1 ml) was added I-36 (40 mg, 0.131 mmol) in dry THF (2 ml) at (-5) - 0°C and stirred at rt. t. within 10 min. 3,3-Difluoroazetidine hydrochloride (34 mg, 0.263 mmol) and DIEA (51 mg, 0.394 mmol) in dry THF (2 ml) were added dropwise at 0°C and the reaction mixture was stirred at RT. within 1 h. The reaction mixture was extinguished with a saturated solution of NH ₄ Cl and was extracted with EtOAc (50 ml x 2). The combined organic layers were washed with water (20 ml), brine (10 ml) and dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel chromatography eluting with 50% EtOAc in n-hexane to give compound 353 as an off-white solid.

1H NMR (400 MHz, DMSO-d6) 9.25 (s, 1H), 9.06-9.05 (d, J=2.8, 1H), 8.96-8.95 (d, J= 2.0, 1H), 8.52-8.51 (d, J=2.4, 1H), 8.27-8.25 (m, 1H), 7.80-7.78 (d, J =7.2, 2H), 7.72-7.67 (m, 1H), 7.56-7.48 (m, 3H), 7.44-7.41 (m, 1H), 4.44 -4.38 (t, J=16.4, 4H).

In table. 2 lists the compounds prepared according to the examples above.

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table 2

conn. no. Structure ¹ H NMR data and HPLC and/or MS retention times one ί Ζ / X n Ζ 'Them ^? / IZ 0-4 X Ή NMR (400 MHz, Methanol-D δ 8.90 (dd, 7=13.2, 2.3 Hz, 2H), 8.59-8.43 (br, 3H), 7.97-7.81 (m, 2H), 7.55-7.35 (br, 2H), 2.56 (s, 3H), 2.48-2.45 (m, 6H) Method 1: RT=2.69 min .; M+H=443.1 2 Vo HN a ( -b .v. L. .V o ¢. D ~ / Ή NMR (400 MHz, MeraHon-d4) δ 8.92 (d, J=2.4 Hz, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.55-8.45 (m, 3H), 7.96 (m, 1H), 7.87 (m, 1H), 7.78 (m, 1H), 7.52-7.39 (m, 2H), 7.32 ( m, 1H), 6.68 (m, 1H), 2.46 (s, 3H). Method 2: RT=0.89 min; M+H=414.3 3 W 'dg D 'z' - d Ή NMR (400 MHz, Methanol-D δ 8.898.84 (m, 2H), 8.52 (m, 1H), 8.48 (m, 1H), 8.18 (m, 1H), 7.86 ( m, 1H), 7.67 (m, 1H), 7.44-7.32 (m, 2H), 4.18-4.06 (m, 4H), 2.46 (s, 3H), 2 .41-2.26 (m, 2H) Method 1: RT=2.41 min, M+H=403.3 four /x^F NJ N _ _N * V .N. 1 1XU' Ή NMR (400 MHz, Methanol-D δ 8.87 (dd, 7=4.7, 2.3 Hz, 2H), 8.52 (m, 1H), 8.49 (m, 1H), 8, 19 (m, 1H), 7.86 (m, 1H), 7.67 (m, 1H), 7.45-7.34 (m, 2H), 5.42-5.25 (m, 1H) , 3.85-3.55 (m, 4H), 2.46 (s, 3H), 2.392.19 (m, 2H) Method 1: RT=2.41 min, M+H=435.3 5 l,f N- ^J nD A-A ^D ^ъ \_/ '1D F Ή NMR (400 MHz, Methanol-D δ 8.88 (dd, 7=5.4, 2.3 Hz, 2H), 8.52 (m, 1H), 8.48 (m, 1H), 8, 22 (m, 1H), 7.86 (m, 1H), 7.69 (m, 1H), 7.45-7.36 (m, 2H), 4.44 (m, 4H), 2.46 (s, WN) Method 2: RT=0.76 min, M+H=439.l

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Ή NMR (500 MHz, DMS0-d6) δ 8.98 (s, Ch-λ. 1H), 8.94 (dd, 1=16.9, 2.3 Hz, 2H), 8.57 (ddd, 1=4.8, 1.7, 0.7 Hz, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.28 (dd, 1=7.0, 2.7 Hz, 1H), 7.80 (ddd, 1=7.7, 1.7, 0 .8 Hz, 1H), 7.72 (ddd, 1=9.1, 4.1, 2.7 Hz, 1H), 7.49 (dd, 1=11.2, 6 .v. ΙΛ' ¹ N ^J 9.1Hz, 1H), 7.37(dd, 1=7.7, 4.7Hz, 1H), 5.41(dtt, 1=57.5, 6.1, 3.1Hz, 1H ), 4.34 (dddd, 1=21.7, 10.4, 6.0, 1.4 Hz, 2H), 4.04 (dddd, 1=24.9, 10.4, 3.1, 1.4 Hz, 2H), 2.44 (s, 3H). Method 1: RT=2.39 min; M+H=421.l Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.66 (d, 7=2.4 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H) , 8.12 (m, 1H), 8.07 (m, 1H), 7.64 (m, 1H), 7 JK.-N 0 1 λ. .ΟΜ_ ? F ^F . r< 7.34 (m, 1H), 4.19-4.01 (m, 4H), 2.67 (m, 2H), 2.41-2.24 (m, 2H), 1.97 (m, 1H), 0.99 (m, 6H). Method 1: RT=3.11 min; M+H=368.3 Ή NMR (400 MHz, Methanol-D) δ 8.59 (d, 7=2.5 Hz, 1H), 8.46 (d, 7=2.2 Hz, 1H), eight h \ \ \ ( ζ οζ' Ύΐχ mr.: SD m ο^ζ η \ 8.06 (m, 1H), 7.97 (m, 1H), 7.56 (m, 1H), 7.30-7.24 (m, 1H), 4.33 (m, 4H), 2 .57 (m, 2H), 1.92-1.81 (m, 1H), 0.89 (m, 6H). Method 2: RT=l.09 min. M+H=404,l Ή NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1 Η), 8.70 (d, 1=3.01 Hz, 1 Η), 8.55 (d, 1=2.76 Hz , 1 Η), 8.20 (dd, J=6.90, 2.64 Hz, 9 ΗΝ 4 DUL ( b ... 1 Y/O Ν' 1F 1 H), 7.56-7.78 (m, 1 H), 7.45 (dd, 1=11.42, 9.16 Hz, 1 H), 7.15 (d, 1=3.01 Hz, 1 Η), 4.41 (t, 1=12.67 Hz, 4 Η), 2.95 (s, 6 Η). Method 1: RT=2.84 min; M+H=391,l

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ten O..L-J . X Cr ⁵ t / \ ^r h 7 Z-^ / 7 Ή NMR (400 MHz, Methanol-^), δ 8.42 (d, 7=2.51 Hz, 1 H), 8.22 (d, 7=2.76 Hz, 1 H), 8.05 ( dd, 7=6.78, 2.76 Hz, 1 H), 7.587.62 (br, 1 H), 7.30 (dd, 7=11.04, 9.16 Hz, 1 H), 7, 01 (d, 7=2.64 Hz, 1 N), 4.10 (t, 7=7.65 Hz, 4 N), 3.99 (t, 7=7.22 Hz, 4 N), 2 .41-2.49 (w, 2 H), 2.27-2.35 (w, 2 H). Method 1: RT=2.80 min; M+H=367.1 and BUT NM -N /, ,<' 0 ,N. .1 V <-/ and Ή NMR (400 MHz, DMSO-7 ₆ ) δ 10.53 (s, 1H), 9.49 (d, 7=2.3 Hz, 1H), 9.06 (d, 7=2.6 Hz, 1H), 8.96 (d, 7=2.3 Hz, 1H), 8.74 (ddd, 7=4.8, 1.9, 0.9 Hz, 1H), 8.53 (dd, 7 =7.0, 2.7Hz, 1H), 8.14(dt, 7=8.0, 1.1Hz, 1H), 8.017.91(m, 2H), 7.62(dd, 7= 11.2, 9.1 Hz, 1H), 7.50-7.38 (m, 2H), 6.14 (dd, 7=7.0, 3.7 Hz, 1H). Method 2: RT=0.91 min; M+H=418,l 12 F. For >-\ one ! N 4 λ H 7 Q ·..l! HN 4' b 1 NMR (400 MHz, DMSO-7 ₆ ) δ 10.59 (s, 1H), 9.48 (d, 7=2.3 Hz, 1H), 9.03 (d, 7=2.5 Hz, 1H ), 8.95 (d, 7=2.3 Hz, 1H), 8.74 (ddd, 7=4.8, 1.9, 0.9 Hz, 1H), 8.42 (dd, 7= 7.0, 2.7Hz, 1H), 8.13(dt, 7=8.1, 1.0Hz, 1H), 7.96(td, 7=7.7, 1.9Hz, 1H ), 7.73 (ddd, 7=9.0, 4.2, 2.7 Hz, 1H), 7.55 (dd, 7=11.2, 9.1 Hz, 1H), 7.42 ( ddd, 7=7.5, 4.8, 1.0Hz, 1H), 3.17(d, 7=5.3Hz, 1H), 0.85(d, 7=5.9Hz, 4H ). Method 1: RT=2.74 min; M+H=374,l 13 to Λ-.Ν '>=-. M ^r L M ) □ J HN-D ] Ή NMR (400 MHz, DMSO-7 ₆ ) δ 9.99 (s, 1H), 9.26 (d, 7=2.3 Hz, 1H), 8.82 (d, 7=2.5 Hz, 1H), 8.73 (d, 7=2.4 Hz, 1H), 8.52 (ddd, 7=4.8, 1.8, 1.0 Hz, 1H), 8.22 (dd, 7 =7.1, 2.7 Hz, 1H), 7.91 (dt, 7=8.0, 1.1 Hz, 1H), 7.74 (td, 7=7.7, 1.8 Hz, 1H), 7.52 (ddd, 7=9.0, 4.2, 2.7 Hz, 1H), 7.34 (dd, 7=11.2, 9.1 Hz,

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1H), 7.21 (ddd, 7=7.5, 4.8, 1.0 Hz, 1H), 2.04 (d, 7=7.0 Hz, 2H), 0.92-0.80 (m, 1H), 0.37-0.22 (m, 2H), 0.01 (dd, 7=4.8, 1.6 Hz, 2H). Method 1: RT=2.80 min; M+H=388,l fourteen G! Ν- ¹ ην4 1 “ ^{b 4} ,=/ F Ή NMR (400 MHz, Methanol-44) δ 8.67 (m, 1H), 8.56 (m, 1H), 8.13 (m, 1H), 8.088.04 (m, 1H), 7.65 (m, 1H), 7.35 (m, 1H), 5.44-5.30 (m, 1H), 4.39 (m, 2H), 4.14 (m, 2H), 2.67 ( m, 2H), 1.97 (m, 1H), 0.99 (m, 6H). Method 1: RT=3.15 min; M+H=386,l fifteen o with _g l Ο· ^ζ 'Ζ^·. Ή NMR (400 MHz, Methanol-b4) δ 8.61 (m, 2H), 8.12 (m, 1H), 7.92 (m, 1H), 7.64 (m, 1H), 7.35 (m, 1H), 5.44-5.29 (m, 1H), 4.39 (m, 2H), 4.14 (m, 2H), 2.15-2.08 (m, 1H), 1.15-1.03 (m, 2H), 0.88-0.77 (m, 2H). Method 1: RT=2.79 min; M+H=370,l 16 Ί-ί 1 ΙΝ^, ^Ν-^ν ъ Λ LUM / ,^· ·<^· -/ -----, [ ^ζ Ή NMR (400 MHz, Methanol-b4) δ 8.72 (m, 1H), 8.57 (m, 1H), 8.43 (m, 1H), 8.138.06 (m, 1H), 7.89 (m, 1H), 7.45 (m, 1H), 2.67 (m, 2H), 2.55 (s, 3H), 2.47 (s, 3H), 1.98 (dt, J= 13.5, 6.8 Hz, 1H), 1.00 (s, 3H), 0.98 (s, 3H). Method 1: RT=3.21 min; M+H=408,l 17 4J ΗΝΗ _Χ V ι' Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.67 (m, 1H), 8.61 (m, 1H), 8.42 (m, 1H), 7.93 (m, 1H), 7, 88 (m, 1H), 7.44 (m, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 2.18-2.07 (m, 1H), 1.13 -1.06 (m, 2H), 0.87-0.79 (m, 2H). Method 1: RT=3.03 min; M+H=392,l

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eighteen 'G ⁵ G 1 T Τ' g Z d X\___y X M Ή NMR (400 MHz, Methanol-b4) δ 8.77 (m, 1H), 8.49 (m, 1H), 8.02 (m, 1H), 7.56 (m, 1H), 7.29 -7.24(m, 1H), 7.01(m, 1H), 5.35-5.20(m, 1H), 4.30(m, 2H), 4.04(m, 2H), 2.16 (m, 1H), 1.85-1.67 (m, 4H), 1.56 (m, 2H), 0.81 (m, 2H). Method 1: RT=3.03 min; M+H=398,l 19 7 ΙΙΝ-Λ _Г L >^.N b .L IH ) CJ- ~ Г Ή NMR (400 MHz, Methanol-b4) δ 8.758.47 (m, 2H), 8.16-8.07 (m, 1H), 7.747.61 (m, 1H), 7.41-7.31 ( m, 1H), 7.247.01 (m, 1H), 5.47-5.26 (m, 1H), 4.464.31 (m, 2H), 4.21-4.06 (m, 2H), 2 ,ΙΟ- Ι.31 (m, 10H), 0.96-0.83 (m, 1H). Method 1: RT=2.99 min; M+H=412,l twenty F ...L bP HN-% ✓ ^Ν γΛ ^b _ L La A7 O F Ή NMR (400 MHz, Methanol-^) δ 8.70 (m, 1H), 8.60 (m, 1H), 8.16-8.08 (m, 1H), 7.63 (m, 1H) , 7.38-7.30(m, 1H), 7.06(m, 1H), 5.44-5.29(m, 1H), 4.46-4.31(m, 2H), 4 .20-4.06(m, 2H), 2.61-2.51(m, 1H), 2.46(m, 1H), 2.41-2.31(m, 1H), 2.32 -2.20(m, 1H), 2.20-2.05(m, 1H), 2.05-1.91(m, 1H), 1.84-1.57(m, 1H). Method 1: RT=2.92 min; M+H=384,l 21 ΗΝ-Λ lLM5 X y—> one Ή NMR (400 MHz, Methanol-<7 ₄ ) δ 8.69 (m, 1H), 8.54 (m, 1H), 8.16-8.10 (m, 1H), 8.07 (m, 1H), 7.68-7.61 (m, 1H), 7.397.32 (m, 1H), 5.44-5.30 (m, 1H), 4.39 (m, 2H), 4.14 (m, 2H), 2.70 (s, 2H), 0.99 (s, 9H). Method 1: RT=2.62 min; M+H=400.2

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22 F N- HN-A JK-N Oh X £ £M T'/ Ή NMR (400 MHz, Methanol-^) δ 8.698.54 (m, 2H), 7.83 (m, 1H), 7.66 (m, 1H), 7.40-7.25 (m, 1H) , 7.20-7.10(m, 1H), 5.43-5.28(m, 1H), 4.43-4.31(m, 2H), 4.20-4.05(m, 2H), 1.49(s, 9H). Method 1: RT=2.72 min; M+H=386,l 23 F g \ N- ^J hn-£ ££.... n £ x ϊ ~ Ή NMR (400 MHz, Methanol-^) δ 8.768.57 (m, 2H), 8.16-8.06 (m, 1H), 7.65 (m, 1H), 7.44-7.31 ( m, 2H), 5.44-5.30 (m, 1H), 4.44-4.34 (m, 2H), 4.21-4.08 (m, 2H), 2.85-2, 72 (m, 1H), 1.87-1.57 (m, 3H), 1.46-1.33 (m, 3H), 0.98-0.67 (m, 4H). Method 1: RT=3.13 min; M+H=400,l 24 V L lz ₄ T ⁵ t£. r ~ z 4J / Ή NMR (400 MHz, Methanol-b4) δ 8.55 (m, 1H), 8.45 (m, 1H), 7.73 (m, 1H), 7.56 (m, 1H), 7.19 (m, 1H), 7.07 (m, 1H), 5.335.18 (m, 1H), 4.33-4.21 (m, 2H), 4.103.96 (m, 2H), 1.90- 1.67 (m, 2H), 1.39 (s, 3H), 1.27 (s, 3H), 0.66 (t, J=7.4 Hz, ZN). Method 1: RT=2.89 min; M+H=400,l 25 F b3 hn-£ - _V -.N _Z z£ O .-. 1 LHJ T ~ Ή NMR (400 MHz, Methanol-b4) δ 8.748.63 (m, 1H), 8.62-8.52 (m, 1H), 8.168.05 (m, 1H), 7.73-7.59 ( m, 1H), 7.407.29 (m, 1H), 7.08 (m, 1H), 5.44-5.26 (m, 1H), 4.39 (m, 2H), 4.20-4 .06 (m, 2H), 1.90-1.61 (m, 2H), 1.52-1.30 (m, 3H), 1.03-0.81 (m, 3H), 0.77 (m, 1H). Method 1: RT=2.78 min; M+H=386,l 26 P hn-4 ,., A _V N. w '0 £££4=^ F ^X H NMR (400 MHz, Methanol-^) δ 8.67 (m, 1H), 8.58 (m, 1H), 8.16-8.08 (m, 1H), 8.05 (m, 1H ), 7.64 (m, 1H), 7.38-7.31 (m, 1H), 5.44-5.30 (m, 1H), 4.39 (m, 2H), 4.14 ( m, 2H), 2.87 (m, 1H), 2.68 (m, 1H), 2.192.04 (m, 2H), 1.98-1.66 (m, 4H), 0.91 (m ,

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1H). Method 1: RT=3.10 min; M+H=398,l 27 1 ri Nhn—/ _r > ^N >->N. b „LL/a j- Г 'X Ή NMR (400 MHz, Methanol-04) δ 8.67 (m, 1H), 8.57 (m, 1H), 8.13 (m, 1H), 8.118.05 (m, 1H), 7.65 (m, 1H), 7.39-7.31 (m, 1H), 5.44-5.30 (m, 1H), 4.39 (m, 2H), 4.14 (m, 2H), 2.87-2.76(m, 2H), 1.69-1.57(m, 2H), 1.04-0.85(m, 6H), 0.76(m, 1H). Method 1: RT=3.18 min; M+H=400,l 28 F / ..-4 ΐ \ N- ³ NIR b .ν. 1I?“O t Ϊ ' Ή NMR (400 MHz, Methanol-a4) δ 9.37 (m, 1H), 8.86 (m, 2H), 8.70 (m, 1H), 8.19 (m, 1H), 8.04 -7.92 (m, 2H), 7.66 (m, 1H), 7.45-7.31 (m, 2H), 5.45-5.30 (m, 1H), 4 46-4, 34 (m, 2H), 4.21-4.08 (m, 2H). Method 1: RT=2.67 min; M+H=407,l 29 F <X..-N ^x = ₄ χνχ p - H\ - a Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.53 (m, 1H), 8.49 (m, 1H), 8.04 (m, 1H), 7.857.79 (m, 1H), 7, 54 (m, 1H), 7.29-7.22 (m, 1H), 4.32 (t, 7=12.3 Hz, 4H), 2.07-1.95 (m, 1H), 0 .98 (m, 2H), 0.71 (m, 2H). Method 2: RT=l,10 min; M+H=388,l thirty = Λ _ν Α Г Г > z-XV^^ o \ J hnX - x ₇ 'X Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.718.62 (m, 1H), 8.25-8.12 (m, 1H), 7.94 (m, 1H), 7.73-7.60 (m, 1H), 7.45-7.29 (m, 2H), 4.44 (m, 4H), 2.19 (m, 1H), 1.97-1.49 (m, 6H), 0.90 (m, 2H). Method 2: RT=l.09 min; M+H=416,l 31 F Λχ .L bij Jr / \ fy ^l -.J HN^ N- _? X Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.59 (m, 1H), 8.50 (m, 1H), 8.05 (m, 1H), 8.02 (m, 1H), 7, 55 (m, 1H), 7.29-7.23 (m, 1H), 4.32 (t, 7=12.3 Hz, 4H), 2.37 (m, 2H), 2.27-1 .98 (m, 4H), 1.91-1.83 (m, 1H). Method 1: RT=3.16 min; M+H=402,l

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32 ⁼ 0 HN X >k.<.N pi b o / ~ F Ή NMR (400 MHz, Methanol-^) δ 8.70 (m, 1H), 8.54 (m, 1H), 8.16 (m, 1H), 8.07 (m, 1H), 7.66 (m, 1H), 7.41-7.34 (m, 1H), 4.43 (t, 7=12.3 Hz, 4H), 2.69 (s, 2H), 0.99 (s, 9H). Method 2: RT=1.27 min; M+H=418,l 33 F' HN <' ^J .'> /, ( b . Λ La <_> A ' F ^? ' Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.64 (m, 1H), 8.61-8.55 (m, 1H), 7.84 (m, 1H), 7.71-7.64 (m, 1H), 7.37-7.28 (m, 1H), 7.17 (m, 1H), 4.42 (m, 4H), 1.52 (m, 9H). Method 2: RT=l.04 min; M+H=404,l 34 F c Г< N-' HN < / ( about I.A 1f' Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.68 (m, 1H), 8.63-8.57 (m, 1H), 8.15 (m, 1H), 7.98-7.91 (m, 1H), 7.69-7.62 (m, 1H), 7.39-7.32 (m, 1H), 4.42 (m, 4H), 1.531.33 (m, 5H), 1.00-0.72 (m, 6H). Method 2: RT=1.14 min; M+H=418,l 35 ^F , GD HN : ^V - ^N ( ⁶ 1. 7 V/ Ά /..... / \ f Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.65 (m, 1H), 8.55 (m, 1H), 7.84 (m, 1H), 7.67 (m, 1H), 7, 40-7.31(m, 1H), 7.17(m, 1H), 4.42(m, 4H), 1.93-1.79(m, 2H), 1.50(m, 3H) , 1.37 (m, 3H), 0.81-0.66 (m, 3H). Method 2: RT=l,10 min; M+H=418,l 36 P J r% N- ^J HN < .A-.-N / ₄ < o J Г N Г T ,/- _r ^ _F > / Ή NMR (400 MHz, Methanol-b/ ₄ ) δ 8.68 (m, 1H), 8.46 (m, 1H), 8.14 (m, 1H), 7.707.63 (m, 1H), 7 .39-7.33(m, 1H), 7.18(m, 1H), 4.43(m, 4H), 1.91-1.79(m, 2H), 1.54-1.36 (m, 4H), 0.92 (m, 3H). Method 2: RT=1.14 min; M+H=404,l

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37 R „W /=^. about HN^ N > Ή NMR (400 MHz, Methanol-^) δ 8.598.54 (m, 1H), 8.45 (m, 1H), 8.07-8.00 (m, 1H), 7.96-7.92 ( m, 1H), 7.55 (m, 1H), 7.29-7.23 (m, 1H), 4.32 (t, J= 12.3 Hz, 4H), 2.76 (m, 2H ), 2.63-2.51 (m, 1H), 2.041.93 (m, 2H), 1.87-1.64 (m, 4H). Method 1: RT=3.26 min; M+H=416,l 38 V \ N-HN { <A^-n /, .$ b ... D Ό 1 F ^Z Ή NMR (400 MHz, Methanol-^) δ 8.67 (m, 1H), 8.58 (m, 1H), 8.16 (m, 1H), 8.108.04 (m, 1H), 7.69 -7.62 (m, 1H), 7.407.33 (m, 1H), 4.43 (t, 7=12.3 Hz, 4H), 2.89-2.78 (m, 2H), 1, 72-1.53 (m, 3H), 1.04-0.86 (m, 6H). Method 2: RT=l.30 min; M+H=418,l 39 /--Achg Ο... ,2:-7 i about Ή NMR (400 MHz, Methanol-d4) δ 9.36 (d, J=2.3 Hz, 1H), 9.00-8.93 (m, 2H), 8.798.75 (m, 1H), 8 .26 (dd, J=6.8, 2.7 Hz, 1H), 8.19-8.14 (m, 2H), 7.70-7.64 (m, 1H), 7.64-7 .56 (m, 1H), 7.46-7.35 (m, 1H), 4.44 (td, J=12.3, 3.0 Hz, 4H). Method 2: RT=0.99 min; M+H=425.0 40 N- ¹ ΗΝ^ UK -N _z rR □ ' Ν—χ Y W _f Aj F NMR (400 MHz, DMSO) δ 8.70 (s, 1 Η), 8.56 (d, 7=2.76 Hz, 1 Η), 8.31 (d, 7=2.76 Hz, 1 Η ), 8.21 (dd, 7=7.03, 2.64 Hz, 1 Η), 7.59-7.72 (m, 1 Η), 7.41 (dd, 7=11.36, 9 .10 Hz, 1 Η), 7.01 (d, 7=2.76 Hz, 1 Η), 5.395.66 (m, 1 Η), 4.20-4.36 (m, 2 Η), 3.894 .09 (m, 6 Η), 2.12-2.28 (m, 2 Η). Method 1: RT=2.66 min. M+H=385.3 41 IM hnH ; yyy ^s F Ή NMR (400 MHz, Methanol-d4) δ 8.68 (m, 1H), 8.56 (m, 1H), 8.12 (m, 1H), 8.07 (m, 1H), 7.65 (m, 1H), 7.36 (m, 1H), 5.405.27 (m, 1H), 3.85-3.68 (m, 2H), 3.59 (m, 2H), 2.67 ( m, 2H), 2.28 (m, 2H), 1.97 (m, 1H), 0.99 (d, J=6.6 Hz, 6H). M+H=400.3

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42 \ _/ .'V >,' , ΰ ζ ζ - ί Τ1. ζ Αζ- / '-π Ή NMR (400 MHz, Methanol-04) δ 8.63 (m, 1H), 8.59 (m, 1H), 8.11 (m, 1H), 7.92 (m, 1H), 7.63 (m, 1H), 7.34 (m, 1H), 5.405.26 (m, 1H), 3.80-3.67 (m, 2H), 3.59 (m, 2H), 2.37- 2.18 (m, 2H), 2.12 (m, 1H), 1.08 (m, 2H), 0.85-0.79 (m, 2H). Method 2: RT=l.03 min; M+H=384.3 43 / V ¹ 'yJ ΗΝ-Α ,Ж ..Ν b %ί ¹ ' Ή NMR (400 MHz, Methanol-^) δ 8.778.54 (m, 2H), 8.27-8.07 (m, 2H), 7.64 (m, 1H), 7.36 (m, 1H) , 5.40-5.23(m, 1H), 3.87-3.51(m, 4H), 3.20(m, 1H), 2.461.96(m, 5H), 1.98-1 .56 (m, 5H). Method 2: RT=l.04 min; M+H=412.3 44 Z^ ^F \ / N -' ΗΝ Ζ A.-Ν ζ Ζ b ... 1 V Ο Ο ^ν ' Ή NMR (400 MHz, Methanol-^) δ 8.67 (m, 1H), 8.65-8.57 (m, 1H), 8.26-8.08 (m, 2H), 7.64 ( m, 1H), 7.35 (m, 1H), 5.40-5.26 (m, 1H), 3.84-3.54 (m, 4H), 2.79-2.68 (m, 1H), 2.39-1.92(m, 6H), 1.82(m, 1H), 1.66-1.19(m, 5H). Method 2: RT=1.26 min; M+H=426.4 45 _ζ --^F V / ΗΝ^ ,^ν^ν b Ν—f b A' Ή NMR (400 MHz, Methanol-^) δ 8.77 (m, 1H), 8.69 (m, 1H), 8.61 (m, 1H), 8.178.09 (m, 1H), 7.63 (m, 1H), 7.40-7.32 (m, 1H), 5.42-5.25 (m, 1H), 3.82-3.53 (m, 4H), 2.63-2 .07 (m, 6H), 1.90-1.89 (m, 3H). Method 1: RT=2.93 min; M+H=398.3 46 /yF N- ^J HN^ A -. ->n ъ yy f Ή NMR (400 MHz, Methanol-DO δ 8.69 (m, 1H), 8.54 (m, 1H), 8.12 (m, 1H), 8.07 (m, 1H), 7.64 ( m, 1H), 7.35 (m, 1H), 5.395.26 (m, 1H), 3.82-3.70 (m, 2H), 3.59 (m, 2H), 2.69 (s , 2H), 2.33-2.09 (m, 2H), 0.99 (s, 9H) Method 2: RT=1.21 min, M+H=414.4

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/X^F Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.698.62 (m, 1H), 8.58 (m, 1H), 7.81 (m, 1H), 7.69 (m, 1H), 7.30 (m, 1H), 7.17 (m, 1H), 47 to Η Λ ί/ and, 5.38-5.23(m, 1H), 3.78-3.66(m, 2H), 3.57(m, 2H), 2.35-2.11(m, 2H), 1, 71- 'Ί F zv ^F 1.22 (m, 9H). Method 2: RT=0.98 min; M+H=400.3 Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.728.65 (m, 1H), 8.47 (m, 1H), 8.18-8.08 (m, 1H), 7.74-7.60(m, 1H), 7.43-7.33(m, 1H), 7.26-7.14(m, 1H), 5.39-5.26(m, 48 ν3 ^ζ Η ί HN— 1H), 3.83-3.53 (m, 4H), 3.16-3.01 (m, 1H), 2.85-2.72 (m, 1H), 2.40-2.05 (m, 1F a ^F 4H), 1.54-1.15(m, 4H), 1.03-0.88(m, 2H), 0.84-0.74(m, 1H). Method 2: RT=l.08 min; M+H=414.4 Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.65 (m, 1H), 8.56 (m, 1H), 7.82 (m, 1H), 7.69 ( m, 1H), 7.30(m, 1H), 7.19(m, 1H), 5.40- 49 Ή. _μΓ DN 5.26 (m, 1H), 3.81-3.69 (m, 2H), 3.58 (m, J 2H), 2.35-2.19(m, 2H), 1.87-1.79(m, / X Ε~ 2H), 1.55-1.43(s, 3H), 1.39(s, 3H), 0.85- / X G fV ^F N~ ^J 0.68 (m, 3H). Method 2: RT=l.04 min; M+H=414.3 Ή NMR (400 MHz, Methanol M) δ 8.67 (m, 1H), 8.64-8.56 (m, 1H), 8.12 (m, 1H), 7.69-7.59 (m, 1H), 7.41-7.30 (m, 1H), HN^ 7.22-7.14(m, 1H), 5.40-5.26(m, 1H), fifty , _G / one 3.82-3.55 (m, 4H), 2.97-2.77 (m, 2H), ! p' 2.37-2.21(m, 2H), 1.75-1.65(m, 1H), 1.52-1.21(m, 3H), 1.11-0.82(m, 3H ). Method 2: RT=1.18 min; M+H=400.3

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51 F Ή NMR (400 MHz, Methanol-A) δ 8.66 (m, 1H), 8.55 (m, 1H), 8.13 (m, 1H), 8.078.03 (m, 1H), 7.62 (m, 1H), 7.35 (m, 1H), 5.40-5.25 (m, 1H), 3.83-3.69 (m, 2H), 3.66-3.50 (m , 2H), 2.90-2.78 (m, 2H), 2.73-2.62 (m, 1H), 2.59-2.45 (m, 1H), 2.39-2.18 (m, 2H), 2.15-2.04 (m, 2H), 1.89-1.78 (m, 3H). Method 1: RT=3.16 min; M+H=412.3 52 / If V, 'Z Z > 1 1,bz L c u_ / Ή NMR (400 MHz, Methanol-A) δ 8.67 (m, 1H), 8.57 (m, 1H), 8.12 (m, 1H), 8.108.05 (m, 1H), 7.64 (m, 1H), 7.35 (m, 1H), 5.40-5.26 (m, 1H), 3.83-3.69 (m, 2H), 3.59 (m, 2H), 2.89-2.77 (m, 2H), 2.382.05 (m, 3H), 1.70-1.57 (m, 2H), 1.040.88 (m, 6H). Method 2: RT=1.25 min; M+H=414.4 53 /x^FN - ¹ HN <i _h ( b ,n AV <_? U ~ ^f Ή NMR (400 MHz, Methanol-A) δ 9.37 (m, 1H), 8.88 (m, 1H), 8.86 (m, 1H), 8.70 (m, 1H), 8.17 (m, 1H), 8.05-7.92 (m, 2H), 7.66 (m, 1H), 7.43 (m, 1H), 7.37 (m, 1H), 5.40- 5.27 (m, 1H), 3.85-3.70 (m, 2H), 3.60 (m, 2H), 2.38-2.09 (m, 2H). Method 2: RT=0.93 min; M+H=421.3 54 / \ r r ^u „g z'> g Λ ' \ j / \ Ή NMR (400 MHz, Methanol-A) δ 8.72 (m, 1H), 8.58 (m, 1H), 8.43 (m, 1H), 8.08 (m, 1H), 7.93 (m, 1H), 7.78 (m, 1H), 7.46 (m, 1H), 7.31 (m, 1H), 6.71-6.63 (m, 1H), 2.68 ( d, 7=7.1 Hz, 2H), 1.98 (m, 1H), 0.99 (2s, 6H). Method 1: RT=3.20 min; M+H=379.3

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55 7'z oh Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.67 (m, 1H), 8.61 (m, 1H), 8.42 (m, 1H), 7.957.87 (m, 2H), 7, 78 (m, 1H), 7.44 (m, 1H), 7.31 (m, 1H), 6.67 (m, 1H), 2.17-2.08 (m, 1H), 1.09 (m, 2H), 0.86-0.79 (m, 2H). Method 2: RT=1.11 min; M+H=363.3 56 with JK-W >- _x . .sh < · - „ hJ ην^ ch Х^'*· Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.71 (m, 1H), 8.69-8.65 (m, 1H), 8.43 (m, 1H), 8.15 (m, 1H ), 7.92 (m, 1H), 7.80-7.76 (m, 1H), 7.46 (m, 1H), 7.33-7.29 (m, 1H), 6.67 ( m, 1H), 3.25-3.18 (m, 1H), 2.27-2.14 (m, 3H), 1.85-1.66 (m, 5H). Method 2: RT=1.27 min; M+H=391.3 57 _r M >-\ _T c 3..- '_? ₀ J ΗΝ^ -.7 .· Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.67 (m, 1H), 8.53 (m, 1H), 8.07 (m, 1H), 8.00 (m, 1H), 7, 77 (m, 1H), 7.47 (m, 1H), 7.347.29 (m, 1H), 7.19 (m, 1H), 6.67 (m, 1H), 2.88 (m, 2H ), 1.98 (m, 3H), 1.88-1.72 (m, 3H), 1.40-1.28 (m, 3H). M+H=405.3 58 ......., τ 'Uz^.o J. ζ ζ.., Μ Ή NMR (400 MHz, DMSO) δ 8.95 (s, 1 Η), 8.56 (d, 7=2.63 Hz, 1 Η), 8.30 (d, 7=2.89 Hz, 1 Η), 8.19 (dd, 7=7.09, 2.70 Hz, 1 Η), 7.60-7.69 (m, 1 Η), 7.42 (dd, 7=11.36, 9.10 Hz, 1 Η), 7.00 (d, 7=2.76 Hz, 1 Η), 5.285.63 (m, 2 Η), 4.20-4.37 (m, 4 Η), 3.934.09 (m, 4 H). Method 1: RT=2.61 min. M+H=403.2 59 hh ho ΗΝ^ , ^ ^ν ^.v /ch b Xhh^^JF Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.73 (m, 1H), 8.55 (m, 1H), 8.43 (m, 1H), 8.09 (m, 1H), 7, 93 (m, 1H), 7.78 (m, 1H), 7.45 (br, 1H), 7.31 (m, 1H), 6.70-6.64 (t, 1H), 2.70 (s, 2H), 0.99 (s, 9H). Method 2: RT=1.29 min; M+H=393.3

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60 |-ό ννΡ .Λ _χ Ν b I chl-o X -,χ / ' / \ F Ή NMR (400 MHz, Methanol-^) δ 8.66 (m, 1H), 8.64-8.54 (m, 1H), 8.12 (m, 1H), 7.94 (m, 1H) , 7.77 (m, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.18 (m, 1H), 6.67 (m, 1H), 2.03- 1.79 (m, 2H), 1.51 (s, 3H), 1.39 (s, 3H), 0.75 (m, 3H). Method 2: RT=1.11 min; M+H=393.3 61 |Ρ ηνΡ ΑΆ· ,Η ^b 1 F Ή NMR (400 MHz, Methanol-b/ ₄ ) δ 8.61 (m, 1H), 8.48-8.38 (m, 1H), 8.15-8.04 (m, 1H), 7, 93 (m, 1H), 7.81-7.74 (m, 1H), 7.53-7.43 (m, 1H), 7.31 (m, 1H), 7.10 (m, 1H) , 6.67 (m, 1H), 2.86-2.75 (m, 1H), 1.89-1.66 (m, 2H), 1.54-1.27 (m, 3H), 1 .06-0.82 (m, ZN). Method 1: RT=3.09 min; M+H=379.3 62 Ε - ΑτΑ>-\ SA Λ AA%j ,. ''Λ·-· ο HN-P ό, Ρ Ή NMR (400 MHz, Methanol-b/ ₄ ) δ 8.748.66 (m, 1H), 8.58 (m, 1H), 8.42 (m, 1H), 8.12-8.04 (m, 1H), 7.92 (m, 1H), 7.78 (m, 1H), 7.45 (m, 1H), 7.31 (m, 1H), 6.67 (m, 1H), 2, 84 (m, 2H), 2.69 (m, 1H), 2.15-2.05 (m, 1H), 1.98-1.67 (m, 3H), 1.51-1.35 ( m, 1H), 1.00 (m, 1H). Method 1: RT=3.26 min; M+H=391.3 63 Μ ΗΝ—4 Αν ^Ν Μ ^ъ 1 F Ή NMR (400 MHz, Methanol-< ₇₄ ) δ 8.71 (m, 1H), 8.59 (m, 1H), 8.42 (m, 1H), 8.128.05 (m, 1H), 7 .95-7.88(m, 1H), 7.78(m, 1H), 7.45(m, 1H), 7.31(m, 1H), 6.70-6.64(m, 1H ), 2.87-2.75 (m, 2H), 1.82-1.56 (m, 3H), 1.05-0.82 (m, 6H). Method 2: RT=1.32 min; M+H=393.3

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64 F ₄ 1] Ή NMR (400 MHz, Methanol-D) δ 9.429.35 (m, 1H), 8.94-8.90 (m, 1H), 8.898.85 (m, 1H), 8.73-8.66 ( m, 1H), 8.518.45 (m, 1H), 8.06-7.89 (m, 3H), 7.817.76 (m, 1H), 7.51-7.40 (m, 2H), 7 .35- 7.29(m, 1H), 6.70-6.64(m, 1H). Method 2: RT=l.01 min; M+H=400.3 65 w HN—/ _: N^ _N ' o ( / ^- Ή NMR (400 MHz, Methanol-D) δ 9.21 (m, 1H), 8.73 (m, 1H), 8.67 (m, 2H), 8.56 (m, 1H), 8.14 (m, 1H), 8.00 (m, 1H), 7.47 (m, 1H), 3.14 (m, 1H), 2.68 (s, 3H), 1.39 (2s, 6H) . Method 1: RT=3.11 min; M+H=391.3 66 HN^ ,.N.. s _z ' o jXhj ' 1 4 Ή NMR (400 MHz, Methanol-D) δ 8.69 (m, 1H), 8.66 (m, 1H), 8.31-8.26 (m, 1H), 8.13 (m, 1H) , 7.76 (m, 1H), 7.39 (m, 1H), 3.13 (m, 1H), 3.03-2.84 (m, 1H), 2.351.70 (m, 6H), 1.38 (m, 7H), 1.06 (m, 3H). Method 1: RT=3.36 min; M+H=381.4 67 F / : ? ⁿ HN A / _z ,< b .... .Ш <_) 1 ' / Ή NMR (400 MHz, Methanol-D) δ 8.748.69 (m, 1H), 8.69-8.64 (m, 1H), 8.648.59 (m, 1H), 8.59-8.53 ( m, 1H), 8.338.26 (m, 1H), 8.16-8.10 (m, 1H), 8.017.94 (m, 1H), 7.86-7.77 (m, 1H), 7 .51- 7.41(m, 1H), 3.14(m, 1H), 1.39(2s, 6H). Method 1: RT=3.22 min; M+H=394.3 68 F-4- 'V Vn _M ^HN 4 o , CF ,W ) Y Ή NMR (400 MHz, Methanol-D) δ 8.73 (m, 1H), 8.67 (m, 1H), 8.48 (m, 1H), 8.14 (m, 1H), 7.91 (m, 1H), 7.47 (m, 1H), 3.193.09 (m, 1H), 2.62 (s, 3H), 1.39 (2s, 6H). Method 1: RT=3.29 min; M+H=448.3

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69 Y ³ ζ ⁼ Ι I τ' ζ Ο g ....... / Ή NMR (400 MHz, Methanol-D δ 8.45 (m, 1H), 8.41 (m, 1H), 8.05 (m, 1H), 7.88 (m, 1H), 7.52 ( m, 1H), 7.15(m, 1H), 2.89(m, 1H), 2.09-2.01(m, 2H), 1.13(2s, 6H), 0.96-0 .83 (m, 1H), 0.42-0.29 (m, 2H), 0.08-0.05 (m, 2H) Method 1: RT=3.06 min; M+H=353 .3 70 F g-D \ / nmD _f ^ ^N ^.N b .. 1. I ... >-ο 'D'' Y Ή NMR (400 MHz, Methanol-D δ 8.72 (m, 1H), 8.67 (m, 1H), 8.56-8.48 (m, 2H), 8.14 (m, 1H), 7.96 (m, 1H), 7.80 (m, 1H), 7.47 (m, 1H), 3.14 (m, 1H), 1.39 (2s, 6H) Method 1: RT= 3.12 min, M+H=412.3 71 F f F HN—D b . ί 0-0 Ύ 'r' Ή NMR (400 MHz, Methanol-D δ 8.69 (m, 1H), 8.66 (m, 1H), 8.30 (m, 1H), 8.158.09 (m, 1H), 7.76 ( m, 1H), 7.40 (m, 1H), 3.18-3.07 (m, 1H), 3.07-2.74 (m, 2H), 2.27-1.73 (m, 6H), 1.56-1.17 (2s, 6H) Method 1: RT=3.35 min, M+H=435.3 72 ΗΝ DD-N l ·$ ъ . L r 'o t' r' Ή NMR (400 MHz, Methanol-D δ 8.71 (m, 1H), 8.66 (m, 1H), 8.36 (m, 1H), 8.14 (m, 1H), 7.84 ( m, 1H), 7.46-7.38 (m, 1H), 6.53-6.45 (m, 1H), 3.14 (m, 1H), 2.54 (s, 3H), 2 .29 (s, 3H), 1.39 (2s, 6H) Method 1: RT=3.31 min, M+H=393.3 73 / / \ - _l ( > 7 'A 4 Z Ζ ΊΊ Ί - o0 Ή NMR (400 MHz, Methanol-D δ 8.72 (m, 1H), 8.67 (m, 1H), 8.44 (m, 1H), 8.28 (m, 1H), 8.14 ( m, 1H), 7.90 (m, 1H), 7.45 (m, 1H), 3.14 (m, 1H), 2.53 (s, 3H), 1.39 (2s, 6H). Method 1: RT=3.00 min, M+H=380.3

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74 CHG HN /, ΐ b LJ..U one ' . Ή NMR (400 MHz, Methanol-^) δ 8.70 (m, 1H), 8.66 (m, 1H), 8.46 (m, 1H), 8.13 (m, 1H), 7.85 (m, 1H), 7.47-7.36 (m, 1H), 3.14 (m, 1H), 2.62 (s, 3H), 2.46 (s, 3H), 1.49- 1.19 (2s, 6H). Method 1: RT=3.23 min; M+H=394.3 75 ,Ν^ ,>Δ A hnA A _v n Ά, ° . L La a ? T'^ _F w Ή NMR (400 MHz, Methanol-^) δ 8.758.69 (m, 1H), 8.69-8.63 (m, 1H), 8.458.39 (m, 1H), 8.16-8.09 ( m, 1H), 7.957.87 (m, 1H), 7.51-7.41 (m, 1H), 3.20- 3.06 (m, 1H), 2.29-2.19 (m, 1H), 1.39 (2s, 6H), 1.27-1.14 (m, 4H). Method 1: RT=3.15 min; M+H=406.3 76 / ___/ n I. i:% z , A l ° Ϊ 7 ^c % Ή NMR (400 MHz, Methanol-^) δ 8.748.68 (m, 1H), 8.69-8.62 (m, 1H), 8.468.39 (m, 1H), 8.16-8.09 ( m, 1H), 7.927.83 (m, 1H), 7.48-7.38 (m, 1H), 3.203.08 (m, 1H), 2.49-2.39 (m, 3H), 2 ,23- 2.12 (m, 1H), 1.38 (2s, 6H), 1.29-1.12 (m, 4H). Method 1: RT=3.24 min; M+H=420.3 77 b A z' - 1 ! . _z c^.ro Ή NMR (400 MHz, Methanol-^) δ 8.728.67 (m, 1H), 8.67-8.63 (m, 1H), 8.398.33 (m, 1H), 8.15-8.09 ( m, 1H), 7.857.77 (m, 1H), 7.45-7.37 (m, 1H), 4.133.97 (m, 2H), 3.22-3.09 (m, 1H), 2 .47- 2.31 (m, 1H), 2.09-1.77 (m, 4H), 1.50 (s, 3H), 1.38 (2s, 6H). Method 1: RT=3.10 min; M+H=383.3 78 F N. Jr ^F '17' ^c iinM\ _r ; ^N ^N b - 1 L^' T~ “ % ^X H NMR (400 MHz, Methanol-^) δ 8.72 (m, 1H), 8.66 (m, 1H), 8.47 (m, 1H), 8.13 (m, 1H), 7, 89 (m, 1H), 7.49-7.41 (m, 1H), 3.14 (m, 1H), 2.63-2.47 (s, 3H), 1.38 (2s, 6H) . Method 1: RT=3.39 min; M+H=448.3

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79 Ο - _λ ~7\ Ho ' zj ⁵ ti t z. z ₄ ίί / \ \ / / Ή NMR (400 MHz, Methanol-^) δ 8.72 (m, 1H), 8.66 (m, 1H), 8.43 (m, 1H), 8.13 (m, 1H), 7.89 (m, 1H), 7.45 (m, 1H), 4.61 (s, 2H), 3.14 (m, 1H), 2.50 (s, 3H), 1.491.34 (2s, 6H) , 1.34-1.20 (s, 9H). Method 1: RT=3.36 min; M+H=466.4 80 /M / > X / MO HNM , _s N n ,W '0 1. X ⁴ ) Ή NMR (400 MHz, Methanol-^) δ 8.69 (m, 1H), 8.66 (m, 1H), 8.36 (m, 1H), 8.13 (m, 1H), 7.80 (m, 1H), 7.41 (m, 1H), 4.16 (m, 1H), 3.97 (m, 1H), 3.60 (m, 1H), 3.13 (m, 1H) , 2.12-2.04 (m, 1H), 2.01-1.92 (m, 1H), 1.75-1.49 (m, 4H), 1.38 (2s, 6H). Method 1: RT=3.17 min; M+H=383.3 81 iλ . o' Ύ Mn HN / ML-N 4 / O L O O T/' Ή NMR (400 MHz, Methanol-^) δ 8.748.68 (m, 1H), 8.68-8.63 (m, 1H), 8.498.44 (m, 1H), 8.16-8.09 ( m, 1H), 7.957.87 (m, 1H), 7.50-7.39 (m, 1H), 3.213.06 (m, 1H), 2.39 (s, 3H), 2.19 (s , 3H), 1.38 (2s, 6H). Method 1: RT=3.18 min; M+H=394.3 82 4 .) MN hnM W- -Ν -M b t ^s ..... ^s % Ή NMR (400 MHz, Methanol-^) δ 8.768.69 (m, 2H), 8.67 (m, 1H), 8.59 (m, 1H), 8.24 (m, 1H), 8.14 (m, 1H), 8.07-7.96 (m, 2H), 7.62 (m, 1H), 7.47 (m, 1H), 3.14 (m, 1H), 1.57- 1.21 (2s, 6H). Method 1: RT=3.18 min; M+H=376.3 83 N., _, , ''''Г Ή m ^{Η Ν} i ..ΧΧ ^Ν 0 ⁰ 1 f ^z Ή NMR (400 MHz, Methanol-^) δ 8.748.69 (m, 1H), 8.68-8.63 (m, 1H), 8.468.40 (m, 1H), 8.16-8.11 ( m, 1H), 7.947.87 (m, 1H), 7.79-7.75 (m, 1H), 7.50- 7.41 (m, 1H), 3.21-3.07 (m, 1H), 2.59 (s, 3H), 1.39 (2s, 6H). Method 1: RT=3.01 min; M+H=380.3

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84 N Л s____/ Μ ΗΝγ _% £ x_.,N 0 . _p / Ή NMR (400 MHz, Methanol-^) δ 9.06 (m, 1H), 8.73 (m, 1H), 8.67 (m, 1H), 8.60 (m, 1H), 8.45 -8.34(m, 2H), 8.17-8.12(m, 1H), 8.01(m, 1H), 7.48(m, 1H), 3.14(m, 1H), 1.39 (2s, 6H). Method 1: RT=3.15 min; M+H=401.3 85 €r HN Z ^ ^N - _.,N z ( b Г ' N f '% Y ^z Ή NMR (400 MHz, Methanol-^) δ 8.71 (m, 1H), 8.66 (m, 1H), 8.47 (m, 1H), 8.41 (m, 1H), 8.14 (m, 1H), 7.90 (m, 1H), 7.45 (m, 1H), 3.14 (m, 1H), 1.39 (2s, 6H). Method 1: RT=3.08 min; M+H=380.3 86 F-4 b-Cl >N hnY / ¹ ^. 0 L b ' ^N ^\ / Ύ ~ Ή NMR (400 MHz, Methanol-^) δ 8.73 (m, 1H), 8.67 (m, 1H), 8.51 (m, 1H), 8.14 (m, 1H), 7.95 (m, 1H), 7.86 (m, 1H), 7.73 (m, 1H), 7.48 (m, 1H), 3.20-3.08 (m, 1H), 1.45- 1.20 (2s, 6H). Method 1: RT=3.22 min; M+H=428.3 87 N=x four ) YN hnY f Y : '° i' F Ή NMR (400 MHz, Methanol-^) δ 9.36 (m, 1H), 8.84 (m, 1H), 8.76 (m, 1H), 8.72 (m, 1H), 8.66 (m, 1H), 8.57 (m, 1H), 8.13 (m, 1H), 7.99 (m, 1H), 7.46 (m, 1H), 3.13 (m, 1H) , 1.38 (2s, 6H). Method 1: RT=3.05 min; M+H=377.3 88 HN 4 A _V N /, ( 'bx £ Y ^N Y T ' / ' Ή NMR (400 MHz, Methanol-^) δ 8.69 (m, 1H), 8.66 (m, 1H), 8.36 (m, 1H), 8.12 (m, 1H), 7.81 (m, 1H), 7.41 (m, 1H), 4.46 (m, 1H), 4.12 (m, 1H), 3.94 (m, 1H), 3.13 (m, 1H) , 2.36 (m, 1H), 2.10 (m, 1H), 1.97 (m, 2H), 1.38 (2s, 6H). Method 1: RT=2.93 min; M+H=369.3

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89 __ 'z. |---y /I h I 'z' τιΛ II 'z-n J, Λ ' - ,J 0 Ή NMR (400 MHz, Methanol-d4) δ 8.73 (m, 1H), 8.66 (m, 1H), 8.43 (m, 1H), 8.14 (m, 1H), 7.92 -7.85(m, 1H), 7.76(m, 1H), 7.59(m, 1H), 7.46(m, 1H), 7.30(m, 1H), 3.14( m, 1H), 1.38 (d, J=6.9 Hz, 6H). Method 1: RT=3.35 min; M+H=427.3 90 one HNi /, ( b . - 1 E / 1F Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.69 (m, 1H), 8.65 (m, 1H), 8.28 (m, 1H), 8.13 (m, 1H), 7, 74 (m, 1H), 7.39 (m, 1H), 3.13 (m, 1H), 1.79 (m, 1H), 1.38 (2s, 6H), 1.0ΙΟ.84 (m , 4H). Method 1: RT=3.07 min; M+H=339.3 91 <•1 4 o , o .1 Z A i - Z O Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.648.57 (m, 2H), 8.14-8.09 (m, 1H), 7.947.89 (m, 1H), 7.66-7.59 (m, 1H), 7.367.29 (m, 1H), 4.17-4.05 (m, 4H), 2.392.26 (m, 2H), 2.17-2.06 (m, 1H), 1.13-1.04 (m, 2H), 0.87-0.77 (m, 2H). Method 1: RT=2.82 min; M+H=352.3 92 _Z N ₄ ,^ _N \=, [ J' Nl I -< M, 0 f 4-j hnX 1 N / » 1 NMR (400 MHz, DMSO) δ 8.69 (s, 1 H), 8.62 (d, 7=2.64 Hz, 1 H), 8.36 (d, 7=2.76 Hz, 1 H ), 8.22 (dd, 7=7.09, 2.70 Hz, 1 H), 7.65-7.72 (m, 1 H), 7.42 (dd, 7=11.29, 9 .16Hz, 1H), 7.15(d, 7=2.89Hz, 1H), 4.41(t, 7=12.23Hz, 4H), 3.98(t, 7= 7.53 Hz, 4 H), 2.20 (quintal, 7=7.56 Hz, 2 H). Method 1: RT=2.81 min. M+H=403.2 93 1 cf ~ T z Z F 'Λ ;l / \ 7 • X Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.768.65 (m, 1H), 8.64-8.58 (m, 1H), 8.148.06 (m, 1H), 7.67-7.60 (m, 1H), 7.387.30 (m, 1H), 7.18-7.01 (m, 1H), 4.173.96 (t, 4H), 3.84-3.69 (t, 1H), 2.62-2.09 (t, 7H), 2.04-1.93 (t, 1H). Method 1: RT=2.94 min; M+H=366.3

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94 f ,N„ _N >=-. _p HN—< N-, Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.718.66 (m, 1H), 8.56-8.50 (m, 1H), 8.158.09 (m, 1H), 8.09-8.04 (m, 1H), 7.687.60 (m, 1H), 7.38-7.30 (m, 1H), 4.184.04 (m, 4H), 2.69 (s, 2H), 2.40- 2.27 (m, 2H), 0.99 (s, 9H). Method 1: RT=3.19 min; M+H=382.4 95 i IN-P y, _{N /r} i '0 ! 1 > 1F Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.698.64 (m, 1H), 8.62-8.56 (m, 1H), 8.158.05 (m, 2H), 7.67-7.61 (m, 1H), 7.377.30 (m, 1H), 4.17-4.05 (m, 4H), 2.842.75 (m, 2H), 2.39-2.26 (m, 2H), 1.801.66 (m, 2H), 1.48-1.34 (m, 4H), 1.0Ι-Ο.87 (m, 3H). Method 1: RT=3.22 min; M+H=382.4 96 r\ N- f IN^( J£_ _N b 1 * / 1 F Ή NMR (400 MHz, Methanol-^) δ 8.65 (m, 1H), 8.59 (m, 1H), 8.15-8.06 (m, 2H), 7.64 (m, 1H) , 7.34 (m, 1H), 4.17-4.05 (m, 4H), 2.85-2.76 (m, 2H), 2.32 (m, 2H), 1.78-1 .64 (m, 2H), 1.43 (m, 3H), 1.00 (m, 3H). Method 1: RT=3.13 min; M+H=368.3 97 P L AND X Λ X .£ J Z to cf° Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.718.62 (m, 1H), 8.63-8.52 (m, 1H), 8.148.07 (m, 1H), 8.07-8.01 (m, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 4.19-4.04 (m, 4H), 2.87 (m, 2H), 2.68 ( m, 1H), 2.39-2.27(m, 2H), 2.16-2.03(m, 2H), 1.99-1.76(m, 4H). Method 1: RT=3.11 min; M+H=380.3 98 > \ N- ^J hn—£ .<>nn ^4' b XX >4 X ^Г 1 ' ^X H NMR (400 MHz, Methanol-b/ ₄ ) δ 8.65 (m, 1H), 8.57 (m, 1H), 8.15-8.02 (m, 2H), 7.64 (m , 1H), 7.33 (m, 1H), 4.18-4.01 (m, 4H), 2.92-2.69 (m, 2H), 2.32 (m, 2H), 1, 84-1.53 (m, 3H), 1.06-0.89 (m, 6H). Method 1: RT=3.18 min; M+H=382.4

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99 Λ A P A g 'z' A' :/ Ή NMR (400 MHz, Methanol-A) δ 9.37 (m, 1H), 8.87 (m, 2H), 8.70 (m, 1H), 8.17 (t, 1H), 8.05 -7.92 (m, 2H), 7.66 (m, 1H), 7.43 (m, 1H), 7.36 (m, 1H), 4.17-4.07 (t, 4H), 2.33 (m, 2H). Method 1: RT=2.66 min; M+H=389.3 100 V \ N- ^J HN^i A-A .Η. ^{b J} .....-A Ή NMR (400 MHz, DMS0-d6) δ 8.78 (d, J=2.63 Hz, 1 Η), 8.73 (s, 1 Η), 8.68 (d, J=2.38 Hz , 1 Η), 8.24 (dd, J=7.03, 2.76 Hz, 1 Η), 8.05 (d, J=l.88 Hz, 1 Η), 7.66-7.73 (m, 1 H), 7.44 (dd, J=11.29, 9.16 Hz, 1 H), 3.98 (t, J=7.59 Hz, 4 H), 3.02-3 .14 (m, 1 Η), 2.10-2.27 (m, 2 Η), 1.30 (d, J=6.90 Hz, 6 H). Method 2: RT=0.94 min; M+H=354,l 101 about Zf ΤΊ .Jb c^Ya? 6-4 Ή NMR (400 MHz, Methanol-A) δ 9.07 (m, 1H), 8.79 (m, 1H), 8.49 (m, 1H), 7.87 (t, 1H), 7.52 -7.43 (m, 1H), 7.36-7.29 (t, 1H), 2.69-2.56 (m, 2H), 2.55 (t, 3H), 2.46 (t , ZN), 2.34-2.12 (t, ZN), 2.07-1.93 (t, 2H). Method 1: RT=3.08 min; M+H=406.3 102 z ^N ^ Y-8 HN 4 .rA Ν Λ _λ < b A d _ ⁿ o F ^Z Ή NMR (400 MHz, Methanol-A) δ 8.83 (m, 1H), 8.62 (m, 1H), 8.48 (m, 1H), 8.258.20 (m, 1H), 7.92 -7.86 (m, 1H), 7.507.43 (m, 1H), 2.73 (s, 2H), 2.55 (w, W), 2.46 (w, W), 1.00 ( m, 9H). Method 1: RT=3.28 min; M+H=422.3 103 Ύ HN { ^ ⁿ _a .-n 4 b U.,C ^N o and ' / Ή NMR (400 MHz, Methanol-A) δ 8.798.68 (m, 2H), 8.13 (m, 1H), 7.98-7.91 (br, 1H), 7.47-7.38 ( m, 1H), 7.31-7.24 (br, 1H), 2.55 (br, 3H), 2.46 (br, 3H), 1.55 (br, 9H). Method 1: RT=2.90 min; M+H=408.3

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104 . AND . ·Λ-o' ΗΝ 4 W-N l / Ό . . LL? Q Ή NMR (400 MHz, Methanol-^) δ 8.86 (m, 1H), 8.78 (m, 1H), 8.14 (m, 1H), 7.94 (m, 1H), 7.42 (m, 1H), 7.38-7.32 (m, 1H), 2.54 (m, 3H), 2.46 (m, 3H), 1.98-1.81 (m, 2H), 1.53 (s, 3H), 1.42 (s, 3H), 0.84-0.74 (m, 3H). Method 1: RT=2.96 min; M+H=422.4 105 Vo ΗΝ 4 A- ν-Ν Ζ- / b ...... A Ο 1 ' / Ή NMR (400 MHz, Methanol-04) δ 8.788.70 (m, 1H), 8.67-8.58 (m, 1H), 8.528.42 (m, 1H), 7.92-7.84 ( m, 1H), 7.527.44 (m, 1H), 7.27 (m, 1H), 2.55 (m, 3H), 2.46 (m, 3H), 1.89 (m, 2H), 1.53-1.40 (m, 3H), 1.04-0.89 (m, 3H), 0.80 (m, 1H). Method 1: RT=3.13 min; M+H=408.3 106 Χο ζ J. ~ χ Ή NMR (400 MHz, Methanol-04) δ 8.77 (m, 1H), 8.62 (m, 1H), 8.45 (m, 1H), 8.17 (m, 1H), 7.88 (m, 1H), 7.45 (m, 1H), 2.90 (m, 2H), 2.74-2.65 (m, 1H), 2.55 (s, 3H), 2.46 ( s, 3H), 2.10 (m, 2H), 1.96-1.80 (m, 4H). Method 1: RT=3.24 min; M+H=420.3 107 hL ΗΝ 4 _. _Ν / ( '0 dr Ο 1 F Ή NMR (400 MHz, Methanol X) δ 8.85 (m, 1H), 8.73-8.66 (m, 1H), 8.49 (m, 1H), 8.31 (m, 1H), 7 .87 (m, 1H), 7.46 (m, 1H), 2.88-2.80 (m, 2H), 2.55 (s, 3H), 2.46 (s, 3H), 1, 72-1.59 (m, 3H), 1.03-0.92 (m, 6H). Method 1: RT=3.3O min; M+H=422.4 108 . Zh.-- ΗΝΧ χ ν /Н ^ъ .ν. I ΧΗ_>U' ~ Ή NMR (400 MHz, Methanol X) δ 9.38 (m, 1H), 8.96 (m, 1H), 8.92 (m, 1H), 8.798.71 (m, 1H), 8.50 (m , 1H), 8.12-8.04 (m, 2H), 7.90 (m, 1H), 7.56-7.42 (m, 2H), 2.55 (m, 3H), 2, 47 (m, ZN). Method 1: RT=2.78 min; M+H=429.3

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109 7 L X . Ύ G G N f L T'^ Ή NMR (400 MHz, Methanol-^) δ 8.71 (m, 1H), 8.66 (m, 1H), 8.42 (m, 1H), 8.14 (dd, 7=2.2, 0.7 Hz, 1H), 7.91 (ddd, 7=9.1, 4.2, 2.7 Hz, 1H), 7.44 (dd, 7=11.0, 9.1 Hz, 1H ), 7.21 (d, 7=3.4 Hz, 1H), 6.31-6.24 (br, 1H), 3.14 (p, 7=6.9 Hz, 1H), 2.44 (s, 3H), 1.49-1.29 (m, 6H). Method 2: RT=l.07 min; M+H=379.3 110 HN N/. ( ъ hala v/ G / Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.71 (m, 1H), 8.66 (m, 1H), 8.38 (m, 1H), 8.14 (m, 1H), 7, 87 (m, 1H), 7.43 (m, 1H), 7.29 (br, 1H), 5.57 (m, 1H), 4.02-3.89 (br, 3H), 3.18 -3.10 (m, 1H), 1.39 (2s, 6H). Method 2: RT=l.05 min; M+H=395.3 111 %-o / HN / I ^ъ A. .VV / G D Ή NMR (400 MHz, Methanol-b4) δ 8.73 (m, 1H), 8.66 (m, 1H), 8.45 (m, 1H), 8.14 (br, 1H), 7.92 (m, 1H), 7.46 (m, 1H), 7.23 (br, 1H), 6.55 (m, 1H), 3.65 (s, 2H), 3.14 (br, 1H) , 2.37(2s, 6H), 1.47-1.31(2s, 6H). Method 2: RT=0.74 min; M+H=422.3 112 / ------( 2 \ BUT x. ΪX Z Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.73 (m, 1H), 8.67 (m, 1H), 8.47 (m, 1H), 8.14 (br, 1H), 7, 93 (m, 1H), 7.54-7.40 (br, 3H), 3.16-3.09 (m, 1H), 1.39 (2s, 6H). Method 2: RT=l.08 min; M+H=390.3 FROM • F \ T L-o HN { ^-^ ζ l O . A AD < ) _γ .X - Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.72 (m, 1H), 8.67 (m, 1H), 8.40 (m, 1H), 8.14 (br, 1H), 7, 89 (m, 1H), 7.45 (m, 1H), 7.31 (m, 1H), 5.90 (t, 1H), 3.19-3.10 (t, 1H), 1.39 (2s, 6H). Method 2: RT=l.07 min; M+H=383.3

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114 -u......= • y- 'LL z z?? u '.........\ X Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.70 (m, 1H), 8.66 (m, 1H), 8.40 (m, 1H), 8.13 (m, 1H), 7, 89 (m, 1H), 7.48-7.38 (m, 1H), 7.09 (m, 1H), 3.14 (m, 1H), 2.40-2.21 (m, 3H) , 2.03 (m, 3H), 1.62-1.15 (2s, 6H). Method 2: RT=1.13 min; M+H=393.3 115 —l/ b hd HN / hh-.N /, i '0 , t O 'O τ ^v / Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.71 (m, 1H), 8.66 (m, 1H), 8.42 (m, 1H), 8.13 (m, 1H), 7, 87 (m, 1H), 7.60 (m, 1H), 7.42 (m, 1H), 6.51 (m, 1H), 3.14 (m, 1H), 2.41 (s, 3H ), 1.44-1.26 (2s, 6H). Method 2: RT=1.11 min; M+H=379.3 116 ύ Vd Hbih hv- ^N <Η ^ъ ...AX ⁿ 4j 1 F Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.72 (m, 1H), 8.66 (m, 1H), 8.50 (m, 1H), 8.13 (m, 1H), 7, 97 (m, 1H), 7.79-7.74 (m, 1H), 7.69-7.62 (m, 2H), 7.53-7.42 (m, 2H), 7.39- 7.31(m, 1H), 3.13(m, 1H), 1.38(2s, 6H). Method 2: RT=1.17 min; M+H=415.3 117 F ^F UP ' W d 4—/ F Ή NMR (400 MHz, Methanol) δ 8.70 (m, 1H), 8.66 (m, 1H), 8.32 (m, 1H), 8.13 (m, 1H), 7.79 (m , 1H), 7.41 (m, 1H), 3.193.04 (m, 3H), 2.60-2.47 (m, 2H), 1.61 (s, 3H), 1.38 (2s, 6H). Method 2: RT=1.12 min; M+H=403.3 118 X ^F HNh h .-x ъ . λ T .. .. Ή NMR (400 MHz, Methanol) δ 8.70 (m, 1H), 8.66 (m, 1H), 8.32 (m, 1H), 8.13 (m, 1H), 7.77 (m , 1H), 7.41 (m, 1H), 3.213.05 (m, 2H), 2.98-2.72 (m, 4H), 1.571.19 (2s, 6H). Method 2: RT=l.08 min; M+H=389.3

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Ή NMR (400 MHz, Methanol-/ ₄ ) δ 8.69 (m, 1H), 8.66 (m, 1H), 8.35 (m, 1H), 8.13 (m, 1H), 7, 82 (m, 1H), 7.40 (m, 1H), 4.33 (m, 3H), 4.25 (m, 3H), 3.73 (s, 3H), 3.13 (m, 1H ), 1.43-1.28 (2s, 6H). Method 2: RT=l.07 min; M+H=459.3

Ή NMR (400 MHz, Methanol-/ ₄ ) δ 8.69 (m, 1H), 8.66 (m, 1H), 8.33 (m, 1H), 8.13 (m, 1H), 7, 81 (m, 1H), 7.41 (m, 1H), 3.763.64 (m, 3H), 3.13 (m, 1H), 2.48-2.26 (m, 6H), 1.48 -1.17 (2s, 6H). Method 2: RT=l.04 min; M+H=423.3

Ή NMR (400 MHz, Methanol-/ ₄ ) δ 8.70 (m, 1H), 8.66 (m, 1H), 8.31 (m, 1H), 8.13 (m, 1H), 7, 75 (m, 1H), 7.40 (m, 1H), 5.375.12 (m, 1H), 3.29-3.22 (m, 1H), 3.14 (m, 1H), 2.73 -2.41 (m, 4H), 1.60-1.16 (2s, 6H). Method 1: RT=3.06 min;

M+H=371.3

Ή NMR (400 MHz, Methanol-/ ₄ ), δ 8.86 (s, 1 Η), 8.81 (s, 1 Η), 7.63-7.67 (m, 1 Η), 8.51 (dd, /=6.72, 2.45 Hz, 1 H), 7.92 (brs, 1 H), 7.85-7.89 (m, 1 H), 7.77 (s, 1 H ), 7.46 (dd,/=11.07, 9.11 Hz, 1 Η), 7.31 (d,/=3.55 Hz, 1 Η), 6.67 (dd, /=3, 48, 1.77 Hz, 1 Η), 3.90-3.93 (m, 4 Η), 3.25-3.28 (m, 4 Η). Method 1: RT=2.65 min; M+H=408,l

Ή NMR (400 MHz, Methanol-/ ₄ ), δ 8.918.94 (brs, 2 H), 8.73 (brs, 1 H), 8.54 (dd, /=6.78, 2.64 Hz, 1 H), 7.87-7.91 (w, 1 H), 7.78 (s, 1 H), 7.47 (dd, /=10.85, 9.10 Hz, 1 H), 7 .32 (d, /=3.14 Hz, 1 H), 6.67 (dd, /=3.51, 1.76 Hz, 1 H), 5.01-5.09 (br, 1 H) , 1.35 (d, /=6.15 Hz, 6 H). Method 1: RT=3.03 min; M+H=424.1

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Ή NMR (400 MHz, DMSO-d6) δ 9.24 (br s, 1 Η), 8.80 (d, J=2.51 Hz, 1 Η), 8.69 (d, J=2.13 Hz, 1 H), 8.22 (dd, 1=7.03, 2.64 Hz, 1 H), 8.05 (d, 1=2.01 Hz, 1 H), 7.63-7, 74 (m, 1 Η), 7.49 (dd, 1=11.17, 9.29 Hz, 1 Η), 4.41 (t, 1=12.74 Hz, 4 Η), 3.08 ( fifth, 1=6.81 Hz, 1 N), 1.30 (d, 1=6.90 Hz, 6 N). Method 1: RT=3.07 min; M+H=390.1

Ή NMR (400 MHz, DMSO-7 ₆ ), δ 9.25 (s, 1 Η), 8.91 (br s, 1 H), 8.76 (br s, 1 H), 8.63 (br s, 1 H), 8.25 (br s, 1 H), 7.69 (br s, 1 H), 7.51 (br t, 7=10.16 Hz, 1 H), 4.41 ( br t, 7=12.67 Hz, 4 H). Method 1: RT=2.98 min.

Ή NMR (400 MHz, DMSO-7 ₆ ), δ 8.98 (s, 1 H), 8.90 (d, 7=2.51 Hz, 1 H), 8.76 (d, 7=2, 51 Hz, 1 H), 8.63 (d, 7=2.51 Hz, 1 H), 8.24 (dd, 7=7.03, 2.76 Hz, 1 H), 7.67-7 .74 (m, 1 H), 7.49 (dd, 7=11.17, 9.16 Hz, 1 H), 5.29-5.51 (m, 1 H), 4.25-4, 39 (m, 2H), 3.96-4.10 (m, 2H).

Method 1: RT=2.82 min.

Ή NMR (400 MHz, DMSO-J ₆ ), δ 8.90 (d, 7=2.26 Hz, 1 Η), 8.76 (d, 7=2.51 Hz, 1 Η), 8.66 (s, 1 H), 8.63 (d, 7=2.26 Hz, 1 H), 8.27 (dd, 7=7.03, 2.76 Hz, 1 H), 7.71-7 .77 (m, 1 Η), 7.48 (dd, 7=11.17, 9.16 Hz, 1 Η), 5.285.48 (m, 1 Η), 3.40-3.78 (m, 4 H), 2.012.27 (m, 2 H). Method 1: RT=2.89 min.

1H NMR (400 MHz, DMSO-7,), δ ^10.53 (s, 1 Η), 8.94 (d, 7=2.51 Hz, 1 Η), 8.77 (d, 7=2 .26 Hz, 1 Η), 8.64 (d, 7=2.26 Hz, 1 Η), 8.58 (dd, 7=7.15, 2.64 Hz, 1 Η), 7.89- 7.97 (m, 1 Η), 7.59 (dd, 7=11.17, 9.16 Hz, 1 Η), 2.52-2.53 (s, 3 Η), 2.40 (s , 3H). Method 1:

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RT=3.03 min. 129 ^: ί ^ζ 22'Τ' ΐ /1 ζ .у £ Ή NMR (400 MHz, DMSO-d6), δ 8.89 (d, 1=2.01 Hz, 1 Η), 8.70-8.80 (m, 2 Η), 8.62 (d, 1 =2.26 Hz, 1 H), 8.25 (dd, J=6.90, 2.38 Hz, 1 H), 7.72 (br d, 1=9.03 Hz, 1 H), 7 .46 (br t, 1=10.16 Hz, 1 Η), 3.98 (br t, 1=7.53 Hz, 4 Η), 2.20 (quint., 1=7.59 Hz, 2 N). Method 1: RT=2.82 min. 130 R / m to Wi / _η Ilf ''—k ο HN—Υ o D Ή NMR (400 MHz, DMSO-2 ₆ ), δ 10.58 (br s, 1 Η), 8.94 (d, 2=2.26 Hz, 1 Η), 8.77 (d, 2=2 .26 Hz, 1 Η), 8.64 (d, 2=2.26 Hz, 1 Η), 8.53 (dd, 2=7.03, 2.51 Hz, 1 Η), 7.928.02 ( m, 2 H), 7.60 (dd, 2=11.04, 9.29 Hz, 1 H), 7.40 (d, 2=3.26 Hz, 1 H), 6.74 (dd, 2=3.26, 1.51 Hz, 1 H). Method 1: RT=2.98 min. 131 f ΗΝ 4 J^N, // { ^b . i. m <> , _τ ^,' - >-/ VJ ^h Ή NMR (400 MHz, Methanol-D), δ 8.47 (d, 2=2.89 Hz, 1 H), 8.38 (d, 2=2.63 Hz, 1 H), 8.07 ( dd, 2=6.84, 2.70 Hz, 1 H), 7.587.62 (t, 1 H), 7.31 (dd, 2=11.11, 9.10 Hz, 1 H), 7, 00 (d, 2=2.76 Hz, 1 H), 5.27-5.46 (m, 1 H), 4.33-4.43 (t, 2 H), 4.08-4.18 ( t, 2H), 3.40 (t, 2=6.53 Hz, 4 H), 2.05-2.12 (t, 4 H). Method 1: RT=3.01 min; M+H=399.1 132 F / N- ³ ην^; .-. _ν ι:,α ^ν '-7 i,” Ή NMR (400 MHz, Methanol-D), δ 8.47 (d, 2=2.89 Hz, 1 H), 8.38 (d, 2=2.63 Hz, 1 H), 8.07 ( dd, 2=6.84, 2.70 Hz, 1 H), 7.587.62 (t, 1 H), 7.31 (dd, 2=11.11, 9.10 Hz, 1 H), 7, 00 (d, 2=2.76 Hz, 1 H), 5.27-5.46 (t, 1 H), 4.33-4.43 (t, 2H), 4.08-4.18 ( t, 2H), 3.40 (t, 2=6.53 Hz, 4 H), 2.05-2.12 (t, 4 H). Method 1: RT=2.65 min; M+H=415.2

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Ή NMR (400 MHz, METAHOJI-d4) δ 8.96 (br s, 1 H), 8.87 (s, 1 H), 8.32 (dd, Ή J=6.27, 2.01 Hz, 1 H), 8.21 (br d, J=4.27 133 HN JY „N /. Z . .1 £± 0 N > i Ό Hz, 1 H), 7.54-7.71 (m, 1 H), 7.41 (dd, J=10.92, 9.16 Hz, 1 H), 5.22-5.49 (m , 1 H), 3.52-3.89 (m, 4 H), 3.21 (d, J=l.25 Hz, 6 1F H), 2.03-2.46 (m, 2H). Method 1: RT=2.75 min; M+H=387,l Ή NMR (400 MHz, Methanol-7 ₄ ), δ 8.69 (d, 7=2.26 Hz, 1 Η), 8.58 (d, 7=2.51 Hz, 1 Xi N- ^J Η), 8.21 (dd, 7=6.84, 2.70 Hz, 1 Η), 7.57- 134 H NO Ή I NO > 7.61 (m, 1 Η), 7.51 (d, 7=2.64 Hz, 1 Η), 7.36 (dd, 7=10.98, 9.10 Hz, 1 Η), 5, 27-5.40 \d ^F < G (m, 1H), 3.43-3.84 (m, 8H), 1.99-2.37 (m, 6H). Method 1: RT=2.98 min; M+H=413,l Ή NMR (400 MHz, Methanol-D, δ 8.979.03 (m, 2 Η), 8.26-8.31 (m, 2 Η), 7.58- 135 λ > z ,) four <(z 'Z EE ^NJ 0 7.62 (m, 1 Η), 7.37 (dd, 7=10.92, 9.16 Hz, 1 Η), 5.27-5.40 (m, 1 Η), 3.90-3 .93 (m, 4H), 3.55-3.84 (m, 4H), 3.31-3.33 (m, <O ^F 4H), 1.97-2.36 (m, 2H). Method 1: RT=2.58 min; M+H=429,l Ή NMR (400 MHz, Methanol-X), δ 8.62 (dd, 7=9.10, 2.32 Hz, 2 H), 8.44 (brs, 1 H), 136 'γ'' N—' HN about O X ... N 0 'I! ,N- 8.10 (dd, 7=6.78, 2.64 Hz, 1 H), 7.60-7.64 (br, 1 H), 7.34 (dd, 7=10.92, 9.16 Hz, 1 H), 5.26-5.39 (w, 1 H), 4.98-5.04 (m, 1 H), 0'N' ^- HH 3.53-3.82 (m, 4H), 2.07-2.35 (t, 2 H), 1.33 (d, 7=2.67 Hz, 6 H). Method 1: RT=2.92 min; M+H=445.1

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137 C .. Y-J Ύ ί> r z ΛΑ ζ 7 M' Z- / \ Ή NMR (400 MHz, Methanol-^), δ 8.68 (d, 7=2.76 Hz, 1 Η), 8.54 (d, >2.38 Hz, 1 Η), 8.09 (dd , >6.84, 2.70 Hz, 1 Η), 7.607.64 (m, 1 Η), 7.53 (d, 7=2.64 Hz, 1 Η), 7.32 (dd, 7= 10.98, 9.10 Hz, 1 Η), 4.11 (t, 7=7.65 Hz, 4 Η), 3.90-3.92 (m, 4 Η), 3.193.21 (m, 4 Η), 2.29-2.36 (m, 2 Η). Method 1: RT=2.58 min; M+H=397.2 138 £ ί IN Υ l A f ^{J b} Ό''N'' n g Ή NMR (400 MHz, Methanol-7 ₄ ), δ 8.618.63 (m, 2 Η), 8.45 (brs, 1 Η), 8.09 (dd, 7=6.78, 2.64 Hz, 1 Η), 7.62-7.64 (m, 1 Η), 7.30-7.35 (m, 1 Η), 7.30-7.35 (m, 1 Η), 4.98- 5.04 (m, 1H), 4.11 (t, 7=7.65 Hz, 4 H), 2.32 (t, 7=7.62 Hz, 2 H), 1.33 (d, 7 \u003d 6.15 Hz, 6 Η). Method 1: RT=2.87 min; M+H=413,l 139 th HN / > £ y l { b G £4 5 Η ρ· Ή NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1 Η), 8.43-8.63 (m, 2 Η), 8.35 (d, J=2.76 Hz, 1 Η ), 7.98 (d, >1.00 Hz, 1 Η), 7.827.94 (m, 1 Η), 7.53 (dd, J=11.29, 9.03 Hz, 1 Η), 7 .39 (d, J=3.01 Hz, 1 Η), 6.67-6.84 (m, 2 Η), 6.09 (q, J=4.77 Hz, 1 Η), 2.73 (d, J=5.02 Hz, 3 Η). Method 1: RT=2.67 min; M+H=352.0 140 i HN Ζ Yr-L A < ⁶ χ £ £/ C7 'N' / ⁷ 1 F' Ή NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1 Η), 8.71 (d, >3.01 Hz, 1 Η), 8.58 (d, J=2.76 Hz, 1 Η), 8.49 (dd, J=7.15, 2.64 Hz, 1 Η), 7.98 (d, J=l.00 Hz, 1 Η), 7.86-7.94 ( m, 1 H), 7.54 (dd, >11.42, 9.16 Hz, 1 H), 7.39 (d, J=3.51 Hz, 1 H), 7.16 (d, J =2.76 Hz, 1 Η), 6.73 (dd, J=3.39, 1.63 Hz, 1 Η), 2.96 (s, 6 Η). Method 1: RT=2.82 min; M+H=366,l

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141 R fNO /-- _N ----- o \ J hnA 7=-=, 6, Ί Ή NMR (400 MHz, Methanol-/ ₄ ), δ 8.48 (d, /=2.89 Hz, 1 H), 8.42 (d, /=2.51 Hz, 1 H), 8.35 (dd, /=6.90, 2.64 Hz, 1 Η), 7.767.89 (m, 1 Η), 7.76 (d, /=0.88 Hz, 1 Η), 7.40 (dd , /=11.04, 9.03 Hz, 1 Η), 7.30 (d, /=3.26 Hz, 1 Η), 7.01 (d, /=2.76 Hz, 1 Η), 6.66 (dd, /=3.45, 1.69 Hz, 1 H), 3.39-3.42 (m, 4 H), 2.07-2.10 (m, 4 H). Method 1: RT=3.18 min; M+H=392.2 142 iz C _z ) ( < ,z I I lx A 1 Ή NMR (400 MHz, METAHOJI-d4) δ 8.68 (d, J=2.45 Hz, 1 Η), 8.52 (br s, 1 Η), 8.17 (dd, J=6.85 , 2.69 Hz, 1 Η), 7.54 (d, J=2.45 Hz, 1 Η), 7.42-7.50 (m, 1 Η), 7.35 (dd, J=11 .00, 9.05 Hz, 1 Η), 2.95 (s, 3 Η), 2.80 (s, 3 Η). Method D RT=2.56 min; M+H=315.1 143 \N—HN—4 <1 -. ...N /ri b nX ^z N )— 1 Ή NMR (400 MHz, METAHOJI-d4) δ 9.00 (d, J=2.01 Hz, 1 Η), 8.91 (d, J=2.76 Hz, 1 Η), 8.31 (d , J=2.76 Hz, 1 Η), 8.25 (dd, J=6.78, 2.51 Hz, 1 Η), 7.54-7.62 (m, 1 Η), 7.40 (dd, J= 10.92, 9.16 Hz, 1 H), 3.24 (s, 6 H), 3.07 (s, 6 H). Method 1: RT=2.60 min; M+H=343,l 144 % ^J 00 z z > C 0 /^ z .. L / Ή NMR (400 MHz, DMSO), δ 9.19 (s, 1 Η), 8.53 (d, /=2.69 Hz, 1 Η), 8.26 (d, /=2.69 Hz, 1 H), 8.19 (dd, /=6.97, 2.69 Hz, 1 H), 7.61-7.65 (m, 1 H), 7.45 (dd, /=11.37 , 9.17 Hz, 1 Η), 6.88 (d, /=2.81 Hz, 1 Η), 4.40 (t, /=12.65 Hz, 4 Η), 3.91 (d, /=7.15 Hz, 4 Η), 2.32-2.39 (m, 2 Η). Method 1: RT=2.82 min; M+H=403,l

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145 [ Ν—4 d _Ν Ή o ο J ¹ 7 Ή NMR (400 MHz, DMSO), δ 9.20 (s, 1 Η), 8.74 (d, 7=2.81 Hz, 1 Η), 8.65 (d, 7=2.69 Hz, 1 Η), 8.21 (dd, 7=7.09, 2.69 Hz, 1 Η), 7.64-7.68 (m, 1 Η), 7.47 (dd, 7=11.31 , 9.11 Hz, 1 Η), 7.40 (d, 7=2.81 Hz, 1 Η), 4.41 (t, 7=12.65 Hz, 4 Η), 3.79-3, 82 (m, 4H), 3.14-3.16 (m, 4H). Method 1: RT=2.65 min; M+H=433,l 146 Ν ην^; . ο /\L 0 1 ι 1 _ ^Ν - ' /= ⁷ Η ρ Ή NMR (400 MHz, DMSO), δ 9.89 (s, 1 Η), 9.20 (s, 1 Η), 8.79 (d, 7=2.57 Hz, 1 Η), 8.65 (d, 7=2.45 Hz, 1 Η), 8.36 (s, 1 Η), 8.20 (dd, 7=7.03, 2.75 Hz, 1 Η), 7.63-7 .67(m, 1H), 7.47(dd, 7=11.25, 9.05Hz, 1H), 4.924.96(m, 1H), 4.40(t, 7=12.72 Hz, 4 H), 1.28 (d, 7=6.36 Hz, 6 H). Method 1: RT=2.89 min; M+H=449,l 147 F ΐ \ N- ^J ΗΝ^ Η ^b ι υ% > Γ Ν' - •-J 1 Ή NMR (400 MHz, DMSO), δ 8.92 (s, 1 Η), 8.52 (d, 7=2.76 Hz, 1 Η), 8.25 (d, 7=2.76 Hz, 1 Η), 8.19 (dd, 7=7.09, 2.70 Hz, 1 Η) 7.61-7.69 (m, 1 Η), 7.42 (dd, 7=11.36, 9.10 Hz, 1 Η), 6.88 (d, 7=2.76 Hz, 1 Η), 5.28-5.49 (m, 1 Η), 4.24-4.38 (m, 2 H), 3.95-4.08 (m, 2 H), 3.91 (t, 7=7.15 Hz, 4 H), 2.33-2.41 (m, 2 H). Method 1: RT=2.75 min; M+H=385.2 148 ί-Z\ ^ Ο τ ^r Ci Г LL. 7 Z >> %__7 Ή NMR (400 MHz, DMSO-d6), δ 8.98 (s, 1 Η), 8.81 (d, 1=2.76 Hz, 1 Η), 8.70 (d, 1=2.26 Hz, 1 H), 8.23 (dd, 1=7.03, 2.76 Hz, 1 H), 8.07 (d, 1=1.76 Hz, 1 H), 7.65-7, 72 (m, 1 Η), 7.47 (dd, 1=11.29, 9.29 Hz, 1 Η), 5.29-5.51 (m, 1 Η), 4.25-4.39 (m, 2 Η), 3.96-4.09 (m, 4 Η), 3.44-3.54 (m, 2 Η), 2.91-3.02 (m, 1 Η), 1 .68-1.86 (m, 4 Η). Method 1: RT=2.65 min; M+H=414.2

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Ή NMR (400 MHz, DMSO), δ 8.60 (s, 1 Η), 8.53 (d, 7=2.76 Hz, 1 Η), 8.25 (d, 7=2.76 Hz, 1 Η), 8.21 (dd, 7=7.03, 2.76 Hz, 1 Η), 7.64-7.71 (m, 1 Η), 7.41 (dd, 7=11.29 , 9.16 Hz, 1 Η), 6.88 (d, 7=2.76 Hz, 1 Η), 5.28-5.46 (m, 1 Η), 3.91 (t, 7=7 .22 Hz, 4 Η), 3.62-3.73 (m, 2 Η), 3.39-3.55 (m, 2 Η), 2.32-2.40 (m, 2 Η), 1.99-2.22 (m, 2 H). Method 1: RT=2.76 min; M+H=399.2

Ή NMR (400 MHz, Methanol-7 ₄ ), δ 9.15 ((d, 7=2.01 Hz, 1 H)), 8.98 (s, 1 H), 8.85 (d, 7= 1.88 Hz, 1 N), 8.33 (dd, 7=6.78, 9.16 Hz, 1 N), 7.61-7.65 (t, 1 N), 7.42 (dd, 7=11.04, 9.16 Hz, 1 N), 5.28-5.41 (m, 1 N), 4.11-4.14 (t, 2 N), 3.57-3.85 (t, 6 N), 3.14-3.20 (t, 1 N), 2.11-2.32 (t, 2 N), 1.91-1.97 (t, 4 N). Method 1: RT=2.60 min; M+H=428.2

Ή NMR (400 MHz, DMSO), δ 10.52 (s, 1 Η), 8.56 (d, 7=2.76 Hz, 1 Η), 8.48 (dd, 7=7.03, 2 .63 Hz, 1 Η), 8.27 (d, 7=2.76 Hz, 1 Η), 7.97 (dd, 7=1.69, 0.82 Hz, 1 Η), 7.867.91 ( t, 1 Η), 7.54 (dd, 7=11.36, 9.10 Hz, 1 Η), 7.38 (dd, 7=3.51, 0.75 Hz, 1 Η), 6, 89 (d, 7=2.76 Hz, 1 Η), 6.73 (dd, 7=3.51, 1.76 Hz, 1 Η), 3.91 (t, 7=7.22 Hz, 4 Η), 2.332.39 (m, 2 Η). Method 1: RT=2.90 min; M+H=378.2 ^X H NMR (400 MHz, DMSO-d6), δ 8.98 (s, 1 H), 8.95 (d, J=2.51 Hz, 1 H), 8.69 (d, J=2.01 Hz, 1 H), 8.33 (d, J=l.76 Hz, 1 H), 8.24 (dd, J=6.90, 2.63 Hz, 1 H ), 7.67-7.74 (t, 1 Η), 7.48 (dd, J=11.29, 9.29 Hz, 1 Η), 5.30-5.52 (t, 1 Η) , 4.26-4.39 (t, 2 Η),

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3.97-4.09 (m, 2 Η), 3.87 (q, J=11.71 Hz, 2 N). Method 1: RT=2.76 min; M+H=412.2 153 z ^N i->-ό ΗΝ £ ('Τ- / ( = Ν ~ ⁷ Η F Ή NMR (400 MHz, METAHOJI-d4), δ 8.99 (d, J=2.20 Hz, 1 Η), 8.71 (d, J=2.69 Hz, 1 Η), 8.62 ( dd, J=6.85, 2.69 Hz, 1 Η), 8.07 (d, J=2.44 Hz, 1 Η), 7.82-7.88 (m, 1 Η), 7, 51 (dd, J=10.88, 9.17 Hz, 1 Η), 3.04 (s, 3 Η), 2.58 (s, 3 Η), 2.49 (s, 3 Η). Method 1: RT=2.76 min; M+H=381,l 154 . _Ζ ^Ν - -Η ΗΝ { χ ^Ν '«Ν λ < b χ Λ X/ Ό Ν - y Ή NMR (400 MHz, METAHOJI-d4), δ 8.92 (d, J=2.20 Hz, 1 Η), 8.80 (d, J=2.69 Hz, 1 Η), 8.53 ( dd, J=6.85, 2.69 Hz, 1 Η), 8.17 (d, J=2.93 Hz, 1 Η), 7.69-7.77 (m, 1 Η), 7, 40 (dd, J=11.00, 9.29 Hz, 1 Η), 3.12 (s, 6 Η), 2.46 (s, 3 Η), 2.37 (s, 3 Η). Method 1: RT=2.84 min; M+H=395,l 155 N. -ρ ρ ΗΝ 4 ί 4 b £ V \ ? - - _f - ^X NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1 Η), 8.57 (d, J=2.64 Hz, 1 Η), 8.54 (dd, J=7.15, 2.64 Hz, 1 H), 8.28 (d, J=2.76 Hz, 1 H), 7.84-7.90 (m, 1 H), 7.54 (dd, J=11, 29, 9.03 Hz, 1 H), 6.90 (d, J=2.76 Hz, 1 H), 3.93 (t, J=7.15 Hz, 4 H), 2.50-2 .50 (m, 3 Η), 2.40 (s, 3 Η), 2.33-2.39 (m, 2 Η). Method 1: RT=2.89 min; M+H=407,l 156 1 ΓΛ Ν- ¹ ην^: Ρ ^Ν ν ^Ν ΓΛ ⁰ . LL .Μ / Τ -...... g Ή NMR (400 MHz, DMSO-d6) δ 8.96 (br s, 1 H), 8.79 (d, J=2.57 Hz, 1 H), 8.69 (d, J=2.32 Hz, 1 H), 8.23 (dd, J=6.97, 2.69 Hz, 1 H), 8.05 (d, J=l.96 Hz, 1 H), 7.64-7, 73 (m, 1 H), 7.46 (dd, J=11.25, 9.17 Hz, 1 H), 5.28-5.52 (m, 1 H), 4.26-4.39 (m, 2 H), 3.96-4.10 (m, 2 H), 3.03-3.14 (m, 1 H), 1.30 (d, J=6.97 Hz, 6 H ). Method 2: RT=0.95 min; M+H=372.2

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157 X* ( \J \ 0 NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1 H), 8.65 (d, >2.64 Hz, 1 H), 8.59 (d, >2.89 Hz, 1 H ), 8.55-8.58 (m, 1 H), 7.837.90 (m, 1 H), 7.55 (dd, > 11.29, 9.16 Hz, 1 H), 7.12 ( br s, 1 H), 3.38 (br t, J=6.40 Hz, 4 H), 2.50 (br s, 3 H), 2.40 (s, 3 H), 1.972.06 ( m, 4H). Method 1: RT=3.12 min; M+H=421,l 158 N, L-T ΗΝΥ b I Τ bM ^z 7 O ' _f - NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1 H), 8.81 (d, >2.76 Hz, 1 H), 8.73 (d, >2.64 Hz, 1 H ), 8.55 (dd, J=7.03, 2.64 Hz, 1 H), 7.86-7.92 (m, 1 H), 7.54-7.59 (m, 1 H) , 7.50-7.54 (m, 1 H), 3.79-3.84 (m, 4 H), 3.15-3.21 (m, 4 H), 2.49-2.50 (m, 3H), 2.40 (s, 3H). Method 1: RT=2.79 min; M+H=437,l 159 .-... ^N >.Ύ-ό I HN 9 ^J O . ^N L <; ^ъ L 1 L, ⁿ '' 9 N - - — HF SNMR (400 MHz, DMSO-d6) δ 10.52 (s, 1 H), 9.95 (br s, 1 H), 8.85 (d, J=2.38 Hz, 1 H), 8, 69 (d, >2.51 Hz, 1 H), 8.56 (dd, >7.03, 2.63 Hz, 1 H), 8.40 (br s, 1 H), 7.86-7 .93 (m, 1 H), 7.57 (dd, > 11.04, 9.16 Hz, 1 H), 4.95 (dt, >12.55, 6.27 Hz, 1 H), 2 .50-2.50 (m, 3 H), 2.40 (s, 3 H), 1.30 (d, >6.27 Hz, 6 H). Method 1: RT=2.97 min; M+H=453.2 160 Λ> P 1 [ Ν-Λ 9 ^X M p /jj ( inX ^N -7 ~-~-J Ή NMR (400 MHz, METAHOJI-d4), δ 8.71 (d, >2.26 Hz, 1 Η), 8.68 (d, J=2.26 Hz, 1 Η), 8.17 (d , >2.01 Hz, 1 Η), 8.14 (dd, >7.03, 2.51 Hz, 1 Η), 7.65 (dt, >9.29, 3.39 Hz, 1 Η) , 7.32-7.39 (m, 1 Η), 4.094.16 (m, 6 Η), 3.61-3.69 (m, 2 Η), 3.05 (br s, 1 H), 2.34 (quint, >7.65 Hz, 2 H), 1.86-1.95 (m, 4 H). Method 1: RT=2.68 min; M+H=396.2

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I Ή NMR (400 MHz, DMSO), δ 9.19 (s, 1 Η), 8.50 (dd, 7=6.59, 2.82 Hz, 2 Η), 8.20 161 RJ? 1 IN- O (dd, 7=7.03, 2.76 Hz, 1 H), 7.58-7.66 (m, 1 Η), 7.44 (dd, 7=11.42, 9.16 Hz, 1 Η), 6.88 Ν- _ί (d, 7=2.76 Hz, 1 Η), 4.40 (t, 7=12.67 Hz, 4 Η), 3.35 (br s, 4 Η), 1.93-2.03 (m, 4 Η). Method 1: RT=3.16 min; M+H=417.2 Ή NMR (400 MHz, Methanol-7 ₄ ), δ 9.09 162 p HN .< '// b (d, J=2.01 Hz, 1 Η), 8.91 (s, 1 Η), 8.78 (s, 1 Η), 8.27 (dd, J=6.78, 2.76 Hz , 1 Η), 7.65 (ddd, J=9.07, 4.11, 2.76 Hz, 1 Η), 7.41 (dd, p - F .VV v / 1=10.92, 9.03 Hz, 1 H), 5.24-5.43 (m, 1 H), P I — 3.54-3.91(m, 6H), 2.07-2.37(m, 2H) Method 1: RT=2.82 min; M+H=426.2 Ή NMR (400 MHz, Methanol-7 ₄ ), δ 8.68 (s, 1 Η), 8.50 (dd, 7=12.61, 2.82 Hz, 2 Η) , 163 G ^N '- )= W/v A P HN-p 8.21 (dd, 7=7.09, 2.70 Hz, 1 H), 7.61-7.67 (m, 1 H), 7.40 (dd, 7=11.36, 9.10 Hz, 1 Η), 6.89 (d, 7=2.76 Hz, 1 Η), 3.97 (t, 7=7.53 Hz, n-.. ₇ 4 Η), 3.36 (br s, 4 Η), 2.19 (quint, J=7.56 Hz, 2 Η), 1.95-2.04 (m, 4 H). Method 1: RT=2.95 min; M+H=381.2 Ή NMR (400 MHz, DMSO-d6) δ 8.79 (d, J=2.26 Hz, 1 Η) 8.68 (d, J=2.01 Hz, 1 Η) 164 ^{! 4Fx-} F _g %h > \ // -1 O 1IN h four., 8.36 (d, J=1.51 Hz, 1 H) 8.15 (dd, J=6.65, 2.64 Hz, 1 H) 7.67 (ddd, J=9.10, 4, 20, 2.76 Hz, 1 H) 7.35-7.36 (m, 1 H) 7.26-7.47 (m, 1 H) 4.13 (t, J=7.65 Hz, 4 Η) 3.74 (q, J=10.88Hz, 2H) 2.34 (quint, J=7.65Hz, 2H) Method 1: RT=2.75 min; M+H=394.2

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165 X X χ ί J i ι'Μ' b A Ή NMR (400 MHz, DMS0-d6), δ 9.24 (s, 1 Η), 8.82 (d, J=2.51 Hz, 1 Η), 8.70 (d, J=2.26 Hz, 1 H), 8.23 (dd, J=6.90, 2.89 Hz, 1 H), 8.07 (d, J=2.01 Hz, 1 H), 7.65-7, 71 (m, 1 Η), 7.49 (dd, J=11.29, 9.03 Hz, 1 Η), 4.41 (t, J=12.67 Hz, 4 Η), 4.00 ( dd, J=10.54, 3.76 Hz, 2 Η), 3.45-3.54 (m, 2 Η), 2.92-3.01 (m, 1 Η), 1.69-1 .86 (m, 4 Η). Method 1: RT=2.81 min; M+H=432.2 166 A J I Jrz Z > >4 > / and.-/, IL Ή NMR (400 MHz, DMSO-d6), δ 9.24 (s, 1 Η), 8.96 (d, J=2.51 Hz, 1 Η), 8.69 (d, J=2.01 Hz, 1 Η), 8.34 (s, 1 Η), 8.24 (dd, J=7.03, 2.51 Hz, 1 Η), 7.66-7.73 (m, 1 Η) , 7.51 (dd, J=11.29, 9.29 Hz, 1 Η), 4.42 (t, J=12.80 Hz, 4 Η), 3.87 (q, J=11.46 Hz, 2H). Method 1: RT=2.85 min; M+H=430,l 167 F r-4 N- ^J HNX . /xb-П ^ъ NЖ 1 r SH NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1 Η), 8.70 (d, J=2.93 Hz, 1 Η), 8.55 (d, J=2.93 Hz , 1 Η), 8.21 (dd, J=6.97, 2.57 Hz, 1 Η), 7.56-7.74 (m, 1 Η), 7.43 (dd, J=11, 49, 9.05 Hz, 1 Η), 7.16 (d, J=2.93 Hz, 1 Η), 5.25-5.57 (m, 1 Η), 4.22-4.40 ( m, 2 Η), 3.87-4.12 (m, 2 Η), 2.96 (s, 6 Η). Method 1: RT=2.69 min; M+H=373,l 168 G HN— η X-F, - O L a 1 £n_ · 'O'N~" H i' Ή NMR (400 MHz, Methanol-X), δ 8.64 (br d, J=2.26 Hz, 1 Η), 8.61 (br d, J=2.64 Hz, 1 Η), 8, 44 (br s, 1 H), 8.10 (dd, J=6.71, 2.70 Hz, 1 H), 7.60-7.67 (m, 1 H), 7.33 (dd, J=10.92, 9.16 Hz, 1 H), 5.25-5.47 (m, 1 H), 5.01 (dt, J=12.52, 6.23 Hz, 1 H), 4.32-4.43 (m, 2 H), 4.07-4.19 (m, 2 H), 1.33 (d, J=6.27 Hz, 6 H). Method 1: RT=2.88 min; M+H=431,l

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169 N. v ΗΝΥ Ή NMR (400 MHz, DMSO-d6), δ 10.57 (s, 1 Η), 9.05 (d, J=2.51 Hz, 1 Η), 8.88 (d, J=2.01 Hz, 1 H), 8.59 (dd, J=7.03, 2.51 Hz, 1 H), 8.43 (d, J=l.76 Hz, 1 H), 7.89-7, 99 (m, 1 H), 7.59 (dd, J=11.04, 9.03 Hz, 1 H), 4.00 (br dd, J=10.79, 3.26 Hz, 2 H) , 3.48 (td, J=11.36, 2.38 Hz, 2 H), 2.98-3.10 (m, 1 H), 2.50 (br s, 3 H), 2.39 (s, 3H), 1.701.89 (m, 4H). Method 1: RT=2.77 min; M+H=436.2 170 V \ N-' ^J »IN—( ΥΚ-Ν b Γ Υ n-b χ Ach Λ------ / \ / Ν' )— 1 1 Ή NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=3.01 Hz, 1 H), 8.66-8.68 (m, 1 H), 8.53 (d, J= 2.76 Hz, 1 H), 8.21 (dd, J=7.03, 2.76 Hz, 1 H), 7.57-7.77 (m, 1 H), 7.40 (dd, J=11.29, 9.03 Hz, 1 H), 7.15 (d, J=2.76 Hz, 1 H), 3.98 (t, J=7.53 Hz, 4 H), 2 .95 (s, 6H), 2.20 (quint, J=7.59 Hz, 2 H). Method 1: RT=2.62 min; M+H=355.2 171 F _Γ \ N- ^J ΗΝ 4 λ ( b ι Ν C b /-Ν )- ⁷ phJ F OJ Ή NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.55 (d, J=2.7 Hz, 1H), 8.27 (d, J=2.8 Hz, 1H ), 8.20 (dd, J=7.l, 2.7Hz, 1H), 7.64 (ddd, J=9.l, 4.1, 2.7Hz, 1H), 7.43 ( dd, J=ll,4, 9.1Hz, 1H), 6.94 (d, >2.8Hz, 1H), 5.40 (dtt, >57.5, 6.1, 3.1Hz, 1H ), 4.75 (s, 4H), 4.31 (dddd, >21.8, 10.4, 6.0, 1.4 Hz, 2H), 4.10 (s, 4H), 4.08 -3.96 (m, 2H). Method 1: RT=2.55 min; M+H=427.2 172 γ ΝΗΝ^ |'T\chx '° ¢1 '...... = ^? Ή NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.54 (d, >2.9 Hz, 1H), 8.51 (d, J=2.8 Hz, 1H) , 8.20 (dd, >7.1, 2.7 Hz, 1H), 7.64 (ddd, >9.0, 4.1, 2.7 Hz, 1H), 7.43 (dd, > 11.4, 9.1 Hz, 1H), 7.07 (d, >2.9 Hz, 1H), 5.40 (ddq, J=57.5, 6.1, 3.0 Hz, 1H) , 4.69 (d, >23.8 Hz, 2H), 4.40-4.23 (m, 2H), 4.094.05 (m, 1H), 4.04-3.95 (m, 1H) , 3.82-

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3.70 (m, 2H), 3.70-3.58 (m, 1H), 3.08 (ddd, J=9.6.1.4, 0.7 Hz, 1H), 1.99- 1.84 (m, 2H). Method 2: RT=0.90 min; M+H=427.2 173 i . 0 . ^F T '' Ι/Λ7 N=- ^{z 4} SNMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.81 (d, J=2.7 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H) , 8.36 (dd, J=7.0, 2.7Hz, 1H), 8.05 (dd, J=2.3, 0.8Hz, 1H), 7.68 (ddd, J=9 ,l, 4.2, 2.7 Hz, 1H), 7.54 (dd, J=11.2, 9.0 Hz, 1H), 3.08 (pd, J=6.9, 0.8 Hz, 1H), 2.72.55 (m, 4H), 1.30 (d, J=6.9 Hz, 6H). Method 1: RT=3.19 min; M+H=395.2 174 v/A /“VAA H ,N. .-. .N. Oh..-. .F pri JI ^F SNMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H) , 8.26-8.15 (m, 1H), 8.05 (dd, J=2.3, 0.8 Hz, 1H), 7.65-7.45 (m, 2H), 4.35 (t, J=6.0 Hz, 2H), 3.18-3.00 (m, 1H), 2.74 (qt, J=11.5, 5.9 Hz, 2H), 1.30 ( d, J=6.9 Hz, 6H). Method 1: RT=3.25 min; M+H=411.2 175 N. -4 Ύ p-0 HN < p _{Z/ 4} < b N. to C ^N \ ) _F - V -- F SNMR (400 MHz, DMSO-d6) δ 10.54 (s, 1 Η), 9.00 (d, J=2.51 Hz, 1 Η), 8.71 (d, J=2.01 Hz, 1 Η), 8.58 (dd, J=7.03, 2.51 Hz, 1 Η), 8.36 (s, 1 Η), 7.86-7.97 (m, 1 Η), 7 .52-7.67 (m, 1 H), 3.88 (q, J=11.13 Hz, 2 H), 2.40 (s, 6 H). Method 1: RT=2.88 min; M+H=434,l 176 K\/n O.^As. O ' Ή NMR (400 MHz, Methanol-7 ₄ ), δ 8.91 (d, 7=1.88 Hz, 1 H), 8.74 (s, 1 H), 8.448.51 (t, 2 H), 7.93 (dt, 7=7.18, 4.44 Hz, 1 H), 7.78 (d, 7=1.13 Hz, 1 H), 7.48 (dd, 7=11.11, 9.22 Hz, 1 H), 7.32 (d, 7=3.51 Hz, 1 H), 6.68 (dd, 7=3.58, 1.69 Hz, 1 H), 3.77 (q, 7=10.75 Hz, 2 H) Method 1: RT=2.86 min; M+H=405.1

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177 f gL N- ^J HN—/ b ¹ ] N—CL \=/ θν' ^F Ή NMR (400 MHz, DMSO-d6), δ 8.94 (s, 1 Η), 8.71 (d, 1=2.76 Hz, 1 Η), 8.61 (d, 1=2.51 Hz, 1 H), 8.21 (dd, 1=7.03, 2.51 Hz, 1 H), 7.65 (dt, 1=8.60, 3.61 Hz, 1 H), 7, 44 (dd, 1=11.17, 9.16 Hz, 1 Η), 7.37 (d, 1=2.51 Hz, 1 Η), 5.28-5.54 (m, 1 Η), 4.24-4.40 (m, 2 Η), 3.93-4.19 (m, 4 Η), 3.18 (dd, 1=11.67, 2.89 Hz, 2 Η), 2 .87 (dd, 1=11.67, 5.90 Hz, 2 Η), 1.26 (d, 1=6.27 Hz, 6 Η). Method 2: RT=0.92 min; M+H=443.2 178 F ri 1 IN -< O ^N _V -N / g7 O - I LA A) ,: 4 V C> Ή NMR (400 MHz, DMSO-d6), δ 8.95 (s, 1 Η), 8.76 (d, 1=2.76 Hz, 1 Η), 8.64 (d, 1=2.76 Hz, 1 Η), 8.20 (dd, 1=7.03, 2.51 Hz, 1 Η), 7.62-7.69 (m, 1 Η), 7.60 (d, 1=3 .01 Hz, 1 Η), 7.45 (dd, 1=11.29, 9.03 Hz, 1 Η), 5.28-5.55 (m, 1 Η), 4.24-4.41 (m, 2 H), 3.94-4.10 (m, 2 H), 3.67-3.82 (m, 4 H), 3.25-3.31 (m, 4 H). Method 2: RT=0.72 min; M+H=463,l 179 1= t \ N- HN^i /A · A, b . L La a / CP'>= / ^Ν χΑ ^₽ Ή NMR (400 MHz, METAHOJI-d4), δ 8.68 (d, 1=2.76 Hz, 1 Η), 8.55 (d, 1=2.26 Hz, 1 Η), 8.11 ( dd, 1=6.78, 2.76 Hz, 1 Η), 7.60-7.67 (m, 1 Η), 7.55 (d, 1=2.76 Hz, 1 Η), 7, 35 (dd, 1=10.92, 9.16 Hz, 1 Η), 5.275.49 (m, 1 Η), 4.34-4.47 (m, 2 Η), 4.084.21 (m, 2 Η), 3.22-3.31 (m, 4 Η), 2.682.76 (m, 4 Η), 2.41 (s, 3 H). Method 2: RT=0.51 min; M+H=428.2 180 F F HN^ L )=^ MJ ^F Ή NMR (400 MHz, DMSO-d6), δ 8.95 (s, 1 Η), 8.87 (d, 1=3.01 Hz, 1 Η), 8.66 (d, 1=2.76 Hz, 1 H), 8.21 (dd, 1=7.15, 2.64 Hz, 1 H), 7.66 (dt, 1=8.85, 3.48 Hz, 1 H), 7, 54 (d, 1=3.01 Hz, 1 Η), 7.45 (dd, 1=11.29, 9.29 Hz, 1 Η), 7.14 (d, 1=1.00 Hz, 1 Η), 6.92 (d, 1=1.00 Hz, 1 Η), 5.30-5.51 (m, 1 Η), 4.40

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(s, 2 H), 4.26-4.38 (m, 2 H), 4.15 (t, J=5.40 Hz, 2 H), 3.97-4.09 (m, 2 H ), 3.76 (t, 1=5.40 Hz, 2 H). Method 2: RT=0.53 min; M+H=451.2 181 P / --Λ b LI ,M >r-N'-'X - hcM'- ^{7 F} Ή NMR (400 MHz, DMSO-d6), δ 8.93 (s, 1 Η), 8.54 (d, 1=2.76 Hz, 1 Η), 8.28 (d, 1=2.76 Hz, 1 Η), 8.20 (dd, 1=7.15, 2.64 Hz, 1 Η), 7.61-7.70 (m, 1 Η), 7.43 (dd, 1=11 .42, 9.16 Hz, 1 Η), 6.92 (d, 1=2.76 Hz, 1 Η), 5.68 (d, 1=6.78 Hz, 1 Η), 5.28- 5.51 (m, 1 Η), 4.57-4.67 (m, 1 Η), 4.25-4.40 (m, 2 Η), 4.20 (t, 1=7.15 Hz , 2 Η), 3.944.11 (m, 2 Η), 3.56-3.65 (m, 2 H). Method 2: RT=0.70 min; M+H=401,l 182 Z A /7 1 \ / '<z z T1 D. c. J. Cr Z-D Ή NMR (400 MHz, DMSO-d6), δ 9.17 (d, 1=2.26 Hz, 1 Η), 9.03 (d, 1=2.51 Hz, 1 Η), 9.00 ( s, 1 Η), 8.75 (d, 1=2.51 Hz, 1 Η), 8.67-8.73 (m, 2 Η), 8.28 (dd, 1=6.90, 2 .64 Hz, 1 Η), 7.84-7.90 (m, 2 Η), 7.68-7.75 (m, 1 Η), 7.50 (dd, 1=11.29, 9, 03 Hz, 1 H), 5.30-5.52 (m, 1 H), 4.27-4.40 (m, 2 H), 3.97-4.10 (m, 2 H). Method 2: RT=0.58 min; M+H=407,l 183 F N- ¹ HN D , M. / ( ^ъ 1 L. ^N O . L / ' _J F Ή NMR (400 MHz, METAHOJI-d4), δ 8.50 (d, 1=2.76 Hz, 1 Η), 8.44 (d, 1=2.51 Hz, 1 Η), 8.10 ( dd, 1=6.78, 2.76 Hz, 1 Η), 7.59-7.65 (m, 1 Η), 7.34 (dd, 1=10.79, 9.03 Hz, 1 Η ), 7.09 (d, 1=2.76 Hz, 1 Η), 5.285.49 (m, 1 Η), 4.77-4.82 (m, 2 Η), 4.704.74 (m, 2 Η), 4.34-4.46 (m, 2 Η), 4.094.21 (m, 2 Η), 3.71 (s, 2 Η), 3.48 (t, 1=6.78 Hz, 2 H), 2.42 (t, 1=6.78 Hz, 2 H). Method 2: RT=0.82 min; M+H=441.2

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184 F / k N·-' HN < Д^-.N z / b Г N 7 ύ A....... ^z Ή NMR (400 MHz, DMSO), δ 8.93 (s, 1 Η), 8.73 (d, 7=2.81 Hz, 1 Η), 8.57 (d, 7=2.69 Hz, 1 Η), 8.19 (dd, 7=7.03, 2.63 Hz, 1 Η), 7.60-7.68 (m, 1 Η), 7.42 (dd, 7=11.31 , 9.11 Hz, 1 Η), 7.23 (d, 7=2.81 Hz, 1 Η), 5.27-5.50 (m, 1 Η), 4.44 (br s, 2 Η ), 4.24-4.37 (m, 2 Η), 3.94-4.07 (m, 2 Η), 3.42 (br d, 7=10.88 Hz, 2 Η), 2, 81-2.92 (m, 2H), 1.80-1.99 (m, 4H). Method 1: RT=2.70 min; M+H=441.3 185 F D N'nyD ,Γ _r ;--N —.. 0 _l nA i II r Ή NMR (400 MHz, DMSO) δ 8.90 (s, 1 Η), 8.33-8.47 (m, 2 Η), 8.17 (dd, 7=6.96, 2.57 Hz, 1 Η), 7.62 (dt, 7=8.78, 3.51 Hz, 1 Η), 7.41 (dd, 7=11.29, 9.16 Hz, 1 Η), 6.83 ( d, 7=2.51 Hz, 1 Η), 6.02 (br t, 7=5.14 Hz, 1 Η), 5.24-5.51 (m, 1 Η), 4.21-4 .40 (m, 2 Η), 3.92-4.09 (m, 2 Η), 3.57 (br t, 7=5.52 Hz, 2 Η), 3.31 (s, 3 Η) , 3.20-3.25 (m, 2 Η). Method 1: RT=2.60 min; M+H=403.2 186 V-Z about r Y L one i g s' si z z Ή NMR (400 MHz, DMSO) δ 8.95 (s, 1 Η), 8.86 (d, 7=2.76 Hz, 1 Η), 8.66 (d, 7=2.51 Hz, 1 Η), 8.51 (s, 1 Η), 8.21 (dd, 7=6.90, 2.64 Hz, 1 Η), 7.62-7.69 (m, 1 Η), 7, 57 (d, 7=2.76 Hz, 1 Η), 7.44 (dd, 7=10.98, 9.22 Hz, 1 Η), 5.29-5.50 (m, 1 Η), 4.57 (s, 2 Η), 4.26-4.37 (m, 2 Η), 4.21 (br t, 7=5.40 Hz, 2 Η), 3.95-4.09 ( m, 2 H), 3.76 (br t, 7=5.33 Hz, 2 H). Method 1: RT=2.27 min; M+H=452.2

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187 F ..7 Г \ N-' ^J HN^( ^N N. b .n. 4V7J i I ' / -f- - _F Ή NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1 Η), 9.00-9.09 (m, 2 Η), 8.82 (s, 1 Η), 8.63 (br d, 1=4.39 Hz, 1 H), 8.29 (dd, J=6.90, 2.51 Hz, 1 H), 7.93 (dd, 1=10.73, 8.47 Hz , 1 H), 7.72 (dt, 1=8.60, 3.48 Hz, 1 H), 7.527.58 (m, 1 H), 7.46-7.51 (m, 1 H), 5.285.55 (m, 1 H), 4.25-4.44 (m, 2 H), 3.934.14 (m, 2 H). Method 1: RT=2.74 min; M+H=425,l 188 y ^F N- ^J IIN-D . L-S ”a;' ~ Ή NMR (400 MHz, DMSO-d6) δ 9.029.05 (m, 2 Η), 9.00 (d, 1=2.38 Hz, 1 Η), 8.72 (dd, 1=4.64, 1.38 Hz, 1 H), 8.69 (d, 1=2.26 Hz, 1 H), 8.29 (dd, 1=6.96, 2.70 Hz, 1 H), 8.14 (dd, 1=8.16, 1.38 Hz, 1 Η), 7.697.76 (m, 1 Η), 7.52-7.55 (m, 1 Η), 7.477.51 (m, 1 Η ), 5.28-5.53 (m, 1 Η), 4.284.39 (m, 2 Η), 3.97-4.10 (m, 2 Η). Method 1: RT=2.76 min; M+H=441.0 189 HN-£ b j. to _Z ^N - >N^'V' ^l W M ^F Ή NMR (400 MHz, DMSO-d6) δ 9.11 (d, 1=2.38 Hz, 1 Η), 9.03 (d, 1=1.88 Hz, 1 Η), 9.01 (s , 1 Η), 8.99 (d, 1=2.51 Hz, 1 Η), 8.62-8.66 (m, 2 Η), 8.28 (dd, 1=6.90, 2, 64 Hz, 1 H), 8.24 (dt, 1=8.22, 1.79 Hz, 1 H), 7.69-7.75 (m, 1 H), 7.56 (dd, 1= 7.40, 4.77 Hz, 1 Η), 7.50 (dd, 1=11.17, 9.16 Hz, 1 Η), 5.23-5.56 (m, 1 Η), 4, 27-4.41(m, 2H), 3.97-4.11(m, 2H). Method 1: RT=2.40 min; M+H=407,l 190 F N- ¹ hn^; r^-sN b ....... 1 VYJ' O.^ ^F ' Ή NMR (400 MHz, DMSO) δ 8.91 (s, 1 Η), 8.73 (d, 7=2.76 Hz, 1 Η), 8.58 (d, 7=2.64 Hz, 1 Η), 8.18 (dd, 1=7.03, 2.64 Hz, 1 Η), 7.57-7.68 (m, 1 Η), 7.41 (dd, 1=11.29, 9.03 Hz, 1 Η), 7.35 (d, 7=2.76 Hz, 1 Η), 5.255.49 (m, 1 Η), 4.23-4.36 (m, 2 Η), 3.934.07 (m, 2 Η), 3.69-3.84 (m, 2 Η), 3.56 (br

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d, 7=10.92 Hz, 2 H), 2.24-2.32 (m, 2 H), 1.15 (d, 7=6.15 Hz, 6 H). Method 1: RT=2.77 min. M+H=443.3 191 F pA N- ^J ΗΝΥ o- ₇ /Н ^b /-Ν' ^y /—' Cj | Ή NMR (400 MHz, DMSO) δ 8.94 (s, 1 Η) 8.60, (d, J=2.76 Hz, 1 Η), 8.56 (d, J=2.76 Hz, 1 Η), 8.22 (dd, J=7.09, 2.70 Hz, 1 Η), 7.62-7.69 (m, 1 Η), 7.44 (dd, J= 11.29, 9.16 Hz, 1 Η), 7.18 (d, 7=2.76 Hz, 1 Η), 5.305.51 (m, 1 Η), 5.10 (d, 7=8.28 Hz, 2 Η), 4.75 (d, 7=8.28 Hz, 2 Η), 4.26-4.38 (m, 2 Η), 3.96-4.09 (m, 2 Η), 3, 74 (t, 7=6.96 Hz, 2 H), 2.58 (br s, 2 H). Method 1: RT=2.65 min. M+H=427.2 192 J HN { N _N . ; o 1 L ^N , Γ-Ν ? - ⁷ / Г Λ-l F SNMR (400 MHz, DMSO) δ 8.94 (s, 1 H), 8.52 (d, J=2.69 Hz, 1 H), 8.26 (d, J=2.81 Hz, 1 H ), 8.19 (dd, J=7.03, 2.63 Hz, 1 H), 7.60-7.68 (m, 1 H), 7.42 (dd, J=11.37, 9 .17 Hz, 1 H), 6.88 (d, 7=2.69 Hz, 1 H), 5.285.50 (m, 1 H), 4.24-4.37 (m, 2 H), 4.024 .08 (m, 1 H), 3.98 (t, 7=7.64 Hz, 3 H), 3.65 (dd, 7=7.15, 5.69 Hz, 2 H), 3.56 (d, J=6.60 Hz, 2 H), 3.29 (s, 3 H), 2.96 (m, 1 H). Method 1: RT=2.76 min. M+H=429.3 193 F .-/ g \ N ^J HN ζ ^ ^Ν ·^-.Ν z / b '; n < ^{y h} > }~ ^y F SNMR (400 MHz, DMSO) δ 8.92 (s, 1 H), 8.52 (d, 7=2.76 Hz, 1 H), 8.28 (d, 7=2.76 Hz, 1 H ), 8.19 (dd, 7=7.03, 2.64 Hz, 1 H), 7.59-7.67 (m, 1 H), 7.42 (dd, 7=11.36, 9 .10 Hz, 1 H), 6.91 (d, 7=2.89 Hz, 1 H), 5.275.50 (m, 1 H), 4.23-4.38 (m, 2 H), 3.944 .10 (m, 6H), 0.68 (s, 4H). Method 1: RT=2.92 min. M+H=411.3+

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N- ^J hnX NMR (400 MHz, DMSO) δ 8.88 (s, 1 H), 8.48-8.59 (m, 2 H), 8.17 (dd, J=7.03, 2.64 Hz, 1 H), 7.54-7.67 (m, 1 H), 7.39 (dd, 194 b f 1 nA 'b 7=11.36, 9.10 Hz, 1 H), 7.03 (d, 7=2.89 Hz, [.,/X- 1 H), 5.19-5.63 (m, 3 H), 4.19-4.40 (m, 2 ^F H), 3.93-4.06(m, 2H), 3.57-3.87(m, 4H). F Method 1: RT=2.77 min. M+H=435.l Ή NMR (400 MHz, DMSO-d6) δ 8.79 (d, J=2.51 Hz, 1 Η), 8.69 (d, J=2.13 Hz, 1 Η ), 8.64 (s, 1 Η), 8.26 (dd, J=6.96, 2.57 Hz, 1 N—' Η), 8.05 (d, J=2.01 Hz, 1 Η), 7.68-7.76 (m, HN < _x 1 H), 7.46 (dd, J= 11.17, 9.16 Hz, 1 H), 195 _Zz M /..- Z b | Ϊ N < ^Z 5.27-5.49 (m, 1 H), 3.62-3.77 (m, 2 H), .A / \ / V C. \ s 3.40-3.59 (m, 2 Η), 3.08 (dt, J=13.61, 6.74 1F Hz, 1 H), 2.02-2.25 (m, 2 H), 1.31 (d, J=6.90 Hz, 6 H). Method 1: RT=2.95 min; M+H=386,l Ή NMR (400 MHz, DMSO-d6) δ 10.54 (br s, 1 Η), 8.83 (d, J=2.51 Hz, 1 Η), 8.70 (d, FROM/ J=2.26 Hz, 1 Η), 8.51 (dd, J=7.03, 2.64 Hz, Ao HN 4 .7^4 Z/ < ^b 1 Η), 8.07 (d, J=2.01 Hz, 1 Η), 7.98 (d, 196 J=0.88 Hz, 1 H), 7.91-7.96 (m, 1 H), 7.57 -. X XD Ό (dd, J=11.17, 9.16 Hz, 1 H), 7.40 (d, J=3.14 one / Hz, 1 Η), 6.74 (dd, J=3.45, 1.69 Hz, 1 Η), 3.04-3.14 (m, 1 Η), 1.31 (d, J=6 .90 Hz, 6H). Method 1: RT=3.04 min; M+H=365.0 Ή NMR (400 MHz, DMSO) δ 8.87-8.98 F (m, 1 H), 8.60 (d, 7=2.89 Hz, 1 H), 8.48 (d, / γ 7=2.76 Hz, 1 N), 8.18 (dd, 7=7.03, 2.64 Hz, N-‘ hnX ,^4 b 1 H), 7.58-7.65 (w, 1 H), 7.41 (dd, 197 7=11.42, 9.16 Hz, 1 N), 7.04 (d, 7=3.01 Hz, AAH=? 1 N), 5.26-5.49 (m, 1 N), 4.23-4.36 (t, 2 Г f N / A J F H), 3.91-4.10 (t, 5 H), 3.73 (br d, 7=10.42 Hz, 1 N), 3.40 (br d, 7=9.66 Hz, 2 N), 1.652.09 (t, 4 N).

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Method 1: RT=2.69 min; M+H=441.3

Ή NMR (400 MHz, DMSOV) δ 8.92 (s, 1 Η), 8.40 (dd, 7=2.64, 1.88 Hz, 2 Η), 8.17 (dd, 7=7, 03, 2.76 Hz, 1 H), 7.57-7.72 (m, 1 H), 7.37-7.46 (m, 1 H), 6.76 (d, 7=2.76 Hz, 1 Η), 6.05 (t, 7=5.52 Hz, 1 Η), 5.29-5.57 (m, 1 Η), 4.24-4.40 (m, 2 Η) , 3.94-4.11 (m, 2 Η), 2.85 (t, 7=6.02 Hz, 2 Η), 1.93 (double fifth, 7=13.35, 6.58 , 6.58, 6.58, 6.58 Hz, 1 N), 0.99 (d, 7=6.53 Hz, 6 N).

Method 1: RT=3.00 min; M+H=401.4 Ή NMR (400 MHz, DMSO-Te) δ 8.93 (s, 1 Η), 8.34-8.43 (m, 2 Η), 8.17 (dd, 7= 7.03, 2.51 Hz, 1 Η), 7.59-7.68 (m, 1 Η), 7.41 (dd, 7=11.42, 9.16 Hz, 1 Η), 6, 77 (d, 7=2.76 Hz, 1 Η), 5.97 (t, 7=5.02 Hz, 1 Η), 5.27-5.53 (m, 1 Η), 4.24- 4.40 (m, 2 Η), 3.93-4.10 (m, 2 Η), 3.01-3.10 (m, 2 Η), 1.24 (t, 7=7.15 Hz , 3 H).

Method 2: RT=0.80 min; M+H=373.4

Ή NMR (400 MHz, DMSO) δ 8.93 (s, 1 Η), 8.40 (d, J=2.81 Hz, 1 Η), 8.33 (d, J=2.81 Hz, 1 Η), 8.15-8.21 (m, 1 Η), 7.60-7.71 (m, 1 Η), 7.37-7.48 (m, 1 Η), 6.79 (d , J=2.69 Hz, 1 H), 5.84 (br d, J=7.58 Hz, 1 H), 5.27-5.52 (m, 1 H), 4.26-4, 38 (m, 2 H), 3.96-4.09 (m, 2 H), 3.44-3.57 (m, 1 H), 1.19 (d, J=6.24 Hz, 6 H). Method 1: RT=2.78 min; M+H=387.2

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Ή NMR (400 MHz, DMSO) δ 8.94 (s, 1 Η), 8.55 (d, /=2.64 Hz, 1 Η), 8.28 (d, /=2.76 Hz, 1 Η), 8.19 (dd, /=7.03, 2.76 Hz, 1 Η), 7.62-7.70 (m, 1 Η), 7.43 (dd,/=11.29, 9.16 Hz, 1 H), 6.95 (d, /=2.76 Hz, 1 H), 5.265.51 (m, 1 H), 4.47 (t, /=7.53 Hz, 2 Η), 4.18-4.37 (m, 4 Η), 3.92-4.08 (m, 4 Η), 2.91 (t, J=7.53 Hz, 2 Η).

Method 2: RT=0.78 min; M+H=427.3

Ή NMR (400 MHz, DMSO) δ 8.92 (s, 1 Η), 8.54 (d, /=2.64 Hz, 1 Η), 8.28 (d, /=2.76 Hz, 1 Η), 8.19 (dd, /=7.03, 2.64 Hz, 1 Η), 7.61-7.69 (m, 1 Η), 7.42 (dd, /=11.36, 9.10 Hz, 1 H), 6.93 (d, /=2.76 Hz, 1 H), 5.245.50 (m, 1 H), 4.23-4.38 (m, 2 H), 3.864.06 (m, 6 H), 3.83 (s, 2 H), 3.74 (t, /=6.96 Hz, 2 H), 2.16 (t, /=6.96 Hz, 2H).

Method 2: RT=0.80 min; M+H=441.3

Ή NMR (400 MHz, DMSO) δ 8.93 (s, 1 Η), 8.53 (d, /=2.64 Hz, 1 Η), 8.28 (d, /=2.76 Hz, 1 Η), 8.15-8.24 (m, 1 Η), 7.60-7.67 (m, 1 Η), 7.42 (dd, /=11.36, 9.10 Hz, 1 Η ), 6.89 (d, /=2.76 Hz, 1 Η), 5.28-5.50 (m, 1 Η), 4.24-4.37 (m, 2 Η), 3.89 -4.08(m, 2h), 3.72(s, 4h), 3.43-3.62(m, 4h), 1.731.84(m, 4h). Method 2: RT=0.85 min; M+H=455.3

Ή NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1 Η), 8.53 (br d, /=2.76 Hz, 1 Η), 8.50 (br d, /=2, 76 Hz, 1 H), 8.19-8.28 (m, 1 H), 7.62-7.71 (m, 1 H), 7.43 (dd,/=11.29, 9.16 Hz, 1 H), 6.96 (d, /=2.76 Hz, 1 H), 5.295.50 (m, 1 H), 4.21-4.45 (m, 2 H), 3.894.13 (m, 2 Η), 3.77 (d, /=10.04 Hz, 2 Η), 3.65 (br d, /=8.91 Hz, 2 Η), 2.68-2.80 ( m,

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2H). Method 1: RT=2.84 min; M+H=447.3 205 F HN—{ ,n. ..ν P b g g% - / - N /= o ^L - ^JF Ή NMR (400 MHz, DMSO) δ 8.92 (s, 1 H), 8.51 (d, J=2.76 Hz, 1 H), 8.26 (d, J=2.76 Hz, 1 H), 8.17 (dd, J=7.09, 2.70 Hz, 1 H), 7.58-7.65 (m, 1 H), 7.40 (dd, J=11.36, 9.10 Hz, 1 H), 6.91 (d, J=2.76 Hz, 1 H), 5.235.50 (m, 1 H), 4.23-4.37 (m, 3 H), 4.104.19 (m, 2 H), 3.93-4.07 (m, 2 H), 3.68 (dd, J=8.22, 4.33 Hz, 2 H), 3.20-3 .27 (m, 3H). Method 1: RT=2.59 min; M+H=415.2 206 z // \\ /z /Gy •1 z z D' D X ζ ^X NMR (400 MHz, DMSO-76) δ 10.94 (s, 1H), 9.49 (d, 7=2.3 Hz, 1H), 9.08 (d, 7=2.5 Hz, 1H ), 8.97 (d, 7=2.3 Hz, 1H), 8.75 (ddd, 7=0.9, 1.9, 4.8 Hz, 1H), 8.56 (dd, 7= 2.7, 7.0 Hz, 1H), 8.15 (dt, 7=1.1, 8.1 Hz, 1H), 8.077.92 (m, 2H), 7.82 (d, 7=3 .8 Hz, 1H), 7.65 (dd, 7=9.1, 11.2 Hz, 1H), 7.59 (d, 7=3.8 Hz, 1H), 7.45 (ddd, 7 =1.1, 4.8, 7.5 Hz, 1H). Method 1: RT=2.83 min; M+H=425.4 207 HNX Ad _/Γ χ b . lk ^N -_ T' / Ή NMR (400 MHz, Methylene chloride-7 ₂ ) δ 8.67 (m, 1H), 8.48 (m, 1H), 8.19 (m, 1H), 7.93-7.83 (m, 2H ), 7.26 (m, 1H), 3.683.49 (m, 3H), 3.08 (m, 1H), 1.90-1.76 (m, 2H), 1.37-1.32 ( m, 6H), 1.28-1.07 (m, 4H). Method 1: RT=3.08 min; M+H=383.3 208 pS HNy _x N.. m ,—/ '□ 1 £ Ή NMR (400 MHz, Methylene chloride-7 ₂ ) δ 9.91 (s, 1H), 8.68 (m, 1H), 8.47 (m, 1H), 8.19 (m, 1H), 8, 11-8.02(m, 1H), 7.97(m, 1H), 7.27(m, 1H), 3.09(m, 1H), 2.63(m, 1H), 2.16 (m, 1H), 1.70 (m, 1H), 1.33 (m, 6H). Method 1: RT=3.04 min; M+H=375.3

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209 Xi ^F D—D HNY F ₍ Ld 0 DAKE g ~ / Ή NMR (400 MHz, Methylene chloride-7 ₂ ) δ 8.78 (m, 2H), 8.35 (m, 1H), 8.30 (m, 1H), 7.99 (m, 1H), 7, 81 (m, 1H), 7.36 (m, 1H), 3.19 (m, 1H), 2.30-2.18 (m, 2H), 2.031.95 (m, 2H), 1.42 -1.34 (m, 6H). Method 1: RT=3.14 min; M+H=407.2 210 \V T z d - four. / Ή NMR (400 MHz, Methylene chloride-b2) δ 8.66 (m, 1H), 8.48 (m, 1H), 8.18 (m, 1H), 7.92-7.88 (m, 2H) , 7.27(m, 1H), 3.243.13(m, 1H), 3.08(m, 1H), 2.41-2.29(m, 2H), 2.25-2.12(m , 2H), 2.05-1.89 (m, 2H), 1.37-1.31 (m, 6H). Method 1: RT=3.14 min; M+H=353.3 211 χ, Xg z z' > \ V / \ / Ή NMR (400 MHz, Methylene chloride-02) δ 8.66 (m, 1H), 8.49-8.40 (m, 2H), 8.17 (br, 1H), 7.92-7.84 ( m, 2H), 7.24 (m, 1H), 3.07 (m, 1H), 1.46-1.36 (m, 1H), 1.36-1.30 (br, 6H), 1 .30-1.24 (m, 1H), 1.24-1.15 (br, 1H), 1.10 (br, 3H), 0.65 (m, 1H). Method 1: RT=3.16 min; M+H=353.3 212 F /—X NND F D ., .n _Z -Y b .. L OD) T Ή NMR (400 MHz, Methylene chloride-02) δ 9.74 (m, 1H), 8.64 (m, 1H), 8.44 (m, 1H), 8.15 (m, 1H), 8.05 (m, 1H), 7.93 (m, 1H), 7.31 (m, 1H), 3.30 (m, 2H), 3.08 (m, 1H), 1.46-1.17 ( m, 6H). Method 1: RT=3.08 min; M+H=381.2 213 . Xl A ,L ., N'N' D _c > O « “ ► ' / =N ^1H NMR (400 MHz, Methylene chloride-02) δ 9.14 (m, 1H), 8.64 (m, 1H), 8.45 (m, 1H), 8.22 (m, 1H), 8, 00 (m, 1H), 7.91 (m, 1H), 7.28 (m, 1H), 3.07 (m, 1H), 2.96-2.84 (m, 1H), 2.71 (m, 1H), 2.27 (m, 1H), 1.33 (m, 6H), 1.15 (m, 3H). Method 1: RT=3.27 min; M+H=409.3

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214 N=, / n Г _ ~ F -.- Ν . N.'ν' έ " l _F Ή NMR (400 MHz, Methylene chloride-c12) δ 8.88 (m, 1H), 8.64 (m, 1H), 8.45 (m, 1H), 8.19 (m, 1H), 7.99 -7.92(m, 1H), 7.90(m, 1H), 7.27(m, 1H), 3.07(m, 1H), 2.43(m, 2H), 2.24- 2.07 (m, 2H), 1.97-1.86 (m, 2H), 1.33 (m, 6H). Method 1: RT=3.23 min; M+H=409.3 215 X / ΗΝ < W- --Ν l <'0 J,X ^N Q 1 f' Ή NMR (400 MHz, Methylene chloride-d2) δ 8.66 (m, 1H), 8.47 (m, 1H), 8.19 (m, 2H), 7.92-7.86 (m, 2H) , 7.27(m, 1H), 3.08(m, 1H), 2.47-2.39(m, 2H), 1.58(m, 2H), 1.38-1.29(m , 6H), 0.78-0.66 (m, 1H), 0.45-0.38 (m, 2H), 0.07-0.01 (m, 2H). Method 1: RT=3.23 min; M+H=367.3 216 .· ' ΗΝ < ^v Ak-N / \ 0 ' N { ) . F Ή NMR (400 MHz, Methylene chloride-d2) δ 8.66 (m, 1H), 8.47 (m, 1H), 8.18 (m, 1H), 8.05 (m, 1H), 7.91 -7.83(m, 2H), 7.26(m, 1H), 3.08(m, 1H), 2.74(m, 1H), 2.44(m, 2H), 2.17- 2.10 (m, 2H), 1.94-1.78 (m, 2H), 1.78-1.66 (m, 2H), 1.37-1.30 (m, 6H). Method 1: RT=3.19 min; M+H=367.3 217 X ' ^C T ^J zz > A f \ Ή NMR (400 MHz, Methylene chloride-d2) δ 8.66 (m, 1H), 8.48 (m, 1H), 8.21 (m, 1H), 7.89 (m, 1H), 7.84 (m, 1H), 7.79 (m, 1H), 7.27 (m, 1H), 3.08 (m, 1H), 2.20 (m, 2H), 1.38-1.21 ( m, 6H), 1.11-0.89 (m, 9H). Method 1: RT=3.29 min; M+H=369.3 218 Γ'ά M , _: 4 NH Г ^d hx yU ^— ( 'Ж F Ή NMR (400 MHz, DMSO-r/J δ 10.13 (s, 1H), 9.48 (d, 7=2.3 Hz, 1H), 9.04 (d, J=2.5 Hz, 1H), 8.95 (d, 7=2.3 Hz, 1H), 8.77-8.70 (m, 1H), 8.64-8.58 (m, 1H), 8.40 (d , 7=8.4Hz, 1H), 7.58(dd, 7=11.2, 9.1Hz, 1H), 7.46-7.37(m, 3H), 6.86(d, 7=1.3 Hz, 1H), 2.77-2.72(m, 2H), 2.48-2.42(m, 2H).

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Method 1: RT=2.80 min; M+H=386,l 219 < t. .four ) ( G „ϊ IX Z- ,XJ<° O''' 'z' o 0^0 σ Ή NMR (400 MHz, Chloroform-d) δ 8.70 (m, 1H), 8.51 (m, 1H), 7.96 (m, 1H), 7.907.81 (m, 2H), 7.27 -7.19(m, 1H), 6.73(m, 1H), 3.08(m, 1H), 1.43-1.28(m, 6H). Method 2: RT=0.90 min; M+H=348.3 220 <x N- ^J hnX ?XN b . ΛΑ.Η ) T ' Y Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.52 (m, 1H), 8.14-7.90 (m, 2H), 7.87 (m, 1H) , 7.28-7.20(m, 1H), 6.44(m, 1H), 3.76-3.57(m, 2H), 3.46-3.31(m, 2H), 3 .08 (m, 1H), 1.98-1.78 (m, 2H), 1.54-1.18 (m, 6H), 0.74-0.54 (m, 4H). Method 2: RT=l.05 min; M+H=394.3 221 C' HN < /Xn < < b N / b f' Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.49 (m, 1H), 8.15-7.89 (m, 2H), 7.89-7.84 ( m, 1H), 7.24(m, 1H), 6.50(m, 1H), 3.63(m, 2H), 3.50-3.38(m, 1H), 3.16-2 .93 (m, 2H), 2.46-2.04 (m, 2H), 1.68-1.56 (m, 1H), 1.51-1.20 (m, 6H), 1.12 (m, ZN). Method 2: RT=l.02 min; M+H=382.3 222 x\ Ν-' ΗΝχ f-fXX ⁰ TX Ή NMR (400 MHz, Chloroform-d) δ 8.70 (m, 1H), 8.51 (m, 1H), 7.99-7.91 (m, 2H), 7.87 (m, 1H) , 7.28-7.21(m, 1H), 6.52(m, 1H), 4.15(m, 4H), 3.08(m, 1H), 1.53-1.18(m , 6H), 0.70 (m, 4H). Method 2: RT=l.01 min; M+H=380.3 223 \ / N- ^J HN { /S-xN ₄ b . , 1.....>'U 1 F Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.51 (m, 1H), 8.13-7.80 (m, 3H), 7.27-7.19 ( m, 1H), 6.38 (m, 1H), 3.713.51 (m, 4H), 3.08 (m, 1H), 1.61-1.31 (m, 6H), 1.24 (m , 2H), 0.81 (m, 1H), 0.31 (m, 1H). Method 2: RT=0.99 min; M+H=380.3

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224 x / N—' ηνΧ '° Τ X Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.53 (m, 1H), 7.96 (m, 1H), 7.927.83 (m, 2H), 7.27 -7.21(m, 1H), 6.55(m, 1H), 3.45(m, 2H), 3.10(m, 1H), 3.06-2.98(m, 3H), 1.37(m, 6H), 1.26-1.22(m, 3H). Method 2: RT=0.96 min; M+H=356.3 225 With/ to Τ' ζ) V/ \ / Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.53-8.45 (m, 1H), 8.17-7.84 (m, 3H), 7.27- 7.19 (m, 1H), 6.60 (m, 1H), 4.12-3.95 (m, 1H), 3.69-3.50 (m, 4H), 3.44-3, 29 (m, 3H), 3.09 (m, 1H), 2.242.01 (m, 2H), 1.54-1.18 (m, 6H). Method 2: RT=0.92 min; M+H=398.3 226 X P ΗΝ ( ,Α Ν _Ζ b χ ΑΧ Ο ί Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.51 (m, 1H), 7.97-7.89 (m, 2H), 7.87 (m, 1H) , 7.28-7.19 (m, 1H), 6.28 (m, 1H), 4.04 (m, 4H), 3.09 (m, 1H), 2.22 (m, 4H), 1.94-1.83(m, 2H), 1.49-1.14(m, 6H). Method 2: RT=l.06 min; M+H=394.3 227 F ί J ^F i ι ^Η νΧΜ Ν— ^ζ ' Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.49 (m, 1H), 8.09 (m, 1H), 7.87 (m, 1H), 7.81 (m, 1H), 7.28-7.20 (m, 1H), 7.09 (m, 1H), 4.08 (m, 2H), 3.19 (m, 3H), 3.09 ( m, 1H), 1.37 (m, 6H). Method 2: RT=l.04 min; M+H=410.3 228 Ζ Ό ' τ ζ η: ι Ί ζ Η ζ ( four ? / Ή NMR (400 MHz, Chloroform-d) δ 8.71 (m, 1H), 8.51 (m, 1H), 7.96 (m, 1H), 7.897.81 (m, 2H), 7.24 (m, 1H), 6.71 (m, 1H), 3.51 (m, 1H), 3.09-3.03 (m, 6H), 1.421.28 (m, 6H). Method 2: RT=0.90 min; M+H=342.3

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229 . N., (ί / Ή NMR (400 MHz, Chloroform-d) δ 8.62 (m, 1H), 8.44 (m, 1H), 7.89 (m, 1H), 7.817.77 (m, 1H), 7.75 (m, 1H), 7.18-7.12 (m, 1H), 6.61 (m, 1H), 4.13 (m, 1H), 3.73-3.62 (m, 2H), 3.13-2.90 (m, 6H), 2.06-1.97 (m, 3H), 1.77-1.74 (m, 2H), 1.28 (m, 6H). Method 1: RT=2.42 min; M+H=423.3 fYW Y' ⁴ ^ ? ΗΝ^ Y 0 b NMR (400 MHz, DMSO) δ ppm 8.91 (s, 1 H), 8.73 (d, 7=2.76 Hz, 1 H), 8.58 (d, 1 / G--U 7=2.64Hz, 1H), 8.18 (dd, J=7.03, 2.64Hz, γ 1 H), 7.57-7.68 (m, 1 H), 7.41 (dd, 230 ΗΝ—ΐ .<·· ^Ν -χ^Ν b . ..λ W ) J=11.29, 9.03 Hz, 1 H), 7.35 (d, 7=2.76 Hz, 1 H), 5.25-5.49 (m, 1 H), 4.23- 4.36(m, 2 -X _Ν X,' o .- F H), 3.93-4.07(m, 2H), 3.69-3.84(m, 2H), F 3.56 (br d, 7=10.92 Hz, 2 H), 2.24-2.32 (m, 2 H), 1.15 (d, 7=6.15 Hz, 6 H). Method 1: RT=2.79 min; M+H=433.3 Ή NMR (400 MHz, DMSO) δ ppm 8.94 (s, 1 H) 8.60 (d, 7=2.76 Hz, 1 H), 8.56 (d, 7=2.76 Hz, 1 H), 8.22 (dd, 7=7.09, 2.70 Hz, 1 H), 7.62-7.69 (m, 1 H), 7.44 (dd, 231 ΗΝ—Ζ 7=11.29, 9.16 Hz, 1 H), 7.18 (d, 7=2.76 Hz, A / /—\ ζ ρ ζ 0-J Q. 1 H), 5.30-5.51 (m, 1 H), 5.10 (d, 7=8.28 Hz, 2 H), 4.75 (d, 7=8.28 Hz, 2 H ), 4.26- t-d one' F 4.38 (m, 2 H), 3.96-4.09 (m, 2 H), 3.74 (t, 7=6.96 Hz, 2 H), 2.58 (br s, 2 H ). Method 1: RT=2.65 min; M+H=427.2 Ή NMR (400 MHz, DMSO) δ ppm 8.94 (s, 1 H), 8.52 (d, 7=2.69 Hz, 1 H), 8.26 (d, 7=2.81 Hz, 1 H), 8.19 (dd, 7=7.03, 2.63 Hz, 232 fX Ν' ^{1 ΗΝ} 4 _Ν Μ ⁰ 1 H), 7.60-7.68 (m, 1 H), 7.42 (dd, 7=11.37, 9.17 Hz, 1 H), 6.88 (d, 7=2.69 Hz, pN” G' 1 H), 5.28-5.50 (m, 1 H), 4.24-4.37 (m, 2 H), 4.02-4.08 (m, 1 H), 3.98 ( t, 7=7.64 Hz, 3 H), 3.65 (dd, 7=7.15, 5.69 Hz, 2 H), 3.56

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(d, 1=6.60 Hz, 2 H), 3.29 (s, 3 H), 2.96 (m, 1 H). Method 1: RT=2.70 min; M+H=429.3 233 1 N- ^J HN 4 χ ^ν ·^-.ν λ δ b . . ν C Y F V Ή NMR (400 MHz, DMSO) δ ppm 8.92 (s, 1 H), 8.52 (d, 7=2.76 Hz, 1 H), 8.28 (d, 7=2.76 Hz, 1 H), 8.19 (dd, 7=7.03, 2.64 Hz, 1 H), 7.59-7.67 (m, 1 H), 7.42 (dd, 7=11.36 , 9.10 Hz, 1 H), 6.91 (d, 7=2.89 Hz, 1 H), 5.27-5.50 (m, 1 H), 4.23-4.38 (m , 2H), 3.94-4.10 (m, 6H), 0.68 (s, 4H). Method 1: RT=2.92 min; M+H=411.3 234 F HN^ 'θ _z 1 L?-O ^F $X~ A F ΉNMR (400 MHz, DMSO) δ 8.88 (s, 1 Η), 8.48-8.59 (m, 2 Η), 8.17 (dd, 1=7.03, 2.64 Hz, 1 Η), 7.54-7.67 (m, 1 Η), 7.39 (dd, 7=11.36, 9.10 Hz, 1 Η), 7.03 (d, 7=2.89 Hz , 1 Η), 5.19-5.63 (m, 3 Η), 4.19-4.40 (m, 2 Η), 3.93-4.06 (m, 2 Η), 3.57 -3.87 (m, 4 H). Method 1: RT=2.77 min; M+H=435,l 235 О x ' Q ,7 ^- % pz H z - A IX z Αχ Ή NMR (400 MHz, DMSO) δ 8.93-9.02 (m, 1 Η), 8.68 (d, 7=2.76 Hz, 1 Η), 8.53 (d, 7=2, 76 Hz, 1 H), 8.20 (dd, 7=7.03, 2.64 Hz, 1 H), 7.62-7.69 (m, 1 H), 7.43 (dd, 7= 11.36, 9.10 Hz, 1 H), 7.35 (d, 7=2.76 Hz, 1 H), 5.28-5.51 (m, 1 H), 4.20-4, 38 (m, 4 Η), 3.94-4.14 (m, 2 Η), 3.79 (d, 7=10.79 Hz, 2 Η), 3.50 (br d, 7=10, 67 Hz, 2 H), 1.88-2.01 (m, 4 H). Method 1: RT=2.63 min; M+H=441.3 236 F A NT HNA _l X L. ⁿ x ? r 'N' - i— x- ¹ -- ^{1 F} 0 Ή NMR (400 MHz, DMSO) δ 8.96 (s, 1 Η), 8.69 (d, 7=2.69 Hz, 1 Η), 8.59 (d, 7=2.57 Hz, 1 Η), 8.19 (dd, 7=7.03, 2.63 Hz, 1 Η), 7.61-7.70 (m, 1 Η), 7.31-7.47 (m, 2 Η ), 5.27-5.50 (m, 1 Η), 4.23-4.39 (m, 2 Η), 3.93-4.08 (m, 2 Η), 3.56 (br d , 7=11.98 Hz, 2 Η), 2.74 (br t, 7=10.45 Hz, 2 Η), 2.23-

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2.33 (m, 1 H), 1.94 (br d, /=10.76 Hz, 2 H), 1.65-1.80 (m, 2 H). Method 1: RT=2.55

min.; Μ+Η=457.3 237 Vz g -η g ζ ζ; ζ X ψ // Ζ ^. ........ν -ζ Ή NMR (400 MHz, DMSO) δ 8.96 (s, 1 Η), 8.72 (d, /=2.76 Hz, 1 Η), 8.62 (d, /=2.76 Hz, 1 Η), 8.20 (dd, /=7.03, 2.76 Hz, 1 Η), 7.59-7.72 (m, 1 Η), 7.44 (t, /=10.41 Hz , 1 Η), 7.38 (s, 1 Η), 5.26-5.52 (m, 1 Η), 4.254.39 (m, 2 Η), 3.96-4.10 (m, 2 Η), 3.233.31 (m, 2 Η), 3.12-3.21 (m, 4 Η), 2.762.90 (m, 4 Η). Method 1: RT=2.88 min; M+H=496.4 238 Z Λ 'ΐ ζ D ,· b Ή NMR (400 MHz, DMSO) δ 8.89-8.98 (m, 1 Η), 8.71 (d, /=2.89 Hz, 1 Η), 8.62 (d, /=2, 64 Hz, 1 H), 8.19 (dd, /=7.03, 2.64 Hz, 1 H), 7.58-7.70 (m, 1 H), 7.36-7.51 ( m, 2 Η), 5.22-5.54 (m, 1 Η), 4.63 (dd, /=7.84, 5.96 Hz, 2 Η), 4.22-4.46 (m , 4 Η), 3.924.11 (m, 2 Η), 3.58-3.76 (m, 2 Η), 2.602.84 (m, 3 Η), 1.65-1.85 (m, 3 Η), 1.171.32 (m, 2 H). Method 1: RT=2.74 min; M+H=469.3 239 F Ν-' ΗΝ < -Ν l Ζ b GM' ^: - Μ ^Ζ F4^JF S4 Ή NMR (400 MHz, DMSO) δ 8.93 (s, 1 Η) 8.54 (d, /=2.76 Hz, 1 Η), 8.26 (d, J=2.76 Hz, 1 Η ), 8.19 (dd, /=7.09, 2.70 Hz, 1 Η), 7.60-7.67 (m, 1 Η), 7.42 (dd, /=11.36, 9 .10 Hz, 1 Η), 6.93 (d, /=2.76 Hz, 1 Η), 5.295.51 (m, 1 Η), 4.23-4.38 (m, 2 Η), 3.924 .09 (m, 6 Η), 3.41 (s, 4 Η). Method 1: RT=2.84 min; M+H=443.3

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240 F ό _Γ > ^Ν - Ν W 'θ ... LL ⁿ a ) ^F Ή NMR (400 MHz, DMS0) δ 8.93 (s, 1 Η), 8.68 (d, 7=2.89 Hz, 1 Η), 8.53 (d, 7=2.76 Hz, 1 Η), 8.20 (dd, 7=7.09, 2.70 Hz, 1 Η), 7.59-7.65 (m, 1 Η), 7.41 (dd, 7=11.36, 9.10 Hz, 1 Η), 7.11 (d, 7=3.01 Hz, 1 Η), 5.275.48 (m, 1 Η), 4.73 (d, 7=6.27 Hz, 2 Η) 4.23-4.36 (m, 2 Η), 3.93-4.06 (m, 2 Η), 3.70 (d, 7=11.29 Hz, 2 Η) 3.48 ( br d, 7=10.92 Hz, 2 Η), 3.08-3.16 (m, 1 Η), 1.99 (d, 7=8.53 Hz, 1 H). Method 1: RT=2.52 min; M+H=427.3 241 F ci N-' HN A l b . £ V O K/ N' ) ' ^u \_J F Ή NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1 Η), 8.49 (dd, 7=7.09, 2.82 Hz, 2 Η), 8.20 (dd, 7= 7.03, 2.64 Hz, 1 Η), 7.60-7.67 (m, 1 Η), 7.42 (dd, 7=11.48, 9.10 Hz, 1 Η), 6, 88 (d, 7=2.89 Hz, 1 H), 5.28-5.50 (m, 1 H), 4.24-4.39 (m, 2 H), 3.97-4.08 (m, 2 Η), 3.51 (t, 7=6.78 Hz, 2 Η), 3.30 (s, 2 Η), 1.96 (t, 7=6.78 Hz, 2 Η) , 0.60-0.71 (m, 4 Η). Method 1: RT=3.16 min; M+H=425.3 242 D. N D S ' _P d - „d A Ή NMR (400 MHz, DMSO) δ 8.41-8.52 (m, 3 Η), 8.23 (dd, 7=7.09, 2.70 Hz, 1 Η), 7.60-7, 69 (m, 1 Η), 7.38 (dd, 7=11.42, 9.16 Hz, 1 Η), 6.86 (d, 7=2.89 Hz, 1 Η), 3.52 ( dt, 7=15.34, 6.89 Hz, 3 Η), 3.28 (s, 5 Η), 1.95 (t, 7=6.78 Hz, 2 Η), 1.81 (t, 7=6.78 Hz, 2 H), 0.52-0.71 (m, 8 H). Method 1: RT=3.26 min; M+H=447.3

Ή NMR (400 MHz, DMSO) δ 8.89 (s, 1 Η), 8.50 (d, 7=2.76 Hz, 1 Η), 8.22 (s, 1 Η), 8.16 ( d, 7=6.68 Hz, 1 Η), 7.59-7.64 (m, 1 Η), 7.40 (dd, 7=11.36, 9.10 Hz, 1 Η), 6, 85 (d, 7=2.76 Hz, 1 Η), 5.25-5.49 (m, 1 Η), 4.144.36 (m, 2 Η), 3.93-4.05 (m, 2 Η), 3.86 (s, 4 Η), 2.18 (t, 7=7.59 Hz, 4 Η), 1.82 (quint.,

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7=7.53 Hz, 2 H). Method 1: RT=3.06 min; M+H=425.3 244 F С N- ¹ HN F NNC --, 1 L ^N VjJ - - _₽ ' Ή NMR (400 MHz, DMSO) δ 8.92 (s, 1 H), 8.49 (dd, 7=9.47, 2.82 Hz, 2 H), 8.20 (dd, 7=7, 03, 2.64 Hz, 1 H), 7.60-7.67 (m, 1 H), 7.41 (dd, 7=11.36, 9.10 Hz, 1 H), 6.88 ( d, 7=2.89 Hz, 1 H), 5.27-5.50 (m, 1 H), 4.244.37 (m, 2 H), 3.94-4.08 (m, 2 H) , 3.553.69 (m, 4 H), 3.41-3.46 (m, 2 H), 3.28 (s, 2 H), 1.92 (t, 7=6.96 Hz, 2 H ), 1.46-1.63 (m, 4H). Method 1: RT=2.86 min; M+H=469.3 245 £A*. - ^f II Г-.М- N f ) ¹ / 0^-. TJ F Ή NMR (400 MHz, DMSO) δ 8.91 (s, 1 H), 8.55 (d, 7=2.64 Hz, 1 H), 8.29 (d, 7=2.89 Hz, 2 H), 8.19 (dd, 7=7.03, 2.76 Hz, 1 H), 7.60-7.66 (m, 1 H), 7.42 (dd, 7=11.29, 9.16 Hz, 1 H), 6.98 (d, 7=2.76 Hz, 1 H), 5.275.49 (m, 1 H), 4.23-4.36 (m, 2 H), 3.944.09 (m, 4 H), 3.86 (d, 7=7.78 Hz, 2 H), 2.38 (br d, 7=7.78 Hz, 2 H), 2.21-2 .28 (m, 2H). Method 1: RT=2.41 min; M+H=454.3 246 -°\ : u:T V c) Ή NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1 H), 8.53 (d, 7=2.76 Hz, 1 H), 8.28 (d, 7=2.76 Hz , 1 H), 8.21 (dd, 7=7.15, 2.64 Hz, 1 H), 7.60-7.71 (m, 1 H), 7.41 (dd, 7=11, 36, 9.10 Hz, 1 H), 6.94 (d, 7=2.76 Hz, 1 H), 3.93 (d, 7=12.05 Hz, 8 H), 3.84 (s , 2H), 3.67-3.80 (m, 6H), 2.09-2.21 (m, 4H). Method 1: RT=2.64 min; M+H=479.4

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247 DG ΝHN0 ,, χ,MΧ/ M .0 F όΓ Ή NMR (400 MHz, Methanol-04) δ 8.838.71 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.12 (dd, J=6.8, 2, 7 Hz, 1H), 7.65 (dt, J=9.3, 3.6 Hz, 1H), 7.35 (dd, J=10.9, 9.1 Hz, 1H), 7.09- 6.97 (m, 1H), 5.32-5.14 (m, 1H), 4.17-4.01 (m, 4H), 3.83-3.56 (m, 2H), 2, 63-2.44 (m, 1H), 2.39-2.25 (m, 2H), 2.09-1.93 (m, 3H), 1.47 (s, 3H), 1.07 ( s, 6H). Method 2: RT=0.93 min; M+H=481.3 248 F g Ν'” ΗΝ Ζ ( 0 ^ _n aJw ⁿ >7 α - ^F SNMR (400 MHz, DMSO) δ 8.95 (s, 1 H) 8.70 (d, /=2.76 Hz, 1 H), 8.60 (d, /=2.76 Hz, 1 H) , 8.19 (dd, /=7.09, 2.70 Hz, 1 H), 7.61-7.69 (m, 1 H), 7.44 (dd, /=11.23, 9, 10 Hz, 1 H), 7.37 (d, /=2.76 Hz, 1 H), 5.275.51 (m, 1 H), 4.25-4.40 (m, 6 H), 3.964, 09 (m, 2H), 3.02-3.10 (m, 4H), 1.912.00 (m, 4H). Method 1: RT=2.65 min; M+H=455.3 249 F Μ g \ Ν "" ΗΝ-Ζ Mk_-N ,Α b % 1 ΙαΜ) Ν' - ⁷ Α Η t' Ή NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1 Η), 8.48 (d, /=2.89 Hz, 1 Η), 8.29 (d, /=2.76 Hz , 1 Η), 8.17 (dd, /=7.15, 2.64 Hz, 1 Η), 7.59-7.66 (m, 1 Η), 7.41 (dd, /=11, 42, 9.16 Hz, 1 H), 7.09 (d, /=2.64 Hz, 1 H), 6.47 (s, 1 H), 5.28-5.50 (m, 1 H ), 4.24-4.38 (m, 2 Η), 3.94-4.08 (m, 2 Η), 2.37 (br s, 1 Η), 0.70-0.77 (m , 2 H), 0.390.47 (m, 2 H). Method 1: RT=2.78 min; M+H=385,l 250 Ε _r T- ^N ->^N }= , . IL _F ζ - —/ o ANJ NM L 1 '' ··- Μ 1 ^H NMR (400 MHz, DMSO) δ 8.66-8.73 (m, 2 H), 8.60 (d, /=2.76 Hz, 1 H), 8.20 (dd, /=7 .03, 2.64 Hz, 1 H), 7.62-7.69 (m, 1 H), 7.35-7.45 (m, 2 H), 3.96 (t, /=7, 53 Hz, 4 Η), 3.22-3.30 (m, 2 Η), 3.11-3.19 (m, 4 Η), 2.78-2.86 (m, 4 Η), 2 .19 (quint., /=7.56

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Hz, 2H). Method 1: RT=2.95 min; M+H=478,l 251 P .—' X. ^N T, Lm NX HN tv- ^OH ',^=0 \ -N \ --A r' Ή NMR (400 MHz, DMSO) δ 8.87-8.99 (m, 1 Η), 8.52 (d, 7=2.51 Hz, 1 Η), 8.28 (d, 7=2, 64 Hz, 1 H), 8.20 (dd, 7=6.96, 2.45 Hz, 1 H), 7.64 (dt, 7=8.72, 3.36 Hz, 1 H), 7 .42 (dd, 7=11.17, 9.29 Hz, 1 Η), 6.92 (d, 7=2.64 Hz, 1 Η), 5.28-5.69 (m, 2 Η) , 4.22-4.42 (m, 2 Η), 3.94-4.10 (m, 2 Η), 3.87 (d, 7=7.40 Hz, 2 Η), 3.69 ( d, 7=7.28 Hz, 2 H), 1.49 (s, 3 H). Method 1: RT=2.53 min; M+H=415.3 252 F G ^F G? ^f + f -NJ Anh Г n A /— AW J \=/ N Ίψ F Ή NMR (400 MHz, DMSO) δ 9.20 (s, 1 Η), 8.72 (d, 7=2.76 Hz, 1 Η), 8.62 (d, 7=2.64 Hz, 1 Η), 8.30 (d, 7=2.38 Hz, 1 Η), 7.597.68 (m, 1 Η), 7.46 (dd, 7=11.23, 9.22 Hz, 1 Η) , 7.38 (d, 7=2.13 Hz, 1 Η), 4.40 (t, 7=12.74 Hz, 4 Η), 3.21-3.27 (m, 2 Η), 3 ,12-3.18 (m, 4 Η), 2.78-2.86 (m, 4 Η). Method 1: RT=2.99 min; M+H=514.3 253 b.t. '............z: Y--------------v. ν' z / 4 zz _ 1 I ¹ k z L O Z Ή NMR (400 MHz, DMSO) δ 8.72 (d, 7=2.76 Hz, 1 Η), 8.54-8.64 (m, 2 Η), 8.22 (dd, 7=7, 03, 2.64 Hz, 1 Η), 7.68 (dt, 7=8.97, 3.48 Hz, 1 Η), 7.33-7.49 (m, 2 Η), 5.255.49 ( m, 1 Η), 3.38-3.79 (m, 6 Η), 3.16 (br d, 7=4.89 Hz, 4 Η), 2.83 (br d, 7=4.27 Hz, 4 Η), 2.00-2.26 (m, 2 Η). Method 1: RT=2.95 min; M+H=510.3 254 <kf ! ^l -n Xn[ 1 (Y .-. .x^x .xVG Oo ; 4 _N 1 Ή NMR (400 MHz, DMSO-d6), δ 8.90 (d, >2.45 Hz, 1 Η), 8.85 (s, 1 Η), 8.74-8.78 (m, 1 Η ), 8.61-8.65 (m, 1 Η), 8.26 (dd, >7.09, 2.69 Hz, 1 Η), 7.69-7.76 (m, 1 Η), 7.47 (dd, >11.25, 9.29 Hz, 1 Η), 4.05 (s, 4 Η), 0.66 (s, 4 Η). Method 1: RT=2.95 min; M+H=416.0, 418.0

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255 F /-( /--Y, (. 7 ^N . J 2 / '' N-\ HN LV )=0 \ F Ή NMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.52 (d, J=2.7 Hz, 1H), 8.26 (d, J=2.8 Hz, 1H ), 8.20 (dd, J=7.0, 2.7Hz, 1H), 7.65 (ddd, J=9.l, 4.1, 2.7Hz, 1H), 7.43 ( dd, J=ll,4, 9.1Hz, 1H), 6.87 (d, J=2.8Hz, 1H), 5.51-5.26 (m, 1H), 4.39-4, 23 (m, 2H), 4.09-3.94 (m, 2H), 3.65 (s, 4H), 1.32 (s, 6H). Method 1: RT=3.08 min; M+H=413.2 256 pvp Vnh " / trans - racemic < F Ή NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.48 (d, J=2.3 Hz, 1H), 9.03 (d, J=2.4 Hz, 1H ), 8.94 (d, J=2.3 Hz, 1H), 8.74 (ddd, J=4.8, 1.9, 0.9 Hz, 1H), 8.39 (dd, J= 7.0, 2.7 Hz, 1H), 8.21-8.10 (m, 1H), 7.96 (td, J=7.7.1.8 Hz, 1H), 7.75-7 .62 (m, 1H), 7.57 (dd, J=11.1, 9.0 Hz, 1H), 7.42 (ddd, J=7.5, 4.8, 1.1 Hz, 1H ), 4.92 (dddd, J=64.6, 6.3, 3.3, 1.6 Hz, 1H), 2.41-2.24 (m, 1H), 1.57 (dddd, J =22.4, 10.3, 6.6, 3.3 Hz, 1H), 1.28 (dq, J=13.0, 6.5 Hz, 1H). Method 1: RT=2.79 min; M+H=392,l 257 _z . /=N f D. o HN^O D Ή NMR (400 MHz, DMSO) δ 8.69 (s, 1 H), 8.52 (d, 7=2.63 Hz, 1 H), 8.28 (d, 7=2.76 Hz, 1 H), 8.20 (dd, 7=7.03, 2.63 Hz, 1 H), 7.62-7.69 (m, 1 H), 7.40 (dd, 7=11.29, 9.16Hz, 1H), 6.91(d, 7=2.76Hz, 1H), 4.01(s, 4H), 3.97(t, 7=7.53Hz, 4H) , 2.19 (quint., 7=7.56 Hz, 2 Η), 0.68 (s, 4 Η). Method 1: RT=2.90 min; M+H=393.2

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V 7z. 6 Ή NMR (400 MHz, DMSO) δ 9.21 (br s, 1 H), 8.54 (s, 1 H), 8.28 (d, 7=1.63 Hz, 1 H), 8.20 (br d, 7=6.65 Hz, 1 H), 7.63 (br d, 258 T HN, X T 7=8.41Hz, 1H), 7.45(t, 7=9.91Hz, 1H), 6.92(d, 7=2.01Hz, 1H), 4.40(t , 7=12.86 A. ίΊ — Hz, 4H), 4.02(s, 4H), 0.68(s, 4H). Method 1: RT=3.03 min; M+H=429.2 !HNMR (400 MHz, DMSO) δ 8.60 (s, 1 H), 8.54 (br s, 1 H), 8.28 (d, 7=2.76 Hz, 1 H), . ,—N F 8.22 (dd, 7=7.03, 2.76Hz, 1H), 7.64-7.72 259 [>4. ⁿ ~Q>n ,, Г _l A. X- rb ,. z - J 0 H > (m, 1 H), 7.41 (dd, 7=11.17, 9.16 Hz, 1 H), 6.92 (d, 7=2.76 Hz, 1 H), 5.27-5 .48 (m, 1 H), 4.02 (s, 4 H), 3.57-3.77 (m, 4 H), 2.032.24 (m, 2 H), 0.68 (s, 4 H). Method 1: RT=2.93 min; M+H=425.2 Ή NMR (400 MHz, DMSO-d6), δ 8.81 (s, . hnX 'Xf l>\ z ^N X. X 1 H), 8.70 (d, J=2.93 Hz, 1 H), 8.55 (d, J=2.69 Hz, 1 H), 8.22 (dd, J=7.09, 2.69 Hz 260 • 0 n-n /V Vx L|J T 1 H), 7.63-7.72 (m, 1 H), 7.42 (dd, J=11.37, 9.17 Hz, 1 H), 7.15 (d, J=2.93 Hz, 1 Η), 3.97-4.14 (m, 4 Η), 2.95 (s, 6 Η), 0.65 N. F (s, 4H). Method 1: RT=2.87 min; M+H=381.0 Ή NMR (400 MHz, DMSO) δ 8.94 (s, 1 Η), 8.56 (dd, 7=8.28, 2.38 Hz, 2 Η), 8.21 (dd, F X 7=6.96, 2.57 Hz, 1 H), 7.64 (dt, 7=8.91, Fp- , ( .. za .N-. *------ 3.26 Hz, 1 H), 7.43 (dd, 7=10.79, 9.54 Hz, 261 ζ )> n ”’T Y 0; / χχ NH ri 1 Η), 7.08 (d, 7=2.51 Hz, 1 Η), 5.27-5.50 (m, 1 Η), 4.24-4.39 (m, 2 Η), 3 .92-4.11 (m, 2 Η), 3.83 (br t, 7=13.30 Hz, 2 Η), 3.59 (br t, 7=7.15 Hz, 2 H), 2.60 (br d, 7=7.53 F Hz, 2H). Method 1: RT=2.67 min; M+H=447.2

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262 F G . ^F — - - Ν , ) ^f A — N ' _N —NH <N P Ή NMR (400 MHz, DMSO) δ 8.95 (s, 1 Η), 8.58 (d, 7=2.76 Hz, 1 Η), 8.35 (d, 7=2.76 Hz, 1 Η), 8.20 (dd, 7=7.03, 2.64 Hz, 1 Η), 7.60-7.68 (m, 1 Η), 7.44 (dd, J=11.36, 9.10 Hz, 1 Η), 7.05 (d, 7=2.76 Hz, 1 Η), 5.285.51 (m, 1 Η), 4.24-4.38 (m, 2 Η), 4.104.17 (m, 2 H), 3.95-4.10 (m, 4 H), 1.79 (t, 7=8.91 Hz, 2 H). Method 1: RT=2.84 min; M+H=434.9 263 IA ^l -N /—\ F 4 7 NH _z ⁴ >> A F d ⁴ Ή NMR (400 MHz, DMSO) δ 8.96 (s, 1 Η), 8.53 (d, 7=1.88 Hz, 1 Η), 8.37 (d, 7=1.88 Hz, 1 Η), 8.19 (dd, 7=6.96, 2.45 Hz, 1 Η), 7.62-7.69 (m, 1 Η), 7.39-7.50 (m, 1 Η ), 7.14 (d, 7=2.01 Hz, 1 Η), 5.28-5.52 (m, 1 Η), 4.41 (br d, 7=6.02 Hz, 2 Η) , 4.26-4.38 (m, 2 Η), 4.21 (br d, 7=10.92 Hz, 2 Η), 3.96-4.10 (m, 2 Η), 3.70 (br d, 7=10.92 Hz, 2 H), 2.72-2.76 (m, 1 H), 1.88 (d, 7=8.03 Hz, 1 H). Method 1: RT=2.49 min; M+H=427.3 264 /=( 4 ;^n I h 7 \। --Ά A 0,N- Xnh d / F Ή NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.07-8.96 (m, 2H), 8.84 (d, J=4.3 Hz, 1H), 8 .30 (dd, J=7.0, 2.7 Hz, 1H), 7.727.62 (m, 1H), 7.52 (dd, J=11.2.9.1 Hz, 1H), 7, 33 (dd, J=4.4, 1.2Hz, 1H), 6.04 (s, 1H), 5.41 (dtt, J=57.4, 6.1, 3.1Hz, 1H) , 4.404.25 (m, 2H), 4.27-4.16 (m, 1H), 4.103.94 (m, 2H), 3.90-3.77 (m, 1H), 3.062.94 (m , 1H), 2.86 (did, J=11.7, 8.7,4.4 Hz, 1H). Method 1: RT=1.69 min; M+H=385.2

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265 / 7' ( > XT! τ χΝΗ t" F SNMR (400 MHz, DMSO) δ 8.93 (s, 1 H), 8.58 (d, 7=2.76 Hz, 1 H), 8.32 (d, 7=2.76 Hz, 1 H ), 8.20 (dd, 7=7.03, 2.64 Hz, 1 H), 7.65 (dd, 7=7.34, 4.58 Hz, 1 H), 7.44 (dd, 7=11.17, 9.16 Hz, 1 H), 7.03 (d, 7=2.89 Hz, 1 H), 5.29-5.51 (m, 1 H), 4.24- 4.38(m, 2H), 4.18(t, 7=8.34Hz, 2H), 3.95-4.10(m, 4H), 3.65-3.85(m , 1H). Method 1: RT=2.86 min; M+H=453,l 266 z L V L i + hz A Λ Vi one CA za νχ SNMR (400 MHz, DMSO) δ 8.93 (s, 1 H), 8.60 (d, 7=2.76 Hz, 1 H), 8.31 (d, 7=2.76 Hz, 1 H ), 8.20 (dd, 7=6.96, 2.57 Hz, 1 H), 7.60-7.69 (m, 1 H), 7.44 (dd, 7=11.04, 9 .16 Hz, 1 H), 7.04 (d, 7=2.76 Hz, 1 H), 5.275.54 (m, 1 H), 4.26-4.38 (m, 2 H), 4.174 .24 (m, 2 H), 3.95-4.13 (m, 4 H), 3.853.94 (m, 1 H). Method 1: RT=2.44 min; M+H=410.3 267 F /X m X Q C )> K x j A HN LA xo % r Ή NMR (400 MHz, Methanol-b4) δ 8.86 (dd, 1=3.4, 2.2 Hz, 1H), 8.74 (d, J=4.4 Hz, 0.5H), 8 .67 (d, 1=4.5Hz, 0.5H), 8.17 (dd, 1=6.8, 2.7Hz, 0.5H), 8.13 (dd, 1=6.8 , 2.7Hz, 0.5H), 7.66(dddd, 1=8.8, 4.3, 2.7, 1.7Hz, 1H), 7.37(ddd, 1=10.9 , 9.1, 3.7 Hz, 1H), 7.28 (dd, 1=4.4, 0.8 Hz, 0.5H), 7.18 (dd, 1=4.5, 0.9 Hz, 0.5H), 5.93 (dd, 1=9.2, 5.6Hz, 0.5H), 5.73 (dd, 1=9.3, 6.1Hz, 0.5H) , 5.37 (dtt, 1=57.1, 6.1, 3.2 Hz, 1H), 4.48-4.32 (m, 3H), 4.24-4.15 (m, 2H) , 4.11 (ddd, 1=10.3, 3.2, 1.4 Hz, 1H), 3.052.91 (m, 1H), 2.34-2.21 (m, 1H), 2.03 (s, 1.5H), 1.71 (s, 1.5H). Method 2: RT=0.66 min; M+H=427.2

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F o Q NH /V/ NbV AND A N F .nA ^f SNMR (400 MHz, DMSO-d6) δ 10.69 (s, 1 H), 8.64 (d, J=2.69 Hz, 1 H), 8.37 (d, J=2.81 Hz, 1 H), 8.32 (dd, J=7.03, 2.51 Hz, 268 <f F F or F 1 H), 7.61-7.67 (m, 1 H), 7.52 (dd, J=11.19, 9.11 Hz, 1 H), 7.15 (d, J=2.81 Hz, o _x V -N AND- N _znJ 1 H), 4.80-5.03 (m, 1 H), 4.41 (t, J=12.29 Hz, 4 H), 2.24-2.33 (m, 1 H), 1.46-1.67 Άνη (m, 1H), 1.27 (dd, J=13.27, 6.54Hz, 1H). < F Method 1: RT=2.89 min; M+H=406.0 about & “Ά /¼ X SNMR (400 MHz, DMSO-d6) δ 10.75 (s, 1 H), 9.48 (d, J=2.26 Hz, 1 H), 9.03 (d, J=2.38 Hz, 1 H), 8.95 (d, J=2.26 Hz, 1 H), w/ Vnh 8.74 (d, J=4.14 Hz, 1 H), 8.39 (dd, J=6.96, s .,, or 2.57 Hz, 1 H), 8.13 (d, J=8.03 Hz, 1 H), 269 -X c .-0 7.96 (td, J=7.75, 1.69 Hz, 1 H), 7.65-7.74 (m, 1 H), 7.57 (dd, J=11.11, 9.10 Hz, 1 H), 7.42 (dd, J=7.22, 5.21 Hz, 1 H), 4.78-5.06 (m, 1 H), 2.26-2.35 (m , 1H), 1.49-1.66 and 9 ) - ⁴ > ^nh < (m, 1 H), 1.24-1.33 (m, 1 H). Method 1: F RT=2.80 min; M+H=392.2 Ή NMR (400 MHz, DMSO) δ 8.94 (s, 1 H), F Anh 8.72 (d, 7=2.81 Hz, 1 H), 8.63 (d, 7=2.57 /=0 nA -N. Hz, 1H), 8.16-8.27 (m, 1H), 7.61-7.67 270 o, v 'X (m, 1H), 7.40-7.47 (m, 2H), 5.26-5.54 Eun ύ (m, 1 H), 4.24-4.40 (m, 2 H), 3.96-4.08 (m, 2 H), 3.29-3.33 (m, 1 H), 3 ,21 (br d, /F 7=5.01 Hz, 4 H), 3.11 (br d, 7=4.40 Hz, 4 H). Method 1: RT=1.86 min; M+H=414.3

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274 ^NH G-F/ 0' b ^{N J} c W 1 I M'N^N' Ή NMR (400 MHz, DMSO) δ 8.68 (s, 1 Η), 8.57 (d, 7=2.57 Hz, 1 Η), 8.32 (d, 7=2.69 Hz, 1 Η), 8.20 (dd, 7=7.09, 2.69 Hz, 1 Η), 7.62-7.69 (m, 1 Η), 7.41 (dd, 7=11.25, 9.17 Hz, 1 Η), 7.03 (d, 7=2.81 Hz, 1 Η), 4.134.22 (m, 2 Η), 3.98 (q, J=7.78 Hz, 6 Η), 3.76 (br dd, 7=9.54, 4.77 Hz, 1 Η), 2.19 (quint, 7=7.55 Hz, 2 H). Method 1: RT=2.87 min; M+H=435.3 275 x, .... Y -N' O. N'--fX Ύνη r-N / ) F Ή NMR (400 MHz, DMSO) δ 8.52-8.66 (m, 2 Η), 8.32 (d, 7=2.81 Hz, 1 Η), 8.23 (dd, 7=6, 97, 2.57 Hz, 1 H), 7.68 (dt, 7=9.08, 3.35 Hz, 1 H), 7.42 (dd, 7=11.19, 9.23 Hz, 1 Η), 7.03 (d, 7=2.69 Hz, 1 Η), 5.24-5.50 (m, 1 Η), 4.09-4.26 (m, 2 Η), 3, 99 (dd, 7=8.01, 5.44 Hz, 2 Η), 3.50-3.84 (m, 4 Η), 3.38-3.47 (m, 1 Η), 1.97 -2.29 (m, 2 Η). Method 1: RT=2.86 min; M+H=467.3 276 --.. .Cl hNH _r -N \ J F' Ή NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1 Η), 8.90 (d, J=2.51 Hz, 1 Η), 8.70 (d, J=2.51 Hz , 1 H), 8.47 (d, J=2.51 Hz, 1 H), 8.24 (dd, J=7.03, 2.76 Hz, 1 H), 7.64-7.76 (m, 1 Η), 7.48 (dd, J=11.17, 9.16 Hz, 1 Η), 5.26-5.53 (m, 1 Η), 4.23-4.40 ( m, 2 Η), 3.94-4.12 (m, 2 Η). Method 1: RT=2.76 min; M+H=364.0 277 4 jch ..I , OH Q Y / Ynh n one Ή NMR (400 MHz, DMSO-d6) δ ppm 9.00 (d, 1=2.20 Hz, 1 Η), 8.94 (d, J=l.96 Hz, 1 Η), 8.53- 8.63 (m, 2 Η), 8.51 (d, J=2.20 Hz, 1 Η), 7.85-7.95 (m, 1 Η), 7.81 (br d, J= 7.34 Hz, 1 Η), 7.55-7.67 (m, 1 Η), 7.37 (dd, 1=7.46, 4.77 Hz, 1 Η), 4.69 (s, 2 Η), 2.55 (s, 3 Η), 2.45 (s, 3 Η). Method 1: RT=2.50 min; M+H=459.0

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278 ρ Ν'Χ ζ_< ( \ Υχ Ύ Τ ομΑχ Κνη w d-A-d one) Ή NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1 H), 9.00 (d, 7=2.32 Hz, 1 H), 8.93 (d, 7=2.20 Hz , 1 H), 8.60 (td, 7=6.91, 3.30 Hz, 2 H), 8.51 (d, 7=2.20 Hz, 1 H), 7.89-7.97 (m, 1 H), 7.84 (d, 7=7.46 Hz, 1 H), 7.60 (dd, 7=11.07, 9.23 Hz, 1 H), 7.40 (dd , 7=7.58, 4.77 Hz, 1 H), 2.45 (s, 3 H), 2.41 (s, 3 H). Method 1: RT=2.61 min; M+H=446,l 279 ( > D'D Ο / Ν- ΝΗ ΝγΟ Ή NMR (400 MHz, Methanol X 4 ) δ 8.51 (d, 1=2.6 Hz, 1H), 8.38 (dd, 1=6.9, 2.7 Hz, 1H), 8.28 (d , 1=2.8 Hz, 1H), 7.85 (ddd, 1=9.1, 4.2, 2.7 Hz, 1H), 7.41 (dd, 1=11.1, 9.1 Hz, 1H), 7.10 (d, 1=2.8 Hz, 1H), 4.23 (t, 1=8.2 Hz, 2H), 4.08 (dd, 1=8.0, 5 .4 Hz, 2H), 3.64 (qt, 1=8.8, 5.4 Hz, 1H), 2.55 (s, 3H), 2.46 (s, 3H). 280 Ν M-D^ % λXD Λ ^ν - 'NX _F HN Vo F X IJ Ή NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1 Η), 8.99 (s, 1 Η), 8.44 (d, 1=1.76 Hz, 1 Η), 8, 36 (d, 1=2.76 Hz, 1 Η), 8.31 (d, 1=5.77 Hz, 1 Η), 7.67 (dd, J=5.52, 2.01 Hz, 1 Η), 7.14 (d, 1=2.76 Hz, 1 Η), 4.42 (t, 1=12.17 Hz, 4 Η), 4.04 (t, 1=7.53 Hz, 4 H), 2.16-2.29 (m, 2 H). Method 1: RT=2.76 min; M+H=386.0 281 . , . L CIS i ^N ' q N- HNH _r -N F SD F Ή NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1 Η), 9.47 (d, 1=2.20 Hz, 1 Η), 9.38 (s, 1 Η), 8, 95 (d, 1=2.20 Hz, 1 Η), 8.71-8.77 (m, 1 Η), 8.49 (d, 1=1.71 Hz, 1 Η), 8.42 ( d, 1=5.62 Hz, 1 Η), 8.12 (d, 1=8.07 Hz, 1 Η), 7.96 (td, 1=7.76, 1.83 Hz, 1 Η) , 7.72 (dd, 1=5.62, 1.96 Hz, 1 Η), 7.39-7.47 (m, 1 Η), 4.49 (t, 1=12.72 Hz, 4 H). Method 1: RT=2.81 min; M+H=408.0

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282 . -Ν Γ~Ί D_/ ¹¹ ί VN ,ΝΗ ' and Ή NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 Η), 8.91 (s, 1 Η), 8.42 (d, J=l.76 Hz, 1 Η), 8, 26-8.32 (m, 2 H), 7.66 (dd, J=5.77, 2.01 Hz, 1 H), 6.91 (d, J=2.76 Hz, 1 H), 4.00-4.08 (m, 8 H), 2.17-2.28 (m, 2 H), 0.68 (s, 4 H). Method 1: RT=2.93 min; M+H=376.0 283 I . /—<> /VYV I ^N JJ 0 }' ⁷ N--'- _N k V............NH L F Ή NMR (400 MHz, DMSO-d6), δ 9.47 (d, J=2.26 Hz, 1 Η), 9.08 (br s, 1 Η), 8.90-9.00 (m, 2 Η), 8.70-8.79 (m, 1 Η), 8.13 (d, J=8.03 Hz, 1 Η), 8.03 (d, J=2.51 Hz, 1 Η ), 7.96 (td, J=7.72, 1.88 Hz, 1 Η), 7.72-7.78 (m, 1 Η), 7.66 (d, J=9.03 Hz, 1 Η), 7.42 (ddd, J=7.53, 4.77, 1.00 Hz, 1 Η), 5.285.53 (m, 1 Η), 4.25-4.42 (m, 2 Η), 3.954.11 (m, 2 H). Method 1: RT=2.69 min; M+H=423.0 284 Cl /=( ddd / N \ c ^N D _O Ά d Ή NMR (400 MHz, DMSO) δ 8.80 (s, 1 Η), 8.55 (s, 1 Η), 8.35 (d, 7=2.81 Hz, 1 Η), 7.96 ( d, 7=2.45 Hz, 1 Η), 7.71 (dd, 7=8.99, 2.51 Hz, 1 Η), 7.58 (d, 7=9.05 Hz, 1 Η) , 7.16 (d, 7=2.81 Hz, 1 Η), 4.40 (br t, 7=12.23 Hz, 4 Η), 3.96 (br t, 7=7.52 Hz, 4 H), 2.08-2.32 (m, 2 H). Method 1: RT=2.81 min; M+H=419.2 285 P 4 L. FNH[- °' DSST'' Cl Ή NMR (400 MHz, DMSO) δ 9.46 (d, 7=1.96 Hz, 1 Η), 8.93 (s, 2 Η), 8.82 (s, 1 Η), 8.73 ( br d, 7=4.04 Hz, 1 Η), 8.12 (br d, 7=8.07 Hz, 1 Η) 8.04 (d, 7=2.20 Hz, 1 Η) 7.94 (br t, 7=7.15 Hz, 1 Η) 7.75 (dd, 7=8.86, 2.26 Hz, 1 Η), 7.62 (d, 7=8.93 Hz, 1 Η ), 7.41 (dd, 7=6.97, 5.01 Hz, 1 Η), 3.97 (br t, 7=7.46 Hz, 4 Η), 2.19 (quint., 7= 7.55 Hz, 2 N). Method 1: RT=2.69 min; M+H=405.2

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LX % /= New York N XNCl 'N.L 'ϊ :) Ή NMR (400 MHz, DMSO) δ 8.79 (s, 1 Η), 8.45 (s, 1 Η), 8.27 (d, 7=2.57 Hz, 1 Η), 7.96 ( d, 7=2.32 Hz, 1 Η), 7.71 (dd, 7=8.86, 2.38 Hz, 1 Η), 7.57 (d, 7=8.80 Hz, 1 Η) , 6.93 (d, 286 HiVy / 7=2.69 Hz, 1 Η), 4.01 (s, 4 Η), 3.96 (br t, 7=7.58 Hz, 4 Η), 2.19 (quint., 7=7, 61 Hz, 2 N), 0.68 (s, 4 N). Method 1: RT=2.98 min; M+H=409.3 Ή NMR (400 MHz, DMSO-d6) δ 8.70 (s, .. 1 Η), 8.68 (s, 1 Η), 8.29 (s, 1 Η), 8.25 (d, 287 γ> 4 at four An J=2.81 Hz, 1 Η), 7.52-7.66 (m, 2 Η), 7.37- 7.45 (m, 1 H), 6.90 (d, J=2.69 Hz, 1 H), a J 3.97-4.05 (m, 8 Η), 2.18-2.23 (m, 2 Η), 0.69 (s, 4h). Method 1: RT=2.82 min; M+H=375,l Ή NMR (400 MHz, Methanol-b4) δ 9.03 (d, J=2.2 Hz, 1H), 8.73 (d, J=4.9 Hz, 1H), 8.19 (dd, J =6.8, 2.7 Hz, 1H), 7.63 (ddd, J=9.l, 4.2, 2.7 Hz, 1H), 7.37 (dd, J=10.9, 288 -Ν with? NH / h - Ί _.ζι YJ N - _N ' 9.1Hz, 1H), 7.32(dd, J=5.0, 0.9Hz, 1H), 4.92(ddt, J=2.7, 1.4, 0.7Hz, 1H ), 4.23 (d, J=10.3 Hz, 1H), 4.17-4.07 (m, 2H), 3.74 F (td, J=ll.6, 2.5 Hz, 1H), 3.37-3.32 (m, 2H), 2.33 (p, J=7.6 Hz, 2H), 2.15- 1.98 (m, 2H), 1.92-1.57 (m, 4H). Method 2: RT=0.89 min; M+H=396.0 Ή NMR (400 MHz, Methanol-b4) δ 9.05 (d, J=2.2 Hz, 1H), 8.73 (d, J=4.8 Hz, 1H), / 7 8.18 (dd, J=6.8, 2.7 Hz, 1H), 7.63 (ddd, 289 N 0 NH .-Y /γΎγ' J=9.l, 4.1, 2.7 Hz, 1H), 7.37 (dd, J=10.9, 9.1 Hz, 1H), 7.32 (dd, J=4.8, 0.9Hz, 1H), FROM/ F ^N AJ ^4\G 5.20-5.12 (m, 1H), 4.17-4.04 (m, 4H), 3.99 (ddd, J=11.8, 10.6, 3.0 Hz, 1H), 3.893.75 (m, 2H), 3.59 (dd, J=11.5, 9.9 Hz, 1H), 3.40-3.32 (m, 2H), 2.33 (p, J= 7.7 Hz, 2H).

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Method 2: RT=0.74 min; M+H=398.0 290 --Ν F ,DO ^N G'Ur ° SUDO ν ^Ν Ή NMR (400 MHz, DMSO) δ 8.69 (s, 1 Η), 8.62 (d, 7=2.64 Hz, 1 Η), 8.36 (d, 7=2.76 Hz, 1 Η), 8.22 (dd, 7=7.09, 2.70 Hz, 1 Η), 7.65-7.72 (m, 1 Η), 7.42 (dd, 7=11.29, 9.16 Hz, 1 H), 7.15 (d, 7=2.89 Hz, 1 H), 4.41 (t, 7=12.23 Hz, 4 H), 3.98 (t, 7 \u003d 7.53 Hz, 4 Η), 2.20 (quint., 7 \u003d 7.56 Hz, 2 N). Method 1: RT=2.73 min; LCMS: M+H=403.2 291 F i /> N J Τ o >' * iDO^ C ΝΗ ί F Ή NMR (400 MHz, DMSO) δ 8.95 (s, 1 Η), 8.56 (d, 7=2.63 Hz, 1 Η), 8.30 (d, 7=2.89 Hz, 1 Η), 8.19 (dd, 7=7.09, 2.70 Hz, 1 Η), 7.60-7.69 (m, 1 Η), 7.42 (dd, 7=11.36, 9.10 Hz, 1 Η), 7.00 (d, 7=2.76 Hz, 1 Η), 5.285.63 (m, 2 Η), 4.20-4.37 (m, 4 Η), 3.934.09 (m, 4H). Method 1: RT=2.63 min; M+H=403.2 292 zuz. ^Z. ! RL y 4 y _r .z Ζ Ή NMR (400 MHz, DMSO) δ 8.70 (s, 1 Η), 8.56 (d, 7=2.76 Hz, 1 Η), 8.31 (d, 7=2.76 Hz, 1 Η), 8.21 (dd, 7=7.03, 2.64 Hz, 1 Η), 7.59-7.72 (m, 1 Η), 7.41 (dd, 7=11.36, 9.10 Hz, 1 Η), 7.01 (d, 7=2.76 Hz, 1 Η), 5.395.66 (m, 1 Η), 4.20-4.36 (m, 2 Η), 3.894.09 (m, 6H), 2.12-2.28 (m, 2H). Method 1: RT=2.63 min; M+H=385.3 293 _F Dmn O \u003d% x y C / \u003d N--V ^J Mn _r .-N 'P F Ή NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1 Η), 8.83 (d, J=2.26 Hz, 1 Η), 8.66 (s, 1 Η), 8, 44 (br s, 1 Η), 8.24 (dd, J=7.03, 2.51 Hz, 1 Η), 8.05 (s, 1 Η), 7.64-7.73 (m, 1 Η), 7.47 (dd, J=11.17, 9.16 Hz, 1 Η), 5.28-5.52 (m, 1 Η), 4.25-4.41 (m, 2 Η), 3.96-4.11 (m, 2 Η), 3.29 (br d, J=9.03 Hz, 2 H), 2.91 (br d, J=8.28 Hz, 3 H), 1.96 (br d, J=12.55 Hz, 2 H), 1.82 (br d, J=ll.04 Hz, 2 H). Method 2: RT=0.51 min; M+H=413.2

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294

295

296

297

Ή NMR (400 MHz, DMSO-d6) δ 9.48 (d, J=2.26 Hz, 1 Η), 9.42 (d, J=l.25 Hz, 1 Η), 9.01-9 .13 (m, 3 Η), 8.76-8.83 (m, 1 Η), 8.68 (d, J=2.51 Hz, 1 Η), 8.29 (dd, J=7, 03, 2.51 Hz, 1 Η), 7.67-7.78 (m, 1 Η), 7.50 (dd, J=ll.17, 9.16 Hz, 1 Η), 5.26- 5.57(m, 1h), 4.21-4.46(m, 2h), 3.92-4.15(m, 2h). Method 1: RT=2.53 min; M+H=408,l

Ή NMR (400 MHz, METAHOL-d4) δ 9.14 (d, J=2.26 Hz, 1 Η), 8.77 (d, J=2.26 Hz, 1 Η), 8.57 (d , J=2.26 Hz, 1 Η), 8.17 (dd, J=6.78, 2.76 Hz, 1 Η), 7.85 (d, J=l.00 Hz, 1 Η), 7.64-7.71 (m, 2 Η), 7.38 (dd, J=11.04, 9.03 Hz, 1 Η), 5.27-5.51 (m, 1 Η), 4 .35-4.47 (m, 2 Η), 4.09-4.23 (m, 2 Η). Method 1: RT=1.95 min; M+H=396,l

Ή NMR (400 MHz, METAHOJI-d4) δ 8.69 (d, J=2.45 Hz, 1 Η), 8.65 (d, J=2.20 Hz, 1 Η), 8.11-8 .18 (m, 2 Η), 7.61-7.69 (m, 1 Η), 7.27-7.43 (m, 6 Η), 5.26-5.49 (m, 1 Η) , 4.33-4.46 (m, 2 Η), 4.08-4.21 (m, 2 Η), 3.63 (s, 2 Η), 3.11 (br d, J=11, 74 Hz, 2 H), 2.72-2.85 (m, 1 H), 2.20-2.31 (m, 2 H), 1.82-2.01 (m, 4 H). Method 1: RT=2.16 min; M+H=503.2

Ή NMR (400 MHz, DMSO-d6) δ 13.13 (br s, 1 H), 9.08 (d, J=2.26 Hz, 1 H), 9.02 (s, 1 H), 8 .84 (d, J=2.51 Hz, 1 H), 8.47 (s, 1 H), 8.40 (d, J=2.26 Hz, 1 H), 8.26 (dd, J =7.03, 2.76 Hz, 2 H), 7.69 (ddd, J=9.16, 4.14, 2.76 Hz, 1 H), 7.48 (dd, J=11.17 , 9.16 Hz, 1 H), 5.30-5.51 (m, 1 H), 4.26-4.40 (m, 2 H), 3.97-4.10 (m, 2 H ). Method 2: RT=0.69 min; M+H=396,l

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Ή NMR (400 MHz, DMSO), δ 8.94 (s, 1 F f/ Η), 8.62 (d, 7=2.57 Hz, 1 Η), 8.36 (d, /—\ xjj ^F 7=2.81 Hz, 1 H), 8.20 (dd, 7=7.03, 2.63 Hz, ^N- J 1 Η), 7.57-7.71 (m, 1 Η), 7.44 (dd, 298 0/ ^f N 'N' >NH 7=11.19, 9.11 Hz, 1 H), 7.14 (d, 7=2.81 Hz, 0 1 Η), 5.26-5.53 (m, 1 Η), 4.22-4.51 (m, 6 l' Η), 3.91-4.11 (m, 2 Η). Method 1: RT=2.74 min; M+H=421.2 Ή NMR (400 MHz, DMSO) δ 9.19 (s, 1 Η) F F--/ 8.62 (d, 7=2.76 Hz, 1 H), 8.35 (d, 7=2.89 7 7 --N F Hz, 1 Η), 8.19 (dd, 7=7.03, 2.64 Hz, 1 Η), 299 XNH O' ri- _F 7.61-7.67 (m, 1 Η), 7.45 (dd, 7=11.36, 9.10 _ X J one Hz, 1 Η), 7.13 (d, 7=2.76 Hz, 1 Η), 4.35- ----; N F N' 4.45 (m, 8°). Method 1: RT=2.90 min; M+H=439.2 c Ή NMR (400 MHz, DMSO) δ 8.57-8.65 F G7-| (m, 2 Η) 8.35 (d, J=2.76 Hz, 1 Η) 8.22 (dd, ______/' .-X,N-J' •<y J=7.09, 2.70 Hz, 1 H) 7.64-7.72 (m, 1 H) to _z Vn 300 o A -A N 7.42 (dd, J= 11.29, 9.16 Hz, 1 H) 7.14 (d, V—NH N J=2.76 Hz, 1 Η) 5.27-5.47 (m, 1 Η) 4.40 (t, i) J=12.23 Hz, 4 H) 3.39-3.76 (m, 4 H) 1.98- p 2.25 (m, 2H). Method 1: RT=2.73 min; M+H=435.3 Ή NMR (400 MHz, METAHOJI-d4) δ F ,............................( n X 9.11 (d, J=l.96 Hz, 1 H), 8.76 (d, J=2.20 ( } n P Ί Hz, 1H), 8.54 (d, J= 1.96 Hz, 1 H), 8.16 (dd, Ύν J=6.72, 2.57Hz, 1H), 7.76(s, 1H), 7.63- 301 HN NW >o 7.70 (m, 2H), 7.37 (dd, J=11.00, 9.29 Hz, to V-- ¹ 1 H), 5.27-5.50 (m, 1 H), 4.33-4.48 (m, 2 / one H), 4.09-4.22 (m, 2 H), 3.84 (s, 3 H). Method 1: RT=1.97 min; M+H=410.2

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302 F AgN JJ 0. y- ^z NΑ 'MnH tM,. A ^h fA/ Ή NMR (400 MHz, DMSO), δ 8.55-8.62 (m, 2 Η), 8.31 (d, /=2.76 Hz, 1 Η), 8.22 (dd, /=7 .03, 2.76 Hz, 1 H), 7.68 (dt, /=8.97, 3.42 Hz, 1 H), 7.42 (dd, /=11.29, 9.16 Hz, 1 Η), 7.01 (d, /=2.76 Hz, 1 Η), 5.28-5.64 (m, 2 Η), 4.20-4.33 (m, 2 Η), 3 .93-4.07 (m, 2 Η), 3.60-3.76 (m, 4 Η), 2.10-2.22 (m, 2 Η). Method 2: RT=0.83 min; M+H=417,l 303 1 ^z N -N^ 1 1 IN VA Mo _r -N fA F Ή NMR (400 MHz, DMSO) δ 9.22 (s, 1 Η), 8.58 (d, /=2.64 Hz, 1 Η), 8.31 (d, /=2.76 Hz, 1 Η), 8.20 (dd, /=6.96, 2.70 Hz, 1 Η), 7.61-7.68 (m, 1 Η), 7.46 (dd,/=11.29, 9.16 Hz, 1 H), 7.01 (d, /=2.89 Hz, 1 H), 5.425.64 (m, 1 H), 4.41 (t, /=12.67 Hz, 4 Η), 4.21-4.33 (m, 2 Η), 3.93-4.06 (m, 2 Η). Method 1: RT=2.74 min; M+H=421.3 304 z < 'z 'Ά A Ή NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=2.26 Hz, 1 Η), 8.98 (s, 1 Η), 8.84 (d, J=2.76 Hz , 1 Η), 8.36 (d, J=2.26 Hz, 1 Η), 8.31 (s, 1 Η), 8.25 (dd, J=7.03, 2.76 Hz, 1 Η), 8.02 (s, 1 Η), 7.65-7.73 (m, 1 Η), 7.48 (dd, J=11.17, 9.16 Hz, 1 Η), 5, 29-5.52(m, 1H), 4.26-4.39(m, 2H), 3.97-4.10(m, 2H), 3.91(s, 3H). Method 2: RT=0.75 min; M+H=410.2 305 ^7th O.....Z0 Ή NMR (400 MHz, METAHOJI-d4) δ 8.69 (d, J=2.51 Hz, 1 Η), 8.65 (d, J=2.26 Hz, 1 Η), 8.12-8 .17 (m, 2 Η), 7.62-7.68 (m, 1 H), 7.32-7.45 (m, 3 H), 7.06-7.13 (m, 2 H), 5.27-5.48 (m, 1 H), 4.33-4.46 (m, 2 Η), 4.07-4.23 (m, 2 Η), 3.61 (s, 2 Η), 3.08 (br d, J=11.80 Hz, 2 Η), 2.70-2.86 (m, 1 Η), 2.24 (td, J=ll.86, 2.38 Hz, 2 Η), 1.93-2.01 (m, 2 Η), 1.81-1.93 (m, 2 Η).

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Method 2: RT=0.64 min; M+H=521.2 306 F , ₌ / _N Λ / \ .Ά-- 'ο η ^H \ D--D X ΐχ Ή NMR (400 MHz, DMSO-d6) δ 8.678.74 (m, 2 Η), 8.54 (d, J=2.69 Hz, 1 Η), 8.22 (dd, 1=7.21, 2.81 Hz, 1 Η), 7.59-7.77 (m, 1 Η), 7.41 (dd, 1=11.37, 9.17 Hz, 1 Η), 7.14 (d, 1=2.93 Hz, 1 H), 3.98 (t, 1=7.58 Hz, 4 H), 2.20 (t, 1=7.58 Hz, 2 H). Method 1: RT=2.62 min; M+H=361.2 307 F .—/ N- / \ /Ά X- η 4 x ^N ₄ .,. v ^D / ^? ~ NQ HN D—0 z ^D \ J F< 1 Ή NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1 Η), 8.69 (d, 1=2.93 Hz, 1 Η), 8.56 (d, 1=2.93 Hz , 1 Η), 8.21 (dd, 1=6.85, 2.69 Hz, 1 Η), 7.60-7.72 (m, 1 Η), 7.46 (dd, 1=11, 37, 9.17 Hz, 1 H), 7.14 (d, 1=2.93 Hz, 1 H), 4.41 (t, 1=12.72 Hz, 4 H). Method 1: RT=2.73 min; M+H=397.2 308 V ”1 ZD - 9 zc ? / \ < ₄ z σ Y A o----z _m Ή NMR (400 MHz, DMSO-d6) δ 8.69 (d, 1=2.93 Hz, 1 Η), 8.62 (s, 1 Η) 8.55 (d, 1=2.69 Hz, 1 Η), 8.24 (dd, 1=7.21, 2.81 Hz, 1 Η), 7.64-7.74 (m, 1 Η), 7.43 (dd, 1=11.25 , 9.05 Hz, 1 Η), 7.14 (d, 1=2.93 Hz, 1 Η), 5.27-5.50 (m, 1 Η), 3.51-3.77 (m , 4 Η), 2.04-2.25 (m, 2 Η). Method 2: RT=0.79 min; M+H=393.2 309 F ^F -A A XX ,. ^Ib Xb+D 1 Ϊ 'Ά №V ' F Ή NMR (400 MHz, DMSO-d6) δ 9.27 (s, 2 Η), 9.06 (d, 1=2.01 Hz, 1 Η), 8.82 (s, 1 Η), 8, 63 (br d, 1=4.27 Hz, 1 Η), 8.28 (dd, 1=6.78, 2.51 Hz, 1 Η), 7.93 (dd, 1=11.42, 8 .41 Hz, 1 Η), 7.67-7.76 (m, 1 Η), 7.477.59 (m, 2 Η), 4.42 (t, 1=12.67 Hz, 4 Η). Method 1: RT=2.85 min; M+H=443,l

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310 F Ν Hmm i Ί Μ ⁰¹ F Ή NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1 Η), 9.02 (dd, J=16.81, 2.01 Hz, 2 Η), 8.64-8.75 ( m, 2 H), 8.28 (dd, J=6.78, 2.51 Hz, 1 H), 8.14 (d, J=8.28 Hz, 1 H), 7.677.77 (m, 1 H), 7.45-7.57 (m, 2 H), 4.43 (t, J=12.67 Hz, 4 H). Method 1: RT=2.86 min; M+H=459,l 311 F ο; ν-'χ > ΝΗ 0 / F Ή NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1 Η), 8.90 (d, J=2.26 Hz, 1 Η), 8.72 (d, J=3.01 Hz , 1 Η), 8.31 (d, J=8.28 Hz, 1 Η), 8.25 (dd, J=7.03, 2.51 Hz, 1 Η), 7.66-7.73 (m, 1 Η), 7.43-7.51 (m, 1 Η), 7.20 (dd, J=8.41, 4.14 Hz, 1 Η), 5.29-5.51 ( m, 1 Η), 4.24-4.39 (m, 2 Η), 3.96-4.10 (m, 2 Η). Method 1: RT=2.41 min; M+H=330,l 312 1 ,=< ν^ν _χ ΟΧ D Λ ^Ν Ια But ,-Ν Ή NMR (400 MHz, DMSO-d6) δ 8.939.06 (m, 3 Η), 8.54-8.68 (m, 3 Η), 8.29 (dd, J=6.90, 2.38 Hz, 1 Η), 7.67-7.76 (m, 1 Η), 7.49 (t, J=10.16 Hz, 1 Η), 5.27-5.55 (m, 1 Η) , 4.25-4.42(m, 2H), 3.94-4.14(m, 2H), 2.68(s, 3H). Method 1: RT=2.48 min; M+H=422,l 313 Γ'] '“-Ν _Ζ 4 > ΝΗ η θ' \ , _ .Λ A Α ο w g F Ή NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1 Η), 9.04 (d, J=2.26 Hz, 1 Η), 8.82 (d, J=l.51 Hz , 1 Η), 8.75 (s, 1 Η), 8.63 (br d, J=4.52 Hz, 1 Η), 8.30 (dd, J=6.90, 2.64 Hz, 1 Η), 7.93 (dd, J=10.92, 8.91 Hz, 1 Η), 7.73 (dt, J=9.03, 3.39 Hz, 1 Η), 7.55 ( dt, J=8.34, 4.24 Hz, 1 Η), 7.48 (dd, J=11.29, 9.03 Hz, 1 Η), 3.91-4.07 (m, 4 Η ), 2.21 (quint., J=7.53 Hz, 2 Η). Method 2: RT=0.85 min; M+H=407,l

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314 F m . N.. G Y i X d a_/ x-zh. „.A χ HN - G Ch one ' ^Χ Η NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1 Η), 8.69 (d, J=3.01 Hz, 1 Η), 8.54 (d, J=2.76 Hz, 1 H), 8.21 (dd, J=7.03, 2.76 Hz, 1 H), 7.61-7.71 (m, 1 H), 7.43 (dd, J=11 .42, 9.16 Hz, 1 Η), 7.14 (d, J=3.01 Hz, 1 Η), 5.28-5.53 (m, 1 Η), 4.22-4.43 (m, 2 H), 3.92-4.11 (m, 2 H). Method 1: RT=2.63 min; M+H=379.3 315 Υχ . Ϊ. h / νΖΎΎ τ Μ kad U ί 1 ^H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=2.51 Hz, 1 H), 9.00 (d, 1=2.26 Hz, 1 H), 8.76 ( s, 1 H), 8.72 (dd, J=4.64, 1.38 Hz, 1 H), 8.68 (d, J=2.26 Hz, 1 H), 8.29 (dd, J=6.90, 2.64 Hz, 1 Η), 8.14 (dd, J=8.16, 1.38 Hz, 1 Η), 7.68-7.82 (m, 1 Η), 7.407.55 (m, 2 H), 3.99 (t, J=7.53 Hz, 4 H), 2.21 (quint, 1=7.59 Hz, 2 H). Method 1: RT=2.73 min; M+H=423.1 316 _' / „ ν>ν _Ν ; ΥΝί 1 P 1 ^H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J=2.45 Hz, 1 Η), 9.00 (d, 1=2.20 Hz, 1 Η), 8.72 ( dd, J=4.65, 1.47 Hz, 1 Η), 8.65-8.70 (m, 2 Η), 8.32 (dd, J=6.85, 2.69 Hz, 1 Η ), 8.14 (dd, J=8.19, 1.35 Hz, 1 Η), 7.71-7.80 (m, 1 Η), 7.45-7.56 (m, 2 Η) , 5.26-5.52(m, 1H), 3.40-3.81(m, 4H), 2.01-2.28(m, 2H). Method 2: RT=0.89 min; M+H=455.2 317 χ , ,. Ό ( , '7 Ύ ρ/W' ZhNn C? F ^X NMR (400 MHz, DMSO-d6) δ 9.27 (dd, J=2.20, 1.22 Hz, 1 Η), 9.05 (d, J=2.45 Hz, 1 Η), 8 .80-8.86 (m, 1 Η), 8.67 (s, 1 Η), 8.63 (dt, J=4.65, 1.71 Hz, 1 Η), 8.31 (dd, J=7.09, 2.69 Hz, 1 Η), 7.93 (ddd, J=ll.68, 8.38, 1.22 Hz, 1 Η), 7.71-7.79 (m, 1 Η), 7.55 (dt, J=8.38, 4.25 Hz, 1 Η), 7.49 (dd, J=11.25, 9.05 Hz, 1 Η), 5.26- 5.54 (m, 1 Η), 3.423.80 (m, 4 Η), 2.01-2.27 (m, 2 Η).

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Method 2: RT=0.87 min; M+H=439,l 318 /— \7%AA HN ^Z AND F Ή NMR (400 MHz, METAHOJI-d4) δ 8.65 (d, J=2.45 Hz, 1 Η), 8.60 (d, J=2.20 Hz, 1 Η), 8.14 (dd , J=6.72, 2.81 Hz, 1 Η), 8.09 (dd, J=2.08, 1.10 Hz, 1 Η), 7.62-7.70 (m, 1 Η) , 7.36 (dd, J=11.00, 9.05 Hz, 1 Η), 5.26-5.51 (m, 1 Η), 4.33-4.48 (m, 2 Η), 4.06-4.23 (m, 2 Η), 2.50 (d, J=0.98 Hz, 3 Η). Method 1: RT=2.62 min; M+H=344,l 319 Q a/h? about. IL xni i A Ή NMR (400 MHz, DMSO-d6) δ 9.299.35 (m, 1 Η), 8.94-9.07 (m, 2 Η), 8.64 (d, J=2.51 Hz, 1 Η ), 8.62 (d, J=2.76 Hz, 1 Η), 8.27 (dd, J=7.03, 2.76 Hz, 1 Η), 7.85 (d, J=l, 76 Hz, 1 Η), 7.67-7.75 (m, 1 Η), 7.677.75 (m, 1 Η), 7.50 (dd, J=11.17, 9.16 Hz, 1 Η ), 6.61-6.68 (m, 1 Η), 5.27-5.61 (m, 1 Η), 4.23-4.43 (m, 2 Η), 3.95-4, 14(m, 2 Η). Method 1: RT=2.59 min; M+H=396,l 320 П N > NH X _F ° ( у \ ; у . ,, N· - _N F S NMR (400 MHz, DMSO-d6) δ 9.14 (d, J=2.26 Hz, 1 H), 9.01 (d, J=2.51 Hz, 1 H), 8.86-8 .91 (m, 1 Η), 8.78 (s, 1 Η), 8.30 (dd, J=6.90, 2.64 Hz, 1 Η), 7.70-7.78 (m, 1 H), 7.49 (dd, J=11.17, 9.16 Hz, 1 H), 3.98 (t, J=7.53 Hz, 4 H), 2.15-2.27 ( m, 2 H). Method 1: RT=2.82 min; M+H=380,l 321 lz ₄ ,,O In 1 kS ΐ p / \ z .4 Ή NMR (400 MHz, DMSO-d6) δ 9.14 (d, J=2.45 Hz, 1 Η), 8.94-9.07 (m, 2 Η), 8.88 (d, J= l.22 Hz, 1 Η), 8.28 (dd, J=6.85, 2.69 Hz, 1 Η), 7.67-7.80 (m, 1 Η), 7.51 (dd, J=11.13, 9.17 Hz, 1 H), 5.27-5.56 (m, 1 H), 4.23-4.44 (m, 2 H), 3.93-4.13 (m, 2 H). Method 1: RT=2.83 min; M+H=398.0

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322 7V o) ΑΧ > ΝΗ N BUT ' P Ή NMR (400 MHz, DMSO-d6) δ 9.14 (d, J=2.20 Hz, 1 Η), 9.01 (d, J=2.20 Hz, 1 Η), 8.88 (d , J=l.22 Hz, 1 Η), 8.67 (s, 1 Η), 8.32 (dd, J=7.09, 2.69 Hz, 1 Η), 7.73-7.81 (m, 1 Η), 7.50 (dd, J=11.13, 9.17 Hz, 1 Η), 5.285.51 (m, 1 Η), 3.41-3.78 (m, 4 Η ), 1.982.30 (m, 2 Η). Method 1: RT=2.83 min; M+H=412,l 323 U ^D ··· ^Ν _α X7 ΎΝΗ Ρ ρ Ή NMR (400 MHz, DMSO-d6) δ 9.06 (d, J=2.51 Hz, 1 Η), 9.00 (d, J=2.26 Hz, 2 Η), 8.51 (d , J=2.51 Hz, 1 Η), 8.27 (dd, J=7.03, 2.76 Hz, 1 Η), 7.86 (br s, 1 Η), 7.64-7, 77 (m, 1 H), 7.50 (dd, J=11.04, 9.29 Hz, 1 H), 7.19 (br s, 1 H) 5.26-5.57 (m, 1 H), 4.264.44 (m, 2 H), 3.94-4.14 (m, 2 H). Method 1: RT=1.83 min; M+H=396,l 324 ρ FX Π 4 DYN F _τ Ο /-— ,Υ f Α f 3=4 Ή/ ρ Ή NMR (400 MHz, DMSO-d6), δ 9.27 (br s, 1 H), 9.15 (d, J=2.26 Hz, 1 H), 9.01 (d, J=2, 26 Hz, 1 H), 8.89 (dd, J=2.26, 1.00 Hz, 1 H), 8.28 (dd, J=6.90, 2.63 Hz, 1 H), 7.697 .76 (m, 1 H), 7.54 (dd, J=11.17, 9.16 Hz, 1 H), 4.42 (t, J=12.67 Hz, 4 H). Method 2: RT=0.98 min; M+H=416.0 325 Ζ-Χ ζ ΖAj '^-j' \ // \\ 'ζ Α ι Χτ ζ οΧπ and Ή NMR (400 MHz, DMSO-d6), δ 9.04 (d, J=2.45 Hz, 1 Η), 8.97 (s, 1 Η), 8.84 (d, J=2.44 Hz, 1 H), 8.42 (s, 1 H), 8.37 (d, J=2.20 Hz, 1 H), 8.24 (dd, J=7.09, 2.69 Hz, 1 Η), 8.02 (s, 1 Η), 7.63-7.73 (m, 1 Η), 7.47 (dd, J=11.13, 9.17 Hz, 1 Η), 5 .28-5.53 (m, 1 Η), 4.24-4.41 (m, 2 Η), 3.95-4.11 (m, 2 Η), 3.78 (tt, J=7 .34, 3.79 Hz, 1 Η), 0.961.17 (m, 4 Η). Method 1: RT=2.73 min; M+H=436,l

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326 F AV W ( AO 0 W Ν χ _Ν τ 1 Ή NMR (400 MHz, DMSO) δ 10.54 (s, 1 Η), 8.63 (d, 7=2.38 Hz, 1 Η), 8.29-8.41 (m, 2 Η), 7.66 (br d, 7=9.29 Hz, 1 Η), 7.40-7.55 (m, 1 Η), 7.14 (d, 7=2.64 Hz, 1 Η), 4 .40 (t, 7=12.17 Hz, 4 H), 1.72-1.85 (m, 1 H), 0.83 (br d, J=6.02 Hz, 4 H). Method 2: RT=0.93 min; M+H=388.2 327 'r /=< Ν.^Ο O Ν ux 1 IN Vk _r Vo ^F /...... 4 Ή NMR (400 MHz, DMSO) δ 10.53 (s, 1 Η), 8.58 (d, 7=2.51 Hz, 1 Η), 8.26-8.39 (m, 2 Η), 7.60-7.71 (m, 1 H), 7.40-7.55 (m, 1 H), 7.00 (d, 7=2.76 Hz, 1 H), 5.39-5 .67 (m, 1 Η), 4.19-4.35 (m, 2 Η), 3.92-4.09 (m, 2 Η), 1.74-1.82 (m, 1 Η) , 0.83 (br d, 7=5.90 Hz, 4 H). Method 1: RT=2.79 min; M+H=370.2 328 F /-N W wi _N . / - Ν N HN ur >0 X .--N / 1 Ή NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=2.69 Hz, 1 Η), 8.97 (d, J=2.44 Hz, 1 Η), 8.44 (d , J=2.69 Hz, 1 Η), 8.26 (dd, J=7.09, 2.69 Hz, 1 Η), 8.20 (d, J=l.47 Hz, 1 Η), 7.67-7.74 (m, 1 Η), 7.44-7.56 (m, 2 Η), 5.29-5.52 (m, 1 Η), 4.26-4.39 ( m, 2 Η), 3.96-4.11 (m, 2 Η), 2.21 (s, 3 Η). Method 1: RT=1.87 min; M+H=410,l 329 X , / . .. D 7 O X ' ^N ' c) D ο Ν'-- 0 ΝΗ 0 F Ή NMR (400 MHz, DMSO-d6) δ 9.43 (d, J=2.20 Hz, 1 Η), 8.97-9.05 (m, 2 Η), 8.91 (d, J= 2.45 Hz, 1 H), 8.74 (d, J=3.18 Hz, 1 H), 8.28 (dd, J=7.09, 2.69 Hz, 1 H), 8.21 (dd, J=8.93, 4.28 Hz, 1 H), 7.92 (td, J=8.80, 2.93 Hz, 1 H), 7.68-7.75 (m, 1 Η), 7.50 (dd, J=11.25, 9.05 Hz, 1 Η), 5.29-5.53 (m, 1 Η), 4.25-4.41 (m, 2 Η ), 3.95-4.12 (m, 2 Η). Method 2: RT=0.88 min; M+H=425.0

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330 । in II D up to --1 Ή NMR (400 MHz, DMSO-d6) δ 9.43 (d, 1=2.20 Hz, 1 Η), 9.00 (d, J=2.45 Hz, 1 Η), 8.90 (d , 1=2.20 Hz, 1 Η), 8.70-8.81 (m, 2 Η), 8.29 (dd, 1=7.09, 2.69 Hz, 1 Η), 8.21 (dd, 1=8.80, 4.16 Hz, 1 Η), 7.91 (td, J=8.68, 2.93 Hz, 1 Η), 7.68-7.77 (m, 1 Η), 7.47 (dd, 1=11.13, 9.17 Hz, 1 Η), 3.99 (t, 1=7.58 Hz, 4 Η), 2.21 (quint., 1= 7.52 Hz, 2 N). Method 1: RT=2.82 min; M+H=407.0 331 R Ν ,Ν . Ddd 1,. HN 1 >° Ή NMR (400 MHz, DMSO) δ 10.53 (s, 1 Η), 8.70 (d, 7=2.93 Hz, 1 Η), 8.56 (d, 7=2.69 Hz, 1 Η), 8.35 (dd, 7=7.15, 2.63 Hz, 1 Η), 7.63-7.71 (m, 1 Η), 7.48 (dd, 7=11.31, 9.11 Hz, 1 Η), 7.15 (d, 7=2.93 Hz, 1 Η), 2.95 (s, 6 Η), 1.79 (quint., 1=6.24 Hz, 1 N) 0.79-0.87 (t, 4 N). Method 2: RT=0.85 min; M+H=340.2 332 Т η σ f Vn . . _c ={ ⁿ F Ή NMR (400 MHz, DMSO) δ 10.50 (s, 1 Η), 9.18 (d, 7=0.88 Hz, 1 Η), 8.97 (d, 7=2.51 Hz, 1 Η) 8.69-8.81 (m, 1 Η) 8.54 (dd, 7=4.52, 1.88 Hz, 1 Η), 8.33 (dd, 7=7.09, 2, 57 Hz, 1 Η), 7.84 (dd, 7=10.98, 8.85 Hz, 1 Η), 7.57-7.69 (m, 1 Η), 7.387.53 (m, 2 Η ), 1.61-1.75 (m, 1 H), 0.670.85 (m, 4 H). Method 1: RT=2.85 min; M+H=392.2 333 ~Dn Ό ⁴ σ <! 'Vn ' ., ifY ^u F Ή NMR (400 MHz, DMSO) δ 10.57 (s, 1 Η), 9.03 (d, 7=2.26 Hz, 1 Η), 8.99 (d, 7=2.38 Hz, 1 Η), 8.65-8.73 (m, 2 Η), 8.41 (br d, 7=7.28 Hz, 1 Η), 8.13 (d, 7=8.16 Hz, 1 Η ), 7.71 (br s, 1 H), 7.48-7.58 (m, 2 H), 1.73-1.83 (m, 1 H), 0.80-0.88 (m , 4H). Method 1: RT=2.87 min; M+H=408.2

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334 I. 0 W ₄ YNH & I J HO' Ή NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1 Η), 9.00 (d, J=2.20 Hz, 1 Η), 8.94 (d, J=2.20 Hz , 1 Η), 8.62 (dd, J=7.09, 2.45 Hz, 1 Η), 8.57 (d, J=3.67 Hz, 1 Η), 8.51 (d, J =2.20 Hz, 1 H), 7.91-8.01 (m, 1 H), 7.81 (d, J=7.34 Hz, 1 H), 7.60 (dd, J=11 .00, 9.05 Hz, 1 Η), 7.37 (dd, J=7.70, 4.77 Hz, 1 Η), 5.83 (t, J=5.99 Hz, 1 Η), 4.60 (d, J=6.11 Hz, 2 H), 2.45 (s, 6 H). Method 1: RT=2.57 min; M+H=459.0 335 7 ΓΊ about YN>A -NH £Υ N-0 ύ Ή NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1 Η), 9.03 (d, J=2.20 Hz, 1 Η), 8.98 (d, J=2.20 Hz , 1 Η), 8.65 (dd, J=4.65, 1.71 Hz, 1 Η), 8.61 (dd, J=7.09, 2.45 Hz, 1 Η), 8.57 (d, J=2.20 Hz, 1 Η), 8.00-8.07 (m, 1 Η), 7.94 (dt, J=9.05, 3.42 Hz, 1 Η), 7 .60 (dd, J=11.00, 9.29 Hz, 1 Η), 7.48 (dd, J=7.70, 4.77 Hz, 1 Η), 5.55 (br s, 1 Η ), 4.60 (s, 2 H), 2.52 (br s, 3 H), 2.41 (s, 3 H). Method 1: RT=2.49 min; M+H=458.9 336 /Ή \ / Ύ ^Ynh if £ °' hYY ^v Ν'-Υγ- F Ή NMR (400 MHz, DMSO) δ 9.46 (d, >2.32 Hz, 1 H), 8.99 (d, >2.32 Hz, 1 H), 8.93 (d, >2, 32 Hz, 1 H), 8.73 (d, >4.04 Hz, 1 H), 8.51 (s, 1 H), 8.30 (dd, >6.97, 2.57 Hz, 1 H), 8.11 (d, >7.95 Hz, 1 H), 7.95 (td, >7.76, 1.71 Hz, 1 H), 7.74 (dt, >8.99, 3.45 Hz, 1 H), 7.37-7.50 (m, 2 H), 3.42-3.48 (m, 4 H), 1.86 (br s, 4 H). Method 1: RT=2.67 min; M+H=403.3

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337 ₄ /-Ν Ι> Ν <>-Ν F - ν Ζ ι ι Ν ( ) ______ί Ή NMR (400 MHz, DMSO) δ 8.52 (d, /=2.64 Hz, 1 Η), 8.46 (s, 1 Η), 8.28 (d, /=2.76 Hz, 1 Η), 8.23 (dd, /=7.09, 2.57 Hz, 1 Η), 7.67 (dt, /=8.60, 3.54 Hz, 1 Η), 7.40 (dd , /=11.29, 9.16 Hz, 1 Η), 6.92 (d, /=2.76 Hz, 1 Η), 4.02 (s, 4 Η), 3.46-3.49 (m, 4 Η), 1.86 (br t, /=6.34 Hz, 4 Η), 0.68 (s, 4 Η), Μ+Η=407.3. 338 D F MX /.. - A <>0 y A ^N 'Ν' F W NMR (400 MHz, DMSO) δ 8.62 (d, /=2.69 Hz, 1 H), 8.47 (s, 1 H), 8.36 (d, /=2.81 Hz, 1 Η), 8.23 (dd, /=7.09, 2.69 Hz, 1 Η), 7.65-7.73 (m, 1 Η), 7.41 (dd, /=11.25, 9.17 Hz, 1 H), 7.14 (d, /=2.81 Hz, 1 H), 4.40 (t, /=12.23 Hz, 4 H), 3.38-3.41 (m, 4 Η), 1.86 (br t, /=6.48 Hz, 4 Η). Method 1: RT=2.86 min; M+H=417.0 339 F 0 m Μνη „ 'trans - racemic h F Ή NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1 Η), 8.64 (d, J=2.64 Hz, 1 Η), 8.37 (d, J=2.89 Hz , 1 Η), 8.32 (dd, J=7.03, 2.63 Hz, 1 Η), 7.59-7.69 (m, 1 Η), 7.51 (dd, J=11, 11, 9.10 Hz, 1 Η), 7.14 (d, J=2.76 Hz, 1 Η), 4.79-5.06 (m, 1 Η), 4.41 (t, J= 12.23 Hz, 4 Η), 2.23-2.33 (m, 1 Η), 1.49-1.64 (m, 1 Η), 1.27 (dq, J=13,l 1, 6.46 Hz, 1 H). Method 2: RT=0.97 min; M+H=406.2 340 ca / “A V ² / G7: C .Ζ Ζ A IX 1, _h o- V, - L / Ή NMR (400 MHz, METAHOJI-d4) δ 9.12 (s, 1 Η), 8.59 (d, J=2.20 Hz, 1 Η), 8.41-8.47 (m, 1 Η ), 8.33 (d, J=l.96 Hz, 1 Η), 8.24 (d, J=5.62 Hz, 1 Η), 7.64 (dd, J=5.75, 2, 08 Hz, 1 Η), 5.13-5.36 (m, 1 Η), 3.48-3.79 (m, 4 Η), 1.99-2.28 (m, 2 Η). Method 2: RT=0.90 min; M+H=405.l, 407.1

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341 /N. -χ XJ Γ ΧΧ Ύ ^Ν ) Χχ· HN >ο Ή NMR (400 MHz, DMSO-d6), δ 9.46 (d, 1=2.20 Hz, 1 Η), 9.37 (s, 1 Η), 9.26 (s, 1 Η), 8 .95 (d, 1=2.45 Hz, 1 Η), 8.74 (d, 1=3.91 Hz, 1 Η), 8.52 (d, 1=1.71 Hz, 1 Η), 8.37 (d, 1=5.62 Hz, 1 H), 8.12 (d, 1=8.07 Hz, 1 H), 7.96 (td, 1=7.70, 1.71 Hz , 1 Η), 7.74 (dd, 1=5.62, 1.96 Hz, 1 Η), 7.42 (dd, 1=7.09, 5.14 Hz, 1 Η), 4.05 (t, 1=7.58 Hz, 4 H), 2.23 (quintal, 1=7.58 Hz, 2 N). Method 1: RT=2.67 min; M+H=372.0 342 ΊΊ Tv , .7 <) four Ή NMR (400 MHz, DMSO-d6), δ 9.439.50 (m, 2 Η), 9.38 (s, 1 Η), 8.95 (d, 1=2.26 Hz, 1 Η), 8 .74 (d, 1=4.02 Hz, 1 Η), 8.50 (d, 1=1.76 Hz, 1 Η), 8.39 (d, 1=5.77 Hz, 1 Η), 8.13 (d, 1=8.03 Hz, 1 Η), 7.97 (td, 1=7.78, 1.76 Hz, 1 Η), 7.73 (dd, 1=5.65, 1.88 Hz, 1 Η), 7.43 (dd, 1=6.78, 4.77 Hz, 1 Η), 5.315.54 (m, 1 Η), 4.32-4.48 (m, 2 Η), 4.014.17 (m, 2 Η). Method 1: RT=2.67 min; M+H=390.0 343 BUT > ΝΗ 0' >—s L? M 1 .....ΤΧ one Ή NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1 Η), 8.68 (s, 1 Η), 8.30-8.35 (m, 2 Η), 7.63 (br d, 1=8.41 Hz, 1 Η), 7.59 (br d, 1=8.03 Hz, 1 Η), 7.39-7.47 (m, 1 Η), 7.13 (d , 1=2.76 Hz, 1 Η), 4.41 (t, 1=12.23 Hz, 4 Η), 3.99 (t, 1=7.53 Hz, 4 Η), 2.21 ( fifth, 1=7.56 Hz, 2 Η). Method 2: RT=0.84 min; M+H=385.2 344 , ).....: ί ζ> 4 JJ } ΗΝ >=Ο r ^N ' Ή NMR (400 MHz, DMSO-d6) δ 9.44 (d, 1=2.20 Hz, 1 Η), 9.18 (s, 1 Η), 8.91 (d, 1=2.32 Hz , 1 Η), 8.70-8.78 (m, 2 Η), 8.368.42 (m, 1 Η), 8.14 (d, 1=8.07 Hz, 1 Η), 7.95 ( td, 1=7.73, 1.77 Hz, 1 Η), 7.65-7.71 (m, 2 Η), 7.44-7.51 (m, 1 Η), 7.42 (dd , 1=7.15, 5.20 Hz, 1 Η), 4.01 (t, 1=7.58 Hz, 4

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Η), 2.22 (quint., J=7.58 Hz, 2 Η), 1.471.61 (m, 1 Η), 1.19-1.34 (m, 1 Η), 1.001.08 (m , 1 Η), 0.85 (t, J=7.40 Hz, 1 Η).

Method 2: RT=0.74 min; M+H=371.0

345 N^N π TO Ν- one Ή NMR (400 MHz, DMSO-r/J δ 11.31 (s, 1H), 9.60 (d, 7=2.3 Hz, 1H), 9.45 (d, 7=1.5 Hz, 1H), 9.18 (d, 7=2.5 Hz, 1H), 9.08 (t, 7=2.1 Hz, 2H), 8.97 (dd, 7=2.5, 1.5 Hz, 1H), 8.92-8.79 (m, 2H), 8.31-8.15 (m, 2H), 8.08 (td, 7=7.7, 1.9 Hz, 1H) , 7.76 (dd, 7=11.1, 9.1 Hz, 1H), 7.54 (ddd, 7=7.5, 4.8, 1.0 Hz, 1H). Method 1: RT=2.71 min; M+H=412.10 346 Λ ΝΗ DO' θ y /ChkCh/DO ( £ Ν M F 1 NMR (400 MHz, DMSO-7 ₆ ) δ 10.52 (s, 1H), 9.59 (d, 7=2.3 Hz, 1H), 9.13 (d, 7=2.5 Hz, 1H ), 9.05 (d, 7=2.3 Hz, 1H), 8.85 (ddd, 7=4.8, 1.9, 0.9 Hz, 1H), 8.55 (dd, 7= 7.0, 2.7Hz, 1H), 8.24(dt, 7=8.1, 1.1Hz, 1H), 8.07(td, 7=7.7, 1.8Hz, 1H ), 7.81 (ddd, 7=9.1, 4.2, 2.7 Hz, 1H), 7.65 (dd, 7=11.1, 9.1 Hz, 1H), 7.53 ( ddd, 7=7.5, 4.8, 1.0 Hz, 1H), 2.26 (dd, 7=7.4, 4.3 Hz, 1H), 1.59-1.44 (m, 2H), 1.12-0.84 (m, 4H). Method 1: RT=2.85 min; M+H=400,l 347 OCT 7 ' ^Ν ' o DO DODO )DO) ι U 1NMR (400 MHz, DMSO-7 ₆ ) δ 10.12 (s, 1H), 9.48 (d, 7=2.3 Hz, 1H), 9.04 (d, 7=2.5 Hz, 1H ), 8.95 (d, 7=2.3 Hz, 1H), 8.74 (ddd, 7=4.8, 1.8, 0.9 Hz, 1H), 8.48 (dd, 7= 7.1, 2.7 Hz, 1H), 8.13 (dt, 7=8.0, 1.1 Hz, 1H), 8.027.87 (m, 2H), 7.57 (dd, 7=11 .2, 9.1 Hz, 1H), 7.43 (ddd, 7=7.5, 4.8, 1.0 Hz, 1H), 6.93 (s, 1H), 2.47 (s, 2H), 1.24(s, 6H). Method 1: RT=3.08 min; M+H=414,l

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348 Ν'^'Λ ΝΗ Ap b > ^Ν JJ ν -α _ν Α SNMR (400 MHz, DMSO-J ₆ ) δ 10.38 (s, 1H), 9.48 (d, 7=2.3 Hz, 1H), 9.04 (d, 7=2.5 Hz, 1H ), 8.95 (d, 7=2.3 Hz, 1H), 8.74 (ddd, 7=4.8, 1.9, 1.0 Hz, 1H), 8.41 (dd, 7= 7.0, 2.7Hz, 1H), 8.13(dt, 7=8.0, 1.1Hz, 1H), 7.96(td, 7=7.7, 1.9Hz, 1H ), 7.80 (ddd, 7=9.1, 4.2, 2.7 Hz, 1H), 7.59 (dd, 7=11.2, 9.1 Hz, 1H), 7.43 ( ddd, 7=7.5, 4.8, 1.0 Hz, 1H), 1.73 (d, 7=1.0 Hz, 4H). Method 2: RT=0.83 min; M+H=399,l 349 <J cis - racemic F ^X NMR (400 MHz, DM SOW,) δ 10.65 (s, 1H), 9.48 (d, 7=2.3 Hz, 1H), 9.04 (d, 7=2.5 Hz, 1H ), 8.95 (d, 7=2.3 Hz, 1H), 8.74 (ddd, 7=4.8, 1.8, 1.0 Hz, 1H), 8.43 (dd, 7= 7.0, 2.7Hz, 1H), 8.13(dt, 7=8.0, 1.1Hz, 1H), 7.96(td, 7=7.7, 1.8Hz, 1H ), 7.74 (ddd, 7=9.1, 4.2, 2.7 Hz, 1H), 7.57 (dd, 7=11.2, 9.1 Hz, 1H), 7.42 ( ddd, 7=7.5, 4.8, 1.1 Hz, 1H), 4.98 (dtd, 7=66.2, 6.2, 3.7 Hz, 1H), 2.04 (ddt, 7=9.2, 7.0, 3.6Hz, 1H), 1.67(dtd, 7=23.2, 6.7, 3.6Hz, 1H), 1.19(ddt, 7= 12.5, 9.2, 6.4 Hz, 1H). Method 2: RT=0.80 min; M+H=392,l 350 /p ^F 1^.,^ Λ /)—a -j . ⁿ h nI Jx >0 - Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.78 (d, 7=2.4 Hz, 1H), 8.76 (d, 7=2.3 Hz, 1H), 8.44-8, 39 (m, 1H), 8.38 (d, 7=2.2 Hz, 1H), 8.32 (dd, 7=6.8, 2.7 Hz, 1H), 7.88 (s, 1H ), 7.81-7.72 (m, 2H), 7.39-7.26 (m, 2H), 6.83 (s, 1H), 2.43 (s, 2H), 2.35 ( s, 3H), 1.19 (s, 6H). Method 2: RT=0.90 min; M+H=428,l

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Ή NMR (400 MHz, DMSO-A) δ ppm 10.52 (br s, 1 Η), 8.83 (d, 7=2.64 Hz, 1 Η), 8.70 (d, 7=2, 26 Hz, 1 H), 8.56 (dd, 7=7.03, 2.64 Hz, 1 H), 8.07 (d, 7=1.76 Hz, 1 H), 7.86-7 .94 (m, 1 Η), 7.56 (dd, 7=11.11, 9.10 Hz, 1 Η), 3.04-3.15 (m, 1 Η), 2.50-2, 51 (m, 3 H), 2.40 (s, 3 H), 1.31 (d, 7=6.90 Hz, 6H); M+H=394.1

Ή NMR (400 MHz, CD ₃ OD) 9.00-8.99 (d, J=2.4, 1H), 8.84-8.83 (d, J=2.4, 1H), 8.508, 49 (d, J=2.0, 1H), 8.47-8.45 (dd, J=2.4, 6.8, 1H), 7.90-7.86 (m, 1H), 7 .74-7.71 (m, 2H), 7.53-7.50 (m, 2H), 7.47-7.42 (m, 2H), 2.54 (s, 3H), 2.45 (s, 3H); M+H=428,l

Ή NMR (400 MHz, DMSO-d ₆ ) 9.25 (s, 1H), 9.06-9.05 (d, J=2.8, 1H), 8.96-8.95 (d, J =2.0, 1H), 8.52-8.51 (d, J=2.4, 1H), 8.27-8.25 (m, 1H), 7.80-7.78 (d, J=7.2, 2H), 7.72-7.67 (m, 1H), 7.56-7.48 (m, 3H), 7.44-7.41 (m, 1H), 4, 44-4.38 (t, 1=16.4, 4H).

Biological analyzes

The assays described herein illustrate the present invention, but do not limit its scope.

Chlorphenol red-p-O-galactopyranoside adenosine triphosphate bovine serum albumin dimethyl sulfoxide fetal bovine serum phosphate-buffered saline Roswell Park Memorial Institute (RPMI) medium 1640

Abbreviations.

The abbreviations used in this document below have their respective meanings.

CPRG

APR

BSA

DMSO

FBS

PBS

RPMI1640

In vitro growth inhibition assay for the axenic amastigote Leishmania donovani.

The axenic amastigote of the parasite Leishmania donovani is grown at 37°C, 5% CO2 in a medium consisting of RPMI 1640, 4 mM L-glutamine, 20% thermally inactivated FBS, 100 U/ml penicillin and 100 μg/ml streptomycin, 23 μM folic acid. acid, 100 μM adenosine, 22 mM D-glucose, 25 mM MES. Adjust the pH of the medium to 5.5 at 37°C using HCl. First, 20 µl of medium is measured into 384-well plates and 100 nl of the compounds of the present invention in DMSO are added to the wells of the plates. At the same time, control compounds and DMSO are added to the plates, which will act as positive and negative controls, respectively. Then 40 μl of parasite culture (9600 parasites) is added to the wells of the plates. The plates are then placed in incubators. After two days of incubation, 20 μl of Cell TiterGlo® (Promega) is added to the wells of the plates. The luminescent signal of each well is measured using an Envision reader (Perkin Elmer).

Analysis of the suppression of Leishmania donovani parasitemia in mouse macrophages.

The assay measures the increase in parasites in the assay well of a plate using a DNA-incorporating dye, SYBR Green I® dye (INVITROGEN), to stain the nuclei of Leishmania cells. The L. donovani HU3 strain is propagated by infecting BALB/c mice by tail vein injection of 10 ⁷ Leishmania parasites. Infected mice were allowed to develop infection within 9-11 weeks after infection. During this time

- 150 039324 parasites accumulate in the spleen of infected mice in large numbers, and infected mice serve as a source of parasites for in vitro measurement of the effectiveness of the compounds. To test the compound for antileishmanial activity, peritoneal macrophages isolated from uninfected BALB/c mice were plated in 384-well plates at a density of 2x10 ⁴ macrophages per well in 25 ml of medium (RPMI1640, 10% fetal serum albumin, 10 mM HEPES, 1 mM sodium pyruvate, 1% Pen/Strep). The seeded plates are then placed in an incubator set to maintain a temperature of 37° C. and an atmosphere of 5% CO ₂ .

The following day, Leishmania parasites are isolated from the spleens of mice infected for 9-11 weeks and 4x105 isolated parasites in 10 ml of the above medium are added to each well of the plate. The plates are then returned to the incubators and the infection is allowed to develop for 24 hours. After the infection of the macrophages is completed, 5 ml of the compounds of the present invention in the above medium, which also contains 5% DMSO, is added to the wells of the plates containing the infected macrophages. At the same time, control compounds (miltefosine and amphotericin B) and DMSO are added to the plates, which will act as positive and negative controls, respectively. After adding the compound, the plates are returned to the incubator and the parasite-infected cells are cultured for 5 days. After cultivation is complete, 40 ml of 8% paraformaldehyde is added to the wells of the plates and incubated for 15 minutes at room temperature. After incubation, paraformaldehyde is aspirated from the wells of the plates and 40 ml of PBS containing 0.2% Triton X-100 is added to the wells. After 15 minutes of incubation, the solution is again aspirated from the wells and replaced with a solution of Sybr® Green in PBS (1:125,000 dilution). Infected cells are visualized using an Evotec Opera multi-parameter microscope and the number of parasites per well is determined by counting parasite nuclei that are visible by staining with Sybr® Green.

Growth suppression analysis of the kinetoplastid parasite Trypanosoma cruzi.

The compounds of the present invention can be assayed for inhibitory activity against Trypanosoma cruzi amastigotes cultured in 3T3 fibroblast cells. The assay is performed using the non-flagellated form (amastigotes) of T. cruzi, which replicates within the intracellular space of the host cells. Host cells are initially infected with culture-derived trypomastigotes, which rapidly enter host cells and then divide as amastigotes. The protocol involves the use of the Tulahuen T. cruzi strain, which was designed to express the β-galactosidase (Lac-Z) gene in E. coli (Antimicr. Agents Chemoth. 40:2592, 1996). This allows colorimetric data to be read using a CPRG substrate and an absorbance reading plate reader.

3T3 fibroblast cells are resuspended in RPMI-1640 medium without phenol red supplemented with 10% FBS (thermally inactivated), 100 μg/ml penicillin and 100 μg/ml streptomycin. Measure 40 μl of the suspension (1000 cells) into 384-well plates and incubate overnight at 37°C and in an atmosphere containing 5% CO ₂ . The next day, 100 nl of compounds of the present invention in DMSO are added to the wells of the plates containing 3T3 cells. At the same time, control compounds (benznidazole and nifurtimox) and DMSO are added to the plates, which will act as positive and negative controls, respectively. Thereafter, 10 µl of medium containing 10,000 T. cruzi trypomastigotes was added to each well of the plate and the plates were placed back into the incubators. After 6 days of incubation, add 10 µl of reagent solution (0.6 mM CPRG, 0.6% NP-40 in PBS) to the plates and incubate at room temperature for 2 h. T. cruzi present in each well of the plate.

Growth suppression assay for Trypanosoma brucei brucei.

Proliferation is quantified by using the Cell ^TiterGlo® ( ^Promega® ) fluorescent cell viability assay, which measures the number of viable cells in culture based on the quantification of cellular ATP, which is an indicator of metabolically active cells.

The Trypanosoma brucei brucei (Lister 427) strain was grown in Hirumi 9 (HMI-9) medium supplemented with 10% v/v. fetal bovine serum (FBS) and 10% vol./about. SerumPlus. To measure the suppression of cell proliferation, test compounds were serially diluted three times in duplicate in 384-well white plates, resulting in 10 dilutions for each compound. A culture of T. b. was added to each well. brucei in a volume of 40 μl (10,000 parasites/ml) and assay plates were incubated at 37° C. for 2 days in a CO ₂ incubator. Growth inhibition was monitored by measuring levels of ATP, which is used as a surrogate growth marker. Relative luminescence units were measured using TECAN® M1000 30 minutes after the addition of 40 μl Cell TiterGlo®. IC ₅₀ values were determined by data analysis using HELIOS software. The IC ₅₀ is defined as the lowest concentration of a compound that provides 50% growth inhibition of a T. b strain. brucei wild type compared to untreated controls.

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In table. 3 shows the inhibitory efficacy of the compounds (EC ₅₀ ) against L. donovani axenic amastigotes in vitro (column 2); L. donovani in mouse peritoneal macrophages (column 3); T. cruzi (column 4) and T. brucei (column 5). The compounds of the present invention are characterized by an EC ₅₀ value ranging from >10 μM to <0.01 μM. In specific embodiments, the compounds of the present invention have an EC ₅₀ of <1 μM, <500 nM, <100 nM, or <50 nM.

Table 3

conn. no. Amastigotes L. donovani EC ₅ o (µM) L. donovani in mouse macrophages EU ₅₀ (µM) Infectious according to Buckner T. cruzi EU ₅₀ (μM) T. brucei (HAT) EC ₅ o (µM) one 0.0071 n. about. 0.0052 <0.023 2 0.003 0.0044 0.0010 <0.023 3 0.0018 0.0020 0.0016 <0.023 four 0.0013 n. about. 0.0010 <0.023 5 0.0036 n. about. 0.0053 <0.023 6 0.012 n. about. 0.0099 <0.023 7 0.0077 0.004 0.0016 <0.023 eight 0.0077 0.0033 0.0045 <0.023 9 0.0087 0.011 0.0098 0.035 ten 0.016 0.0078 0.0048 <0.023 And 0.0028 n. about. 0.0010 >50

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12 0.041 Η. O. Η. O. <0.023 13 0.071 Η. O. Η. O. <0.023 fourteen 0.012 0.0097 0.0020 <0.023 fifteen 0.013 0.017 0.005 <0.023 16 0.089 Η. O. 0.012 n. about. 17 0.064 Η. O. 0.016 Η. O. eighteen 0.29 Η. O. 0.16 Η. O. 19 0.011 0.081 0.011 <0.023 twenty 0.010 0.037 0.0042 <0.023 21 0.0077 0.0065 0.0017 <0.023 22 0.028 21 0.0072 <0.023 23 0.14 θ,ιι 0.078 <0.023 24 0.88 ι, ο 0.44 0.61 25 0.021 0.047 0.017 <0.023 26 0.0096 n. about. 0.012 <0.023 27 0.033 0.015 0.038 <0.023 28 0.0013 0.0020 0.0010 <0.023 29 0.0082 0.0097 0.011 <0.023 thirty 0.59 n. about. n. about. n. about. 31 0.0062 Η. O. 0.0083 <0.023 32 0.012 0.013 0.005 <0.023 33 0.29 0.56 0.72 0.28 34 0.20 0.27 0.16 0.15 35 0.58 0.52 0.38 0.85 36 0.21 0.25 n. about. n. about. 37 0.023 n. about. 0.026 <0.023 38 0.031 0.033 0.062 0.024 39 0.0024 0.0038 0.0020 <0.023 40 n. about. n. about. n. about. <0.023 41 0.02 Η. O. Η. O. n. about. 42 0.0030 0.006 0.0018 <0.023 43 0.0047 Η. O. 0.0052 n. about. 44 0.029 0.032 0.022 Η. O. 45 0.04 Η. O. 0.028 <0.023

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46 0.0084 0.0035 0.0017 <0.023 47 0.023 0.027 0.0028 Η. 0. 48 0.35 0.33 0.29 0.050 49 25 12 12 3.4 fifty 0.078 0.10 0.079 <0.023 51 0.015 Η. 0. 0.019 <0.023 52 0.019 0.011 0.013 <0.023 53 0.0013 0.0020 0.0010 <0.023 54 0.028 Η. 0. 0.0041 Η. 0. 55 0.057 0.035 0.0063 Η. 0. 56 0.24 0.55 Η. 0. Η. 0. 57 0.71 Η. ο. 0.36 Η. ο. 58 Η. 0. Η. 0. Η. 0. <0.023 59 0.068 0.021 0.0047 <0.023 60 2.0 2.4 0.44 1.3 61 0.24 Η. 0. 0.052 Η. 0. 62 0.039 Η. 0. 0.0051 <0.023 63 0.089 0.09 0.014 Η. 0. 64 0.0022 0.0039 0.0010 <0.023 65 ι, ο 1.2 0.96 1.4 66 0.74 0.87 0.15 0.12 67 0.21 0.31 0.042 >50 68 2.2 2.8 0.16 0.51 69 0.17 0.15 0.068 0.04 70 0.14 0.10 0.022 0.038 71 4.8 2.8 1.4 3.0 72 2.1 1.4 0.18 0.42 73 0.10 0.22 0.057 0.037 74 0.76 0.82 0.057 θ,ιι 75 0.20 0.17 0.12 0.17 76 1.1 0.93 0.41 0.48 77 17 Η. 0. 6.5 8.5 78 0.80 0.87 0.45 0.53 79 h, o 2.4 0.14 0.35

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80 0.41 0.41 0.092 0.17 81 3.16 3.6 0.42 0.36 82 0.47 0.31 0.059 0.054 83 0.014 0.0070 0.0073 <0.023 84 2.4 6.9 3.7 2.03 85 1.2 0.75 0.15 0.18 86 0.13 0.12 0.014 <0.023 87 0.062 0.071 0.016 <0.023 88 5.3 3.2 1.8 1.5 89 0.47 0.27 0.032 0.033 90 0.28 0.31 0.14 0.077 91 0.0087 0.0086 0.0041 <0.023 92 Η. 0. Η. 0. Η. 0. <0.023 93 0.034 0.032 0.0070 <0.023 94 0.012 0.0081 0.0018 <0.023 95 0.42 0.35 0.17 0.085 96 0.023 0.021 0.018 <0.023 97 0.012 0.44 0.0088 <0.023 98 0.025 0.023 0.015 <0.023 99 0.0013 0.0020 0.0010 >50 100 0.0092 Η. 0. 0.0042 <0.023 101 0.30 0.31 0.13 0.15 102 ο,ιι Η. 0. 0.046 Η. 0. 103 0.68 0.40 0.15 0.31 104 3.1 2.1 1.2 4.2 105 0.72 0.89 0.43 0.38 106 0.13 0.085 0.061 >50 107 0.22 0.13 0.077 0.088 108 0.0033 0.004 0.0038 <0.023 109 0.074 Η. 0. 0.015 Η. 0. ON 0.64 Η. 0. 0.15 Η. 0. 111 8.7 Η. 0. 2.9 ten 112 0.016 Η. 0. 0.0028 <0.023 FROM 0.037 Η. 0. 0.00522 Η. 0.

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114 0.31 Η. 0. 0.045 0.054 115 0.15 Η. 0. 0.014 <0.023 116 3.1 Η. 0. 0.88 1.5 117 9.3 Η. 0. 5.5 13 118 0.69 Η. 0. 1.1 1.4 119 1.6 Η. 0. 4.5 13 120 5.2 Η. 0. 4.3 1.8 121 0.21 Η. 0. Η. 0. 0.12 122 0.015 Η. 0. 0.0042 Η. 0. 123 0.0094 0.0089 0.0044 <0.023 124 0.018 Η. 0. 0.016 Η. 0. 125 0.044 0.031 0.034 <0.023 126 0.024 0.014 0.014 <0.023 127 0.025 0.017 0.0068 <0.023 128 0.38 0.19 0.14 0.18 129 0.029 0.031 0.015 <0.023 130 0.19 0.16 0.036 0.040 131 0.007 0.0051 0.0052 <0.023 132 0.011 0.007 0.013 <0.023 133 0.012 0.0080 0.0059 <0.023 134 0.023 0.0054 0.02 <0.023 135 0.0046 0.0086 0.0066 <0.023 136 0.030 0.019 0.17 <0.023 137 0.0088 0.0060 0.0051 <0.023 138 0.011 0.0057 0.047 <0.023 139 0.74 0.32 3.0 <0.023 140 0.10 0.041 0.023 <0.023 141 0.08 0.012 0.022 <0.023 142 7.8 9.2 eleven 4.3 143 0.15 θ,ιι Η. 0. <0.023 144 0.023 0.023 0.017 <0.023 145 0.0054 0.0047 0.018 <0.023 146 0.026 0.012 0.085 <0.023 147 0.0061 0.026 0.0048 <0.023

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148 0.0081 0.012 0.014 <0.023 149 0.011 0.0079 0.0054 <0.023 150 0.014 0.025 0.021 <0.023 151 0.06 0.013 0.012 <0.023 152 0.0037 0.0053 0.0017 <0.023 153 0.21 27 0.15 0.50 154 0.053 0.078 0.023 0.037 155 0.053 0.022 0.018 <0.023 156 0.0093 Η. 0. 0.0051 <0.023 157 0.025 0.018 0.013 <0.023 158 0.016 0.016 0.015 <0.023 159 0.013 0.017 0.037 <0.023 160 0.0043 0.0098 0.0051 <0.023 161 0.0077 0.0073 0.0098 <0.023 162 0.007 0.0045 0.0018 <0.023 163 0.0058 0.0041 0.0027 <0.023 164 0.006 0.01 0.0017 <0.023 165 0.010 0.010 0.04 <0.023 166 0.0025 0.0037 0.0017 <0.023 167 0.0029 0.0082 0.0022 <0.023 168 0.0032 0.0082 0.027 <0.023 169 0.010 0.030 0.014 <0.023 170 0.008 0.011 0.0046 <0.023 171 0.0095 0.016 0.047 <0.023 172 0.0067 0.011 0.033 <0.023 173 0.41 0.50 0.14 0.12 174 2 2.7 0.72 ι,θ 175 0.024 0.0081 0.0049 <0.023 176 0.071 0.069 0.0095 Η. ο. 177 0.027 Η. 0. 0.055 <0.023 178 0.16 Η. 0. 1.6 0.036 179 0.41 Η. 0. 0.043 <0.023 180 0.55 Η. 0. 3.9 0.038 181 0.025 Η. 0. 0.82 <0.023

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182 0.0076 Η. 0. 0.0067 <0.023 183 0.012 Η. 0. 0.055 <0.023 184 0.0073 Η. 0. Η. 0. <0.023 185 0.2 Η. 0. Η. 0. <0.023 186 0.46 Η. 0. Η. 0. 0.24 187 0.0013 Η. 0. Η. 0. <0.023 188 0.0024 Η. 0. Η. 0. <0.023 189 0.003 Η. 0. Η. 0. <0.023 190 Η. 0. Η. 0. Η. 0. >50 191 Η. 0. Η. 0. Η. 0. <0.023 192 Η. 0. Η. 0. Η. 0. <0.023 193 Η. ο. Η. ο. Η. ο. <0.023 194 Η. 0. Η. 0. Η. 0. <0.023 195 0.010 0.0064 0.004 <0.023 196 0.076 27 0.012 <0.023 197 0.199 0.013 0.037 0.005 198 0.546 0.049 0.023 0.005 199 0.502 0.021 0.024 0.005 200 0.974 0.007 0.015 0.005 201 0.192 0.004 0.02 0.005 202 0.463 0.01 0.025 0.005 203 0.49 0.009 0.02 0.005 204 0.074 0.004 0.002 0.005 205 0.197 0.011 0.015 0.005 206 0.002 0.013 0.001 0.005 207 1.827 2.062 1.271 1.821 208 0.921 1.918 0.358 0.375 209 25.0 0.381 5.09 6.538 210 0.494 Η. ο. 0.079 Η. ο. 211 0.496 0.302 0.072 0.035 212 11.31 8.86 1.753 2.027 213 1.561 Η. 0. 0.363 Η. ο. 214 4.6 0.658 1.415 1.056 215 4.7 2.975 0.738 0.947

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216 3.7 4.67 0.435 0.620 217 14.46 Η. 0. 4.35 Η. 0. 218 0.004 0.212 0.038 0.003 219 0.034 Η. 0. 0.015 0.017 220 0.015 Η. 0. 0.006 0.042 221 0.003 Η. 0. 0.001 0.009 222 0.08 Η. 0. 0.045 0.073 223 0.082 Η. 0. 0.037 0.064 224 0.111 Η. 0. 0.046 0.067 225 0.037 Η. 0. 0.05 0.238 226 0.134 Η. 0. 0.129 0.343 227 0.03 Η. ο. 0.011 0.059 228 0.031 Η. 0. 0.01 0.030 229 25.0 Η. 0. 15.55 12,500 230 0.037 0.022 0.047 0.005 231 0.034 0.113 0.126 0.006 232 0.012 0.01 0.012 0.005 233 0.013 0.01 0.005 0.004 234 0.027 0.003 0.009 0.005 235 0.011 0.01 0.011 0.005 236 0.264 29.67 20.0 1.463 237 0.016 0.009 0.021 0.005 238 0.025 0.032 0.033 0.005 239 1.761 0.009 0.01 0.005 240 0.579 0.027 0.021 0.005 241 1.191 0.006 0.003 0.005 242 1.972 0.106 0.007 0.013 243 2.105 0.065 0.082 0.005 244 0.55 0.021 0.014 0.005 245 0.311 1.491 0.951 0.062 246 0.535 0.379 2.845 0.396 247 0.04 0.023 0.014 0.005 248 0.117 0.008 0.011 0.005 249 0.864 0.125 θ,ιι 0.005

- 159 039324

250 0.043 0.01 0.001 0.005 251 0.024 Η. 0. 0.367 0.005 252 0.183 Η. 0. 0.022 0.005 253 0.003 Η. 0. 0.004 0.005 254 0.091 0.673 0.05 0.259 255 0.042 0.028 0.015 0.005 256 0.011 0.038 0.005 0.027 257 0.014 0.007 0.002 0.004 258 0.023 0.039 0.012 0.028 259 0.012 0.016 0.003 0.004 260 0.221 0.224 0.049 0.043 261 0.004 Η. ο. 0.002 Η. ο. 262 0.033 Η. 0. 0.004 Η. 0. 263 0.012 0.068 0.045 0.010 264 0.357 13.68 0.48 0.384 265 0.003 0.004 0.002 0.001 266 0.008 0.029 0.065 0.005 267 1.713 13.83 9.4 0.081 268 0.084 0.273 0.082 0.116 269 0.019 0.032 0.009 0.020 270 0.233 2.174 1.703 0.079 271 0.12 0.003 0.144 0.388 272 0.131 0.085 0.114 0.351 273 0.027 0.006 0.017 0.045 274 0.002 0.003 0.001 0.001 275 0.003 0.003 0.001 0.001 276 0.029 θ,ι 0.021 0.033 277 0.04 0.138 0.144 0.082 278 0.007 Η. ο. Η. ο. 0.013 279 0.01 Η. 0. 0.003 Η. 0. 280 0.033 0.028 0.048 0.040 281 0.009 0.026 0.015 0.014 282 0.034 0.07 0.04 0.027 283 0.007 0.019 0.005 0.008

- 160 039324

284 0.027 0.056 0.015 0.015 285 0.004 0.009 0.003 0.004 286 0.025 0.047 0.014 0.030 287 0.021 0.03 0.021 0.010 288 0.176 Η. 0. Η. 0. 0.260 289 0.199 Η. 0. Η. 0. 0.208 290 0.007 0.004 0.004 0.004 291 0.01 0.005 0.005 0.005 292 0.005 0.008 0.003 0.005 293 6.82 17.61 1.207 0.167 294 0.004 0.004 0.005 0.005 295 0.292 1.973 4.29 0.038 296 0.216 0.002 0.005 0.005 297 0.105 0.472 0.73 0.005 298 0.014 0.004 0.004 0.004 299 0.029 0.007 0.014 0.005 300 0.022 0.006 0.004 0.003 301 0.073 0.097 0.472 0.008 302 0.118 0.015 0.002 0.005 303 0.49 0.015 0.01 0.005 304 0.004 0.003 0.03 0.005 305 θ,ιι 0.003 0.001 0.005 306 0.09 0.004 0.002 0.005 307 0.281 0.012 0.016 0.005 308 0.568 0.002 0.004 0.005 309 0.001 0.002 0.001 0.005 310 0.002 0.002 0.001 0.005 311 0.058 0.033 0.031 0.027 312 0.003 0.002 0.004 0.033 313 0.001 0.002 0.001 0.005 314 0.242 0.006 0.005 Η. 0. 315 0.002 0.002 0.001 0.005 316 0.002 0.002 0.001 0.005 317 0.002 0.002 0.001 0.005

- 161 039324

318 0.027 0.032 0.013 0.015 319 0.001 n. about. 0.001 0.005 320 0.008 n. about. 0.002 0.005 321 0.018 n. about. 0.011 0.005 322 0.012 n. about. 0.003 0.005 323 0.012 0.113 0.062 0.015 324 0.015 0.045 0.016 0.037 325 0.008 0.05 0.036 0.011 326 0.189 0.761 0.119 0.236 327 0.351 1.205 0.149 0.232 328 0.023 0.16 0.083 0.017 329 0.001 0.002 0.001 0.002 330 0.001 0.002 0.001 0.001 331 0.217 0.91 0.138 0.206 332 0.028 0.075 0.015 0.038 333 0.043 n. about. 0.016 n. about. 334 0.236 1.866 1.459 0.269 335 0.013 0.111 0.47 0.036 336 0.002 0.004 0.001 0.001 337 n. about. 0.013 0.004 0.007 338 0.005 0.002 0.003 0.003 339 1.586 0.31 0.112 0.163 340 0.225 0.087 0.061 0.035 341 0.006 0.033 0.01 0.009 342 0.007 0.024 0.017 0.010 343 0.01 0.032 0.014 0.009 344 0.002 0.005 0.003 0.001 345 0.011 0.033 0.004 0.005 346 0.239 0.155 0.034 0.041 347 0.007 0.015 0.002 0.007 348 0.347 0.963 0.142 0.112 349 0.096 0.102 0.085 0.043 350 0.016 0.058 0.016 0.028 351 0.049 0.024 0.015 0.031 352 0.017 0.031 n. about. 0.039 353 0.005 0.004 n. about. 0.013

In table. 4 compares the activity of a compound of formula (I) with compounds having a different nucleus. EC50 values are from the assays described above unless otherwise noted.

- 162 039324

Table 4

Amastigotes L. donovani EC ₅₀ (hM) Infectious no Buckner T cruzi EC ₅₀ (hM) X- 18hM 15hM about TS °t 180hM 48hM F I „VA/A / Yes — N 210hM 45hM FI yY ^N *AS 80hM 22hM F I yP—J 367hM 57hM

It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be made to those skilled in the art and should be included within the spirit and scope of this application and the scope of the appended invention formulas. All publications, patents, and patent applications cited in this document are incorporated herein by reference for all purposes.

Claims (20)

1. Compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof; where ring A is phenyl or pyridinyl; R ¹ is selected from (a) C ₁ . ₆ alkyl which is unsubstituted or substituted with 1-3 substituents independently selected from halogen and C _3-6 cycloalkyl; (b) C _1-4 alkoxy which is unsubstituted or substituted with C _1-4 haloalkyl; (c) -NR ^5a R ^5b where R ^5a and R ^5b are independently hydrogen, C _1-4 alkyl or C _1-4 haloalkyl; or R ^5a and R ^5b together with the nitrogen atom to which they are both attached form a 4-7 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O and S as ring atoms; wherein the 4-7 membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents independently selected from halogen, C _1-4 alkyl and C _1-4 alkoxy; or two substituents on the same or different ring atoms of a 4- to 7-membered heterocycloalkyl together with the atoms to which they are attached, - 163 039324 form a spiro-, bridged or condensed ring B attached to a 4-7-membered heterocycloalkyl; where ring B is C ₃ -6 cycloalkyl or 3-7 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms; or -NR ^5a R ^5b is -N(CD ₃ )2; (d) monocyclic C ₃ -6 cycloalkyl, C ₃ -6 cycloalkenyl or spiropentyl; each of which is unsubstituted or substituted with 1-3 substituents independently selected from halo, cyano, C _1-4 alkyl, C _1-4 haloalkyl, and C _1-4 alkoxy; (e) phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms; each unsubstituted or substituted with 1-2 substituents independently selected from halogen, cyano, C ₁ _ ₄ alkyl, C _1-4 haloalkyl, di-C ₁ _ ₄ alkylamino-C ₁ _ ₄ alkyl, CD3, C ₁ _ ₄ alkoxyC ₁ _ ₄ alkyl, C _1-4 hydroxyalkyl, C _1-4 alkoxy and C ₃ - ₆ cycloalkyl; R ² and R ⁷ are independently hydrogen or C _1-4 alkyl; R ³ is hydrogen or halogen and n is 0 or 1; R ⁴ is selected from (a) hydrogen; (b) halogen; (c) C ₁ _ ₆ haloalkyl or C _1-4 alkyl which is unsubstituted or substituted by C ₃ - ₆ cycloalkyl; (d) -NR ^6a R ^6b where R ^6a is hydrogen or C1-4 alkyl; R ^6b is hydrogen, C 1-4 alkoxycarbonyl, C _1-4 haloalkyl, C ₃ - ₆ cycloalkyl, or C _1-4 alkyl which is unsubstituted or substituted with C _1-4 alkoxy; or R ^6a and R ^6b together with the nitrogen atom to which they are both attached form a 4-7 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms; while 4-7-membered heterocycloalkyl is not substituted or substituted by 1-2 substituents independently selected from halogen, cyano, hydroxyl, C _1-4 alkyl, C ₁ _ ₄ haloalkyl, C ₁ _ ₄ alkoxyC ₁ _ ₄ alkyl, C _{1 -4} alkoxy, oxo, 1,1-dioxo, -C(O)-OR ⁷ or 4-6-membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O and S; or two substituents on the same or different ring atoms of a 4-7 membered heterocycloalkyl together with the atoms to which they are attached form a spiro-, bridged or fused ring C attached to a 4-7 membered heterocycloalkyl; where ring C is selected from C ₃ - ₆ cycloalkyl and 3-7-membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms; and it is independently substituted or substituted with 1-2 substituents independently selected from halo and oxo; (e) C ₃ - ₆ cycloalkyl; (f) a 4-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms; and it is unsubstituted or substituted by -C(O)OR ⁸ or -C(O)R ⁸ where R ⁸ is C _1-4 alkyl and phenylC _1-4 alkyl which is unsubstituted or substituted by 1-2 substituents representing halogen; and (g) a 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O and S as ring atoms; which is unsubstituted or substituted with 1-2 substituents independently selected from halogen, C _1-4 alkyl, C _1-4 hydroxyalkyl and C ₃ - ₆ cycloalkyl; or R ⁴ is -N-(CD ₃ ) ₂ . 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is pyridinyl. 4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, where R ¹ is selected from -(CH ₂ ) ₁ - ₃ CF ₃ , -(CH ₂ )-CH(CH ₃ )-CF ₃ , -( CH ₂ ) -C (CH ₃ ) ₃ , -O (CH ₂ ) ₂ CF ₃ , -(CH ₂ ) ₀ - ₂ -cyclopropyl, -(CH ₂ ) ₀ - ₂ cyclobutyl, -NHCH3, -N (CH ₃ ) ₂ , -N(CD ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), -N(CH ₃ )(CH ₂ CF ₃ ), - 164 039324 5. The compound according to any one of paragraphs.1-3 or its pharmaceutically acceptable salt, where R ¹ represents azetidinyl, which is unsubstituted or substituted by 1-2 substituents independently selected from halogen and C _1-4 alkyl; or two substituents on the same atom of the azetidinyl ring, together with the ring atom to which they are both attached, form spirocyclopropyl or spirotetrahydrofuranyl attached to the azetidinyl ring. 6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, where R ¹ is selected from 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ³ is halogen and n is 1. 8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R ³ is fluorine. 9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen, chlorine, bromine, methyl, isopropyl, -(CH ₂ ) _1-2 CH(CH ₃ ) ₂ , -(CH ₂ ) _0-1 C (CH ₃ ) ₃ , -C (CH ₃ ) ₂ CH ₂ CH ₃ , -CH (CH ₃ ) (CH ₂ ) _1-2 CH ₃ , -CH ₂ -cyclobutyl, -(CH ₂ ) _0-1 CF ₃ , -NH-(CH ₂ ) _0-1 CH ₃ , -N-(CD ₃ ) ₂ , -N(CH ₃ ) ₂ , -NH-CH(CH3) 2 , -NH-( CH2)-CH-(CH3)2, -NHC(O)OCH(CH3)2, -NH(CH2)2OCH3, - 165 039324 10. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -NR ^6a R ^6b ; R ^6a is hydrogen or C _1-4 alkyl; R ^6b is hydrogen, C _1-4 alkoxycarbonyl, or C _1-4 alkyl which is unsubstituted or substituted with C _1-4 alkoxy; or R ^6a and R ^6b together with the nitrogen atom to which they are both attached form a 4-6 membered heterocycloalkyl optionally containing 1-2 additional heteroatoms independently selected from N, O and S as ring atoms; wherein the 4-6 membered heterocycloalkyl is unsubstituted or substituted by 1-2 substituents independently selected from halogen, cyano, hydroxyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyC _1-4 alkyl, C _{1 -4} alkoxy and oxo; or two substituents on the same or different ring atoms of a 4-6-membered gene - 166 039324 terocycloalkyl together with the atoms to which they are attached form a spiro-, bridged or condensed ring C attached to a 4-6-membered heterocycloalkyl; where ring C is selected from C ₃ . ₆ cycloalkyl and 3-5 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O or S as ring atoms; and wherein ring C is independently substituted or substituted with 1-2 substituents independently selected from halo and oxo. 11. The connection according to any one of paragraphs. 1-8 or a pharmaceutically acceptable salt thereof, where R ⁴ is selected from 12. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, where R ⁴ is selected from 13. The connection according to claim 1, where the connection is selected from N-(3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)-3-fluoroazetidine-1-carboxamide, N-(3-(5-bromo- 2H-pyrazolo[3,4-b]pyridin-2-yl)-4-fluorophenyl)azetidine-1-carboxamide, 3-(2-(5-bromo-2H-n-pyrazolo[3,4-b]pyridine-2 -yl)pyridin-4-yl)-1,1-dimethylurea. 14. A compound according to claim 1, wherein the compound is 3-fluoro-N4-fluoro-3-(5-(3(trifluoromethyl)azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridine-2 -yl)phenyl)azetidine-1-carboxamide. 15. The compound of claim 1, wherein the compound is N-[3-(5-{5-azaspiro[2.3]hexan-5-yl}2H-pyrazolo[3,4-b]pyridin-2-yl)- 4-fluorophenyl]azetidine-1-carboxamide. 16. The compound of claim 1, wherein the compound is N-{2-[5-(3,3-difluoroazetidin-1-yl)-2Hpyrazolo[3,4-b]pyridin-2-yl]pyridin-4- yl}azetidine-1-carboxamide. 17. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds: X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } -2,4-d imethyl-1,3 -oxazole-5-car box amide X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide (3K)-3-Fluoro -X-{4-fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4b]pyridin-2-yl]phenyl} pyrrolidine-1-carboxamide - 167 039324 5 3,3-Difluoro^-{4-fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 6 3-Fluoro-M-{4-fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl } azetidin-1-carboxamide 7 ^{4-Fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide eight 3,3-Difluoro-M-{4-fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 9 M-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 3,3-difluoroazetidine-1-carboxamide ten T4-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} azetidin-1-carboxamide And 5-Fluoro-M-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2- yl]phenyl}furan-2-carboxamide 12 ^{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropanecarboxamide 13 2-Cyclopropyl-M-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}acetamide fourteen 3-Fluoro-M-{4-fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide fifteen T4-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 16 M-(4-Fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-dimethyl-1,3-oxazole-5-carboxamide 17 M-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-2,4- dimethyl-1,3-oxazole-5-carboxamide eighteen N-(3-{5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 19 N-(3-{5-Cyclohexyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide twenty T4-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroaz etidine-1-carboxamide 21 T4-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide - 168 039324 22 N-(3-{5-tert-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 23 3-Fluoro-A-{4-fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 24 3-Fluoro-Y-{4-fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 25 A-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 26 M-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}3-fluoroazetidine-1-carboxamide 27 3-Fluoro-N-{4-fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 28 3-Fluoro-M-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 29 Ν-(3-ί 5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3-difluoroazetidine-1-carboxamide thirty Ν-(3-{5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetidine-1-carboxamide 31 A-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridine in-2-yl}-4-fluorophenyl)-3,3difluoroazetidine-1-carboxamide 32 A-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3,3-difluoroazetidine-1-carboxamide 33 M-(3-{5-tert-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetidine-1-carboxamide 34 3,3-Difluoro-A-{4-fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 35 3,3-Difluoro-M-{4-fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 36 A-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3,3difluoroazetidine-1-carboxamide 37 A-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 3,3-difluoroazetidine-1-carboxamide 38 3,3-Difluoro-M-{4-fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide - 169 039324 39 3,3-Difluoro-M-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 40 X{4-Fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 41 (3K)-3-Fluoro-X{4-fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} pyrrolidine-1-carboxamide 42 (ZK)-X(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)3-fluoropyrrolide in-1-carboxamide 43 (3R)-N-(3-j 5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)3-fluoropyrrolide in-1-carboxamide 44 (3K)-X(3-{5-Cyclohexyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)3-fluoropyrrolide in-1-carboxamide 45 (3K)-X(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoropyrrolide in-1-carboxamide 46 (3K)-M-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 47 (3K)-M-(3-{5-tert-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoropyrrolide in-1-carboxamide 48 (3K)-3-Fluoro-X{4-fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} pyrrolidine-1-carboxamide 49 (3K)-3-Fluoro-T4-{4-fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}pyrrolidin-1-carboxamide fifty (3K)-X{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}3-fluoropyrrolide in-1-carboxamide 51 (3K)-X{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 52 (3K)-3-Fluoro-X{4-fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl } pyrrolidine-1-carboxamide 53 (ZI)-3-Fluoro-M-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} pyrrolidine-1-carboxamide 54 X{4-Fluoro-3-[5-(2-methylpropyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} furan-2-carboxamide 55 X(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan2-carboxamide - 170 039324 56 M-(3-{5-Cyclopentyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan- 2-carboxamide 57 T4-(3-{5-Cyclohexyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan2-carboxamide 58 3-Fluoro-M-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl }azetidine-1-carboxamide 59 T4-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}furan-2-carboxamide 60 M-{4-Fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 61 T4-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}furan2-carboxamide 62 M-!3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}furan-2-carboxamide 63 M-{4-Fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 64 M-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 65 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5- methylpyrazine-2-carboxamide 66 N-!4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3methylcyclopentan-1-carboxamide 67 5-Fluoro-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 68 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2methyl-5-(trifluoromethyl)-1,3 -oxazole-4-carboxamide 69 2-Cyclopropyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}acetamide 70 3,5-Difluoro-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 71 N-!4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3(trifluoromethyl)cyclopentan-1-carboxamide 72 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,5dimethylfuran-3-carboxamide - 171 039324 73 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4methyl-1, 3-oxazol-5-carboxamide 74 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,5dimethyl-1,3-oxazol-4 -carboxamide 75 2-Cyclopropyl-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl}-1,3-oxazole-5-carboxamide 76 2-Cyclopropyl-T4-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}-4-methyl-1,3-oxazole -5-carboxamide 78 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4methyl-2-(trifluoromethyl)-1,3 -oxazole-5-carboxamide 79 2-[(tert-Butoxy)methyl]-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}-4-methyl-1,3-oxazol-5-carboxamide 81 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4,5dimethyl-1,3-oxazol-2 -carboxamide 82 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 83 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2methyl-1,3-oxazol-5-carboxamide 84 5-Cyano-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 85 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2methyl-1,3-oxazol-4-carboxamide 86 6-Chloro-3-fluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyridine-2-carboxamide 87 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyrazine-2-carboxamide 89 5-Chloro-2-fluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } benzamide 90 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropanecarboxamide 91 X-(3-{5-Cyclopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)azetidine-1-carboxamide 92 X-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide - 172 039324 93 X-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)azetidine-1-carboxamide 94 X-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 95 X-{4-Fluoro-3-[5-(pentan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide 96 X-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} azetidine-1-carboxamide 97 X-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 98 X-{4-Fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide 99 X-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 100 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide 101 X-(3-{5-Cyclobutyl-2H-pyrazolo[3,4-b]pyrid in-2-yl}-4-fluorophenyl)-2,4dimethyl-1,3-oxazole-5-carboxamide 102 X-{3-[5-(2,2-Dimethylpropyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-2,4-dimethyl-1,3-oxazol-5- carboxamide 103 X-(3-{5-tert-Butyl-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-2,4dimethyl-1,3-oxazole-5-carboxamide 104 M-{4-Fluoro-3-[5-(2-methylbutan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -2,4-d imethyl-1,3 -oxazole-5-carboxamide 105 X-{3-[5-(Butan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-2,4dimethyl-1,3-oxazol-5- carboxamide 106 X-{3-[5-(Cyclobutylmethyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 2,4-dimethyl-1,3-oxazole-5-carboxamide 107 M-{4-Fluoro-3-[5-(3-methylbutyl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,4dimethyl-1,3-oxazol-5-carboxamide 108 X-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-dimethyl-1,3-oxazole-5-carboxamide 109 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5methylfuran-2-carboxamide - 173 039324 110 N-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5methoxyfuran-2-carboxamide 111 5-[(Dimethylamino)methyl]-T4-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4b]pyridin-2-yl]phenyl}furan-2-carboxamide 112 5-Cyano-M-N-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide FROM 5-Fluoro-H-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 114 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-4,5dimethylfuran-2-carboxamide 115 N-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3methylfuran-2-carboxamide 117 3,3-Difluoro-M-N-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -1-methyl ring butan-1 -carboxamide 118 3,3-Difluoro-H-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclobutan-1-carboxamide 121 3-Fluoro-M-!4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclobutan-1-carboxamide 122 N-{4-Fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 123 Propan-2-yl-N-{2-[2-fluoro-5-(furan-2-amido)phenyl]-2H-pyrazolo[3,4- b]pyridin-5-yl}carbamate 124 3,3-Difluoro-H-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 125 T4-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3,3difluoroazetidine-1-carboxamide 126 N-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 127 (3K)-H-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoropyrrolide in-1-carboxamide 128 N-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-2,4-dimethyl1,3-oxazole-5-carboxamide 129 N-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)azetidine-1carboxamide - 174 039324 130 N-(3-J5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)furan-2carboxamide 131 3-Fluoro-PM-{4-fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 132 3-Fluoro-PM-{4-fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 133 (3K)-M-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 134 (3R)-3-Fluoro-X-{4-fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl} pyrrolidine-1-carboxamide 135 (ZK)-3-Fluoro-PM-{4-fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl} pyrrolidine-1-carboxamide 136 Propan-2-yl-PM-[2-(2-fluoro-5-{[(3K)-3-fluoropyrrolidine-1carbonyl]amino}phenyl)-2H-pyrazolo[3,4-b]pyridin-5-yl ]carbamate 137 M-{4-Fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide 138 Propan-2-yl-PM-(2-{5-[(azetidine-1-carbonyl)amino]-2-fluorophenyl}-2Hpyrazolo[3,4-b]pyridin-5-yl)carbamate 139 M-{4-Fluoro-3-[5-(methylamino)-2H-pyrazolo[3,4-b]pyridine-2- yl]phenyl}furan-2-carboxamide 140 PM-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}furan-2-carboxamide 141 ^{4-Fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 142 1-{4-Fluoro-3-[5-(methylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3- methylurea 143 1-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 3,3-dimethylurea 144 PM-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 3,3-difluoroazetidine-1-carboxamide 145 3,3-Difluoro-PM-{4-fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridine-2u l ] phenyl } azeti din-1 -carb oxamide 146 Propan-2-yl-PM-(2-{5-[(3,3-difluoroazetidine-1-carbonyl)amino]-2fluorophenyl}-2H-pyrazolo[3,4-b]pyridin-5-yl)carbamate - 175 039324 147 P-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 148 3-Fluoro-P-{4-fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 149 (3K)-M-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidine-1-carboxamide 150 (3K)-3-Fluoro-P-{4-fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} pyrrolidine-1-carboxamide 151 M-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}furan-2-carboxamide 152 3-Fluoro-P-{4-fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 153 T4-{4-Fluoro-3-[5-(methylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,4dimethyl-1,3-oxazole-5-carboxamide 154 M-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 2,4-dimethyl-1,3-oxazole-5-carboxamide 155 P-{3-[5-(Azetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}- 2,4-dimethyl-1,3-oxazole-5-carboxamide 156 3-Fluoro-P-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 157 P-{4-Fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-dimethyl-1,3-oxazole-5-carboxamide 158 T4-{4-Fluoro-3-[5-(morpholin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}- 2,4-dimethyl-1,3-oxazole-5-carboxamide 159 Propan-2-yl-P-{2-[5-(dimethyl-1,3-oxazol-5-amido)-2-fluorophenyl]-2Hpyrazolo[3,4-b]pyridin-5-yl}carbamate 160 M-{4-Fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 161 3,3-Difluoro-M-{4-fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl}azetidine-1-carboxamide 162 (ZK)-3-Fluoro-P-{4-fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}pyrrolidin-1-carboxamide 163 P-{4-Fluoro-3-[5-(pyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide - 176 039324 164 H-{4-Fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridine-2- yl]phenyl}azetidine-1-carboxamide 165 3 3-Difluoro-N-{4-fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 166 3,3-Difluoro-N-{4-fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]pheni l}az etidine-1-carboxamide 167 M-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3- fluoraz etidine-1-carboxamide 168 Propane-l-i;?-/-]! ]2-fluoro-5-[(3-fluoroazeti din-1-carbonyl)amino]phenyl }- 2H-pyrazolo[3,4-b]pyridin-5-yl)carbamate 169 M-{4-Fluoro-3-[5-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2,4dimethyl-1,3-oxazol-5 -carboxamide 170 M-[3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl }az etidine-1-carboxamide 171 3-Fluoro-M-[4-fluoro-3-(5-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] az etidine-1-carboxamide 172 3-Φτορ-Ν-(4-φτορ-3-{5-[( 15.48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2Hpyrazolo[3,4-b] pyridine-2-u l }phenyl)azetide in-1-carboxamide 173 4,4 _> 4-Trifluoro-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}butanamide 174 3,3,3-Trifluoropropyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl]carbamate 175 M-{4-Fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}-2,4-dimethyl-1,3-oxazole -5-carboxamide 176 M-{4-Fluoro-3-[5-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-b]pyridine-2u l]phenyl} furan-2-carboxamide 177 X-(3-{5-[(25.68)-2,6-Dimethylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-2yl}-4-fluorophenyl)-3-fluoroazetide and n-1-carboxamide 178 Ν- {3-[5-(1,1-Dioxo-thiomorpholino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetidine-1-carboxamide 179 3-Fluoro-M-{4-fluoro-3-[5-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}az etidine-1-carboxamide 180 3-Fluoro-1\1-[4-fluoro-3-(5-{5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-2Hpyrazolo[3,4-b] pyridin-2-yl)phenyl]azetidine-1-carboxamide - 177 039324 181 3-Fluoro-X-{4-fluoro-3-[5-(3-hydroxyazetidin-1-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}azetidine-1-carboxamide 182 3-Fluoro-X-{4-fluoro-3-[5-(pyridin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 183 3-Fluoro-X-[4-fluoro-3-(5-{2-oxa-6-azaspiro[3.4]octan-6-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)phenyl]azetidine-1-carboxamide 184 3 -Φτορ-Ν-[4-φτορ-3 -(5- { 8-oxa-3 -azabicyclo [3.2.1] octan-3 -yl } -2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 185 3-Φτορ-Ν-(4-φτορ-3-[5-[(2-methoxyethyl)amino]-2H-pyrazolo[3,4-b]pyridin2-yl } phenyl)azetidine-1-carboxamide 186 3-Φτορ-Ν-[4-φτορ-3-(5-[5Н,6Н,7Н,8Н-[1,2,4]triazolo[4,3-а]pyrazin-7-yl}- 2H-pyrazolo[3,4-b]pyridin-2-yl)phenyl]azetidine-1-carboxamide 187 3-Fluoro-X-{4-fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl }azetidine-1-carboxamide 188 X-{3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide 189 3-Fluoro-X-{4-fluoro-3-[5-(pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 190 X-(3-{5-[(2K,68)-2,6-Dimethylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-2yl}-4-fluorophenyl)-3-fluoroazetide in -1 -carboxamide 191 3-Fluoro-X-[4-fluoro-3-(5-{6-oxa-1-azaspiro[3.3]heptan-1-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 192 3-Φτορ-Ν-(4-φτορ-3-[5-[3-(methoxymethyl)azetidin-1-yl]-2Н-pyrazolo[3,4- b]pyridin-2-yl}phenyl)azetidine-1-carboxamide 193 X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 194 X-(3-{5-[(ZK,4K)-3,4-Difluoropyrrolidin-1-yl]-2H-pyrazolo[3,4-b]pyridin2-yl}-4-fluorophenyl)-3-fluoroazetidine- 1-carboxamide 195 (3K)-3-Fluoro-T4-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} pyrrolidine-1-carboxamide 196 X-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 197 3-Fluoro-X-[4-fluoro-3-(5-{2-oxa-5-azabicyclo[2.2.2]octan-5-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide - 178 039324 198 3-Φτορ-Ν-(4-φτορ-3-{5-[(2-methylpropyl)amino]-2H-pyrazolo[3,4-b]pyridin2-yl}phenyl)azetidine-1-carboxamide 199 X-{3-[5-(Ethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 200 3-Fluoro-X-(4-fluoro-3-{5-[(propan-2-yl)amino]-2H-pyrazolo[3,4-b]pyridin-2yl} phenyl)azetidine-1-carboxamide 201 3-Φτορ-Ν-[4-φτορ-3-(5-{1-oxa-6-azaspiro[3.3]heptan-6-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 202 3-Fluoro-X-[4-fluoro-3-(5-{6-oxa-2-azaspiro[3.4]octan-2-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)phenyl]azetidine-1-carboxamide 203 3-Fluoro-X-[4-fluoro-3-(5-{7-oxa-2-azaspiro[3.5]nonan-2-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 204 X-[3-(5-{6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)-4-fluorophenyl]-3-fluoroazetidine-1-carboxamide 205 3-Fluoro-X-{4-fluoro-3-[5-(3-methoxyazetidin-1-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 206 5-Cyano-X-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}furan-2-carboxamide 207 2-Ethoxy-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropan-1-carboxamide 208 2,2-Difluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} opane-1-carboxamide ring 209 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-1(trifluoromethyl)cyclopropan-1-carboxamide 210 M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclobutanecarboxamide 211 T4-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2methylcyclopropan-1-carboxamide 212 3,3,3-Trifluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } propanamide 213 4,4,4-Trifluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -3-methylbutanamide 214 5,5,5-Trifluoro-X-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } pentanamide - 179 039324 215 3-Cyclopropyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl]phenyl]propanamide 216 2-Cyclobutyl-M-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} acetamide 217 H-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3,3dimethylbutanamide 218 H-{4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclobut-1-eu-1-carboxamide 219 1-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3,3bis( ^2H3 )methylurea 220 H-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5azaspiro[2.4]heptan-5-carboxamide 221 (3K)-M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl]-3-methylpyrrolidin-1-carboxamide 222 H-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-5azaspiro[2.3]hexane-5-carboxamide 223 (1K,58)-M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl]-3-azabicyclo[3.1.0 ]hexane-3-carboxamide 224 3-Ethyl-1-{4-fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl]-3-methylurea 225 (3K)-M-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl]-3-methoxypyrrolidine-1-carboxamide 226 H-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-2azaspiro[3.3]heptan-2-carboxamide 227 1-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3methyl-3-(2,2,2- trifluoroethyl)urea 228 1-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3,3- dimethylurea 229 T4-{4-Fluoro-3-[5-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-1,4diazabicyclo[3.2.2]nonan-4 -carboxamide 230 H-(3-{5-[(2K,68)-2,6-Dimethylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl)-3-fluoroazetidine- 1-carboxamide 231 3-Fluoro-M-[4-fluoro-3-(5-{6-oxa-1-azaspiro[3.3]heptan-1-yl]-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide - 180 039324 232 3-Fluoro-M-(4-fluoro-3-{5-[3-(methoxymethyl)azetidin-1-yl]-2H-pyrazolo[3,4- b]pyridin-2-yl}phenyl)azetidine-1-carboxamide 233 M-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 234 in -1 -carboxamide 235 3 -Φτορ-Ν-[4-φτορ-3 -(5- { 3-oxa-8-azabicycle o [3.2.1] octan-8-yl } -2Hpyrazolo[3,4-b]pyridin-2-yl )phenyl]azetidine-1-carboxamide 236 1-(2-{2-Fluoro-5-[(3-fluoroazetidine-1-carbonyl)amino]phenyl}-2H-pyrazolo[3,4- b]pyridin-5-yl)piperidine-4-carboxylic acid 237 3-Fluoro-M-(4-fluoro-3-{5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2Hpyrazolo[3,4-b]pyridin-2-yl}phenyl )azetidine-1-carboxamide 238 3-Φτορ-Ν-(4-φτορ-3-ί 5-[4-(oxetan-3-yl)piperidin-1-yl]-2H-pyrazolo[3,4- b]pyridin-2-yl}phenyl)azetidine-1-carboxamide 239 3-Fluoro-A-[4-fluoro-3-(5-{2-thia-6-azaspiro[3.3]heptan-6-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)phenyl]azetidine-1-carboxamide 240 3-Fluoro-A-[4-fluoro-3-(5-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 241 M-[3-(5-{5-Azaspiro[2.4]heptan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 242 M-[3-(5-{5-Azaspiro[2.4]heptan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-5-azaspiro[2,4] heptane-5-carboxamide 243 M-[3-(5-{2-Azaspiro[3.3]heptan-2-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]-3-fluoroazetidine-1-carboxamide 244 3-Fluoro-M-[4-fluoro-3-(5-{8-oxa-2-azaspiro[4.5]decan-2-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)phenyl]azetidine-1-carboxamide 245 3-Fluoro-A-[4-fluoro-3-(5-{6-oxo-2,5-diazaspiro[3.4]octan-2-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide 246 Ν [4 Fluorine 3 (5 {6 oxa 2 azaspiro[3.4] octap 2 yl} 2H pyrazolo[3,4 b]pyridin-2-yl)phenyl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide 247 tert-Butyl-2-(2-{5-[(azetidine-1-carbonyl)amino]-2-fluorophenyl}-2Hpyrazolo[3,4-b]pyridin-5-yl)pyrrolidine-1-carboxylate 248 3-Fluoro-A-[4-fluoro-3-(5-{2-oxa-7-azaspiro[3.5]nonan-7-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl) phenyl]azetidine-1-carboxamide - 181 039324 249 T4-{3-[5-(Cyclopropylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide 250 M-(4-Fluoro-3-{5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2H-pyrazolo[3,4- b]pyridin-2-yl}phenyl)azetidine-1-carboxamide 251 3-Fluoro-X-{4-fluoro-3-[5-(3-hydroxy-3-methylazetidin-1-yl)-2Hpyrazolo[3,4-b]pyridine in-2-yl]phenyl}azetidine- 1-carboxamide 252 3,3-Difluoro-M-(4-fluoro-3-{5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2Hpyrazolo[3,4-b]pyridin-2-yl }phenyl)azetidine-1-carboxamide 253 (3Κ)-3-Φτορ-Ν-(4-φτορ-3-{5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl]-2Hpyrazolo[3,4-b ] pyridine -2-yl } phenyl) pyrrolidine-1-carboxamide 254 T4-(3-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-5azaspiro[2.3]hexane-5-carboxamide 255 T4-{3-[5-(3,3-Dimethylazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide 256 (1 S,2R)-2-Φτop-N-ί4-φτop-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl}cyclopropane-1-carboxamide 257 N-[3-(5-(5-Azaspiro[2.3]hexan-5-yl }-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]azetidine-1-carboxamide 258 M-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4- fluorophenyl]-3,3-difluoroazetidine-1-carboxamide 259 (3K)-M-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2yl)-4-fluorophenyl]-3-fluoropyrrolidine- 1-carboxamide 260 T4-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-5azaspiro[2.3]hexane-5-carboxamide 261 T4-[3-(5-{1,1-Difluoro-5-azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4- b]pyridin-2-yl)-4-fluorophenyl]-3-fluoroazetidine-1-carboxamide 262 T4-{3-[5-(3,3-Difluoropyrrolidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide 263 3-Φτορ-Ν-[4-φτορ-3-(5 {3 oxa 6 azabicyclo[3.1.1 ]heptan-6-yl }-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl]azetidine- 1-carboxamide 264 T4-{3-[5-(Azetidin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4-fluorophenyl}-3fluoroazetidine-1-carboxamide 265 3-Φτορ-Ν-(4-φτορ-3-(5-[3-(trifluoromethyl)azetidin-1-yl]-2Н-pyrazolo[3,4- b]pyridin-2-yl}phenyl)azetidine-1-carboxamide - 182 039324 266 ^{3-[5-(3-Cyanoazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide 267 X-(3-[5-(1-Acetylazetidin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide 268 (lS,2R)-N-{3-[5-(3,3-Diφtorazetidin-l-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-2-fluorocyclopropane- 1-carboxamide 269 (1 R,2 δ)-2-Φτορ-Ν-{4-fluoro-3-[5-(pyride in-2-yl)-2Н-pyrazolo[3,4-b] pyride in2-yl] f enyl } cycle opr opane-1-carboxamide 270 3-Fluoro-N-{4-fluoro-3-[5-(piperazin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 271 (1^28)-M-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-2-fluorocyclopropane- 1-carboxamide 272 (1^28)-M-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2yl)-4-fluorophenyl]-2- fluorocyclopropane-1-carboxamide 273 (lS,2R)-2-Φτop-N-{4-φτop-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl ] phenyl } cycle propane -1 -carboxamide 274 M-(4-Fluoro-3-{5-[3-(trifluoromethyl)azetidin-1-yl]-2H-pyrazolo[3,4b]pyridin-2-yl}phenyl)azetidine-1-carboxamide 275 (ЗR)-3-Φτop-N-(4-φτop-3-{5-[3-(τpφτopmethyl)azetidin-l-yl]-2Hpyrazolo[3,4-b]pyridin-2-yl}phenyl)pyrrolidine -1-carboxamide 276 X-(3-(5-Chloro-2H-pyrazolo[3,4-b]pyridin-2-yl}-4-fluorophenyl)-3fluoroazetidine-1-carboxamide 277 X-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}-4-(hydroxymethyl)-2-methyl-1 ,3-oxazole-5-carboxamide 278 N-{4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}-2-( ^2H3 )methyl-4- methyl-1,3-oxazole-5-carboxamide 279 M-(4-Fluoro-3-{5-[3-(trifluoromethyl)azetidin-1-yl]-2H-pyrazolo[3,4- b]pyridin-2-yl}phenyl)-2,4-dimethyl-1,3-oxazole-5-carboxamide 280 N-{2-(5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyride in-2yl]pyride in-4-yl}azetidine-1-carboxamide 281 3,3-Difluoro-M-{2-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]pyridin-4-yl}azetidine-1-carboxamide 282 X-[2-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2yl)pyride in-4-yl]azetidine-1-carboxamide - 183 039324 283 X-{4-Chloro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl}-3fluoroazetidine-1-carboxamide 284 X-{4-Chloro-3-[5-(3,3-difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 285 X-{4-Chloro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide 286 X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4chlorophenyl]azetide in-1-carboxamide 287 X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2yl)phenyl]azetidine-1-carboxamide 288 X-{4-Fluoro-3-[5-(oxan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide 289 X-{3-[5-(1,4-Dioxan-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 290 X-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 291 3-Fluoro-X-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl } azetidin-1-carboxamide 292 X-{4-Fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 293 3-Fluoro-X-{4-fluoro-3-[5-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 294 3-Fluoro-X-{4-fluoro-3-[5-(pyrazin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 295 3-Fluoro-X-{4-fluoro-3-[5-(1H-imidazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 296 X-{3-[5-(1-Benzylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoroazetide in-1-carboxamide 297 3-Fluoro-X-{4-fluoro-3-[5-(1H-pyrazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 298 X-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} -3-fluoroazetide in-1-carboxamide 299 X-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3,3-difluoroazetidine-1-carboxamide - 184 039324 300 (3K)-X-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]4-fluorophenyl}-3-fluoropyrrolidin-1 -carboxamide 301 3-Fluoro-X-{4-fluoro-3-[5-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 302 (ZK)-3-Fluoro-X-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl } pyrrolidine-1-carboxamide 303 3,3-Difluoro-X-{4-fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 304 3-Fluoro-P-{4-fluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 305 3-Fluoro-X-[4-fluoro-3-(5-{1-[(4-fluorophenyl)methyl]piperidin-4-yl}-2Hpyrazolo[3,4-b]pyridin-2-yl)phenyl] Azetidine-1-carboxamide 306 X-(3-{5-[bis( ^2H3 )methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)azetidine-1-carboxamide 307 X-(3-{5-[bis( ^2H3 )methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)-3,3-difluoroazetidine-1-carboxamide 308 (3K)-X-(3-{5-[bis( ^2H3 )Methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)-3-fluoropyrrolidine-1-carboxamide 309 3,3-Difluoro-X-{4-fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 310 X-{3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3,3-difluoroazetidine-1-carboxamide 311 3-Fluoro-X-(4-fluoro-3-{2H-pyrazolo[3,4-b]pyridin-2-yl}phenyl)azetidine-1carboxamide 312 3-Fluoro-M-(4-fluoro-3-[5-(3-methylpyrazin-2-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl } azetidin-1-carboxamide 313 X-{4-Fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 314 X-(3-{5-[bis( ^2H3 )methylamino]-2H-pyrazolo[3,4-b]pyridin-2-yl}-4fluorophenyl)-3-fluoroazetidine-1-carboxamide 315 X-{3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}azetidine-1-carboxamide 316 (3K)-X-{3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl}-3-fluoropyrrolidin-1-carboxamide - 185 039324 317 (3K)-3-Fluoro-X{4-fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl}pyrrolidin-1-carboxamide 318 3-Fluoro-T4-(4-fluoro-3-{5-methyl-2H-pyrazolo[3,4-b]pyridin-2yl} phenyl)azetidine-1-carboxamide 319 3-Φτορ-Ν-{4-φτορ-3-[5-(1 H-pyrazol-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} azetidine-1-carboxamide 320 X{4-Fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 321 3-Fluoro-X-{4-fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 322 (3K)-3-Fluoro-X{4-fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl } pyrrolidine-1-carboxamide 323 3-Fluoro-X-{4-fluoro-3-[5-(1H-imidazol-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl }azetidine-1-carboxamide 324 3,3-Difluoro-M-{4-fluoro-3-[5-(trifluoromethyl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 325 T4-{3-[5-(1-Cyclopropyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-3-fluoroazetidine-1-carboxamide 326 X-{3-[5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} cyclopropanecarboxamide 327 X{4-Fluoro-3-[5-(3-fluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}cyclopropanecarboxamide 328 3-Fluoro-X-{4-fluoro-3-[5-(4-methyl-1H-imidazol-1-yl)-2H-pyrazolo[3,4- b]pyridin-2-yl]phenyl }azetidine-1-carboxamide 329 3-Fluoro-X-{4-fluoro-3-[5-(5-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridine- 2-yl]phenyl } azetidin-1-carboxamide 330 X{4-Fluoro-3-[5-(5-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 331 X-{3-[5-(Dimethylamino)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} cyclopropanecarboxamide 332 X{4-Fluoro-3-[5-(3-fluoropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } cyclopropanecarboxamide 333 X-{3-[5-(3-Chloropyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} cyclopropanecarboxamide - 186 039324 334 N-(4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}-2-(hydroxymethyl)-4-methyl-1 ,3-oxazole-5-carboxamide 335 H-(4-Fluoro-3-(5-[3-(hydroxymethyl)pyridin-2-yl]-2H-pyrazolo[3,4- b]pyridin-2-yl}phenyl)-2,4-dimethyl-1,3-oxazole-5-carboxamide 336 N-(4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl} pyrrolidine-1-carboxamide 337 X-[3-(5-{5-Azaspiro[2.3]hexan-5-yl}-2H-pyrazolo[3,4-b]pyridin-2-yl)-4fluorophenyl]pyrrolidine-1-carboxamide 338 N-j 3-(5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]-4fluorophenyl} pyrrolidine-1-carboxamide 339 (1 R,2S)-N-{ 3-(5-(3,3-Difluoroazetidin-1 -yl)-2H-pyrazolo[3,4-b]pyridin-2yl]-4-fluorophenyl}-2-fluorocyclopropane -1-carboxamide 340 (3R)-N-(2-{5-Bromo-2H-pyrazolo[3,4-b]pyridin-2-yl}pyridin-4-yl)-3fluoropyrrolide in-1-carboxamide 341 X-{2-[5-(Pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]pyridin-4yl}azetidine-1-carboxamide 342 3-Fluoro-M-{2-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]pyridin-4- yl}azetidine-1-carboxamide 343 N-{3-(5-(3,3-Difluoroazetidin-1-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}azetidine-1-carboxamide 344 M-[3-[5-(Pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl]azetidine-1carboxamide 345 N-(4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl}pyrazine-2-carboxamide 346 N-(4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl]phenyl } spiro[2.2]pentan-1-carboxamide 347 M-[4-Fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2-yl]phenyl [3,3-dimethylcyclobut-1-en-1- carboxamide 348 1-Cyano-M-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl } opane-1-carboxamide ring 349 (18.28)-2-Fluoro-X-{4-fluoro-3-[5-(pyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin2-yl] phenyl } cyclopropan-1 -carboxamide 350 N-(4-Fluoro-3-[5-(3-methylpyridin-2-yl)-2H-pyrazolo[3,4-b]pyridin-2yl] phenyl} -3,3-dimethyl ring but-1 - en-1-carboxamide 351 N-(4-Φτop-3-(5-isopropyl-2H-pyrazolo[3,4-b]pyridin-2-yl)φenyl)-2,4dimethyloxazole-5-carboxamide 18. Pharmaceutical composition for the treatment of a disorder or disease selected from leishmaniasis, forms of Chagas disease and human African trypanosomiasis, containing a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and at least one excipient. 19. The use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment of a disorder or disease selected from leishmaniasis, forms of Chagas disease and human African trypanosomiasis. 20. Use of a compound according to claim 14 for the treatment of Chagas disease.