HK1257531B

HK1257531B - Pyrazolo fused heterocyclic compounds as erk inhibitors

Info

Publication number: HK1257531B
Application number: HK18116491.0A
Authority: HK
Inventors: 张劲涛; 徐汶; 简善忠
Original assignee: 捷思英达医药技术（上海）有限公司
Filing date: 2015-08-20
Publication date: 2022-08-05

Description

Pyrazolo-fused heterocyclic compounds as ERK inhibitors

Disclosed herein are novel heterocyclic compounds that can be used as extracellular signal-regulated kinase (ERK) inhibitors. Also disclosed herein are pharmaceutical compositions comprising at least one such compound, and methods of using at least one such compound in the treatment of diseases modulated by ERK, such as cancer.

Ras-Raf-Mek-Erk intracellular signaling cascade amplification is believed to be a central signaling module that transmits proliferation, survival, growth and differentiation signals from activated Receptor Tyrosine Kinases (RTKs) (e.g., the ErbB family, PDGF, FGF and VEGF (Sebolt-Leopold, J.S.and Herrera, R., Nat.Rev.cancer,41:937-947, 2004; Kolch, W., Nat.Rev.mol.cell biol.,61:827-837,2005) to the interior of cells the signaling axis (signaling axis) contains Ras, Raf, Mek (mitogen-activated protein kinase) and Erk (cell signal-regulated kinase) proteins that all occur as highly homologous subtypes In the case of Mek1, S218 and S222) phosphorylate Meks (Mek1 and Mek 2). Meks is a dual specific threonine/tyrosine kinase that phosphorylates both threonine and tyrosine residues within the TXY motif of Erks, where T represents threonine, Y represents tyrosine, and X represents any amino acid. Erk proteins (Erk1 and Erk2), also known as MAPKs (mitogen-activated protein kinases), are serine/threonine kinases that phosphorylate more than 100 downstream cytosolic and nuclear target proteins involved in cellular processes such as division, proliferation, migration and apoptosis (Yoon, s.and Seger, r., Growth Factors,24:21-44,2006). These phosphorylations essentially modulate, broadly stimulate the activity of target proteins, and can profoundly alter the physiological state of cells.

Pathological activation of the Ras-Raf-Mek-Erk cascade signaling pathway is thought to be the causative mechanism (mechanistic aspect) leading to most human cancers, immune disorders and highly inflammatory conditions. Activation of the signaling pathway may occur as a result of autocrine or paracrine production of too much RTK ligand, either through mutation or overexpression of constitutively active cell surface receptors, or more commonly gain of function mutations by B-Raf and Ras family members. The tumorigenic form of Ras is reported to be associated with 30% of all human cancers. Mutations in K-Ras occur in 90% of pancreatic cancers and in 25% to 50% of colorectal, ovarian mucinous, and non-small cell Lung cancers, while mutations in H-Ras are common in bladder, kidney, and thyroid cancers, and mutations in N-Ras are found in melanoma, hepatocellular carcinoma, and hematological malignancies (Adjei, A., J Natl Cancer Inst,93:1062-74, 2001; Aviel-Ronen, S., et al, Clin Lung Cancer,8:30-8,2006). B-Raf mutations are present in 66% to 70% malignant Melanoma, 70% non-papillary thyroid carcinoma, 35% low grade ovarian serous tumors, as well as many other cancers including, for example, colorectal, thyroid, lung, breast, and ovarian cancers (Thomas, N., Melanoma Res,16:97-103,2006; Singer, G., et al, J Natl Cancer Inst,95: 484-.

Inhibition of the activity of the Ras-Raf-Mek-Erk signaling pathway has been the focus of drug development, particularly for cancer therapy (sebelt-Leopold, J., Oncogene,19: 16564-. Small molecule inhibitors of B-Raf and Mek have been shown to effectively inhibit Ras and Raf mediated cell transformation, Erk activation and dependent processes, cell proliferation in vitro, tumor growth in vivo (Mallon, R., et al, Mol Cancer Ther,31:755-762, 2004; Sebolt-Leopold, J., Curr Pharm Des,101: 1907-doped 1914, 2004; Sebolt-Leopold J.and Herrera, R., Nat Rev Cancer,41: 937-doped 947, 2004). Demonstration of the clinical efficacy of various Raf and Mek small molecule inhibitors in various kinds of Cancer has provided ultimate validation of targeting this signaling pathway for Cancer treatment (Crane, e.and Wang, k., Topics Anti-Cancer Res,2:63-94,2013).

Considering the downstream position of Erk proteins in Ras-Raf-Mek-Erk signaling cascade (signaling cascade), inhibition of Erks may provide an alternative strategy to down-regulate the activity of the pathway. As such, there is a good theoretical basis to develop Erk small molecule inhibitors as novel therapeutics for a wide range of human cancers originating from, for example, the brain, lung, colon, breast, stomach, pancreas, head and neck, esophagus, kidney (renal), kidney (kidney), ovary, skin, prostate, testis, gynecology (gynecology), or thyroid. In addition, Erk inhibitors may also be used to treat, for example, non-cancerous hyperproliferative disorders (e.g., benign hyperplasia of the skin, restenosis, benign prostatic hypertrophy), pancreatitis, kidney disease, pain, diseases associated with angiogenesis (vasculogenesis) or angiogenesis (angiogenesis), acute and chronic inflammatory diseases (e.g., rheumatoid arthritis, atherosclerosis, inflammatory bowel disease), skin diseases (e.g., psoriasis, eczema, and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, asthma, septic shock, T-cell mediated diseases, Chronic Obstructive Pulmonary Disease (COPD).

Disclosed herein is a compound of formula I:

and/or a pharmaceutically acceptable salt thereof,

wherein:

R₁is a hydrogen atom or an alkyl group,

R₂is aryl, heteroaryl, cycloalkyl, alkyl, alkoxy or heterocycloalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, alkyl, alkoxy and heterocycloalkyl is optionally substituted with at least one substituentFrom halogen, hydroxy, -CN, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄An oxo group, an alkyl group optionally substituted with at least one group selected from halogen and alkoxy, and an alkoxy group optionally substituted with at least one group selected from halogen and alkoxy,

R₃and R₄Independently selected from H and alkyl, said alkyl being optionally substituted with at least one alkoxy group, or R₃And R₄And R₃And R₄The attached nitrogens together form a heterocyclyl ring,

ring B is aryl or heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with at least one group selected from alkyl, alkoxy, halogen and-CN,

R₅independently selected from H and alkyl, said alkyl being optionally substituted with at least one alkoxy group,

L₁is that

(CR 'R') n, wherein n is 1,2 or 3, R 'and R' are independently selected from H and alkyl, said alkyl being optionally substituted with at least one group selected from hydroxy and halogen,

aryl, optionally substituted with at least one substituent selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy,

heteroaryl, optionally substituted with at least one substituent selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy,

cycloalkyl optionally substituted with at least one substituent selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy, or

Heterocycloalkyl, optionally substituted with at least one member selected from halogen, -SO₂Alkyl and alkyl substituted, wherein the alkyl is optionally substitutedSubstituted with at least one group selected from halogen, hydroxyl and alkoxy,

L₂is that

cycloalkyl optionally substituted with at least one substituent selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy,

a heterocycloalkyl optionally substituted with at least one group selected from halogen, -SO2 alkyl and alkyl, wherein said alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy, or

WhereinIndicating the point of attachment to a neighboring group,

L₃is that

H，

Aryl, optionally substituted with at least one substituent selected from halogen; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy,

heteroaryl, optionally substituted with at least one substituent selected from halogen; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy,

cycloalkyl, optionally substituted with at least one substituent selected from halogen; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, or

Heterocycloalkyl, optionally substituted with at least one selected from halo; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy,

with the proviso that (1) when B is aryl and L₁When it is heterocycloalkyl, the heterocycloalkyl is pyrrolidinyl.

Also disclosed herein is a pharmaceutical composition comprising a compound of formula I disclosed herein and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Also disclosed herein is a method of inhibiting Erk activity comprising contacting protein Erk with an effective amount of a compound of formula I disclosed herein and/or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of treating a disease treatable by inhibition of Erk in a patient, comprising administering to a patient identified in need of such treatment an effective amount of a compound of formula I disclosed herein and/or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of treating a disease treatable by inhibition of Erk in a patient, the method comprising administering to a patient identified in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of formula I disclosed herein and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Also disclosed herein is a method of treating cancer in a patient, comprising administering to a patient identified as in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of formula I disclosed herein and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the cancer is colon cancer, gastric cancer, leukemia, lymphoma, melanoma, or pancreatic cancer.

Also disclosed herein is a method of treating an inflammatory disease in a patient, comprising administering to a patient identified as in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of formula I disclosed herein and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the inflammatory disease is rheumatoid arthritis, psoriasis, or eczema.

Also disclosed herein is the use of a compound of formula I and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease responsive to the inhibition of Erk, such as cancer or an inflammatory disease. In some embodiments, the cancer is colon cancer, gastric cancer, leukemia, lymphoma, melanoma, or pancreatic cancer. In some embodiments, the inflammatory disease is rheumatoid arthritis, psoriasis, or eczema.

As used herein, the following words, phrases and symbols are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout the text.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONR_aR_bAttached through a carbon atom.

The use of the terms "a", "an", etc. refer to one or more unless specifically stated otherwise.

The term "alkyl" herein refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups comprising from 1 to 18 carbon atoms (e.g., from 1 to 12 carbon atoms, further such as from 1 to 10 carbon atoms, further such as from 1 to 6 carbon atoms).

The term "alkoxy" as used herein refers to a straight or branched chain alkyl group containing from 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, and the like, attached through an oxygen bridge. In some embodiments, the alkoxy group comprises from 1 to 6 carbon atoms connected by an oxygen bridge.

The term "alkenyl" herein refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups comprising at least one C ═ C double bond and from 2 to 18 (e.g., 2 to 6) carbon atoms. Examples of alkenyl groups may be selected from the vinyl group (-CH ═ CH)₂) Prop-1-enyl (-CH ═ CHCH)₃) Prop-2-enyl (-CH)₂CH═CH₂) 2-methylpropan-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1, 3-dienyl groups. The point of attachment may be on unsaturated carbon or saturated carbon.

The term "alkynyl" refers herein to a hydrocarbon radical selected from straight and branched chain hydrocarbon radicals comprising at least one C ≡ C triple bond and from 2 to 18 (e.g. 2 to 6) carbon atoms. Examples of alkynyl groups include ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CCH)₃) 2-propynyl (propargyl, -CH)₂C.ident.CH), 1-butynyl, 2-butynyl and 3-butynyl groups. The point of attachment may be on unsaturated carbon or saturated carbon.

The term "cycloalkyl" herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group can include from 3 to 20 carbon atoms (e.g., from 3 to 8 carbon atoms, further such as from 3 to 6 carbon atoms, from 3 to 5 carbon atoms, or from 3 to 4 carbon atoms). For still further example, a cycloalkyl group can be selected from monocyclic groups comprising from 3 to 12 carbon atoms (e.g., from 3 to 8 carbon atoms, or from 3 to 6 carbon atoms). Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl radicals. Examples of bicycloalkyl groups include bicycloalkyl comprising from 7 to 12 ring atoms arranged as a bridged bicycle selected from [4,4], [4,5], [5,6] and [6,6] ring systems or as a bridged bicycle selected from, for example, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated, and is not aromatic, as aromatic is defined herein. The cycloalkyl group may be substituted with at least one heteroatom selected from, for example, O, S and N.

The term "aryl" herein refers to a group selected from:

5-and 6-membered carbocyclic aromatic rings (e.g., phenyl);

bicyclic ring systems (e.g., 7-to 12-membered bicyclic ring systems) wherein at least one ring is carbocyclic and aromatic, selected from, for example, naphthalene, indane, and 1,2,3, 4-tetrahydroquinoline; and

tricyclic ring systems (e.g., 10-to 15-membered tricyclic ring systems) in which at least one ring is carbocyclic or aromatic, e.g., fluorene.

In some embodiments, the aryl group is selected from 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered cycloalkyl or heterocyclic ring (as defined below in "heterocyclyl" or "heterocyclic") optionally including at least one heteroatom selected from, for example, N, O and S, with the proviso that when the carbocyclic aromatic ring is fused to the heterocyclic ring, the point of attachment is on the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to the cycloalkyl group, the point of attachment may be on the carbocyclic aromatic ring or on the cycloalkyl group. A divalent radical formed from a substituted benzene derivative and having a free valence on a ring atom is named a substituted phenylene radical. A divalent radical obtained from a monovalent polycyclic hydrocarbon radical ending in the name "-yl" by removing one hydrogen atom from a carbon atom having a free valence is named by adding "-ylidene" to the name of the corresponding monovalent radical, for example, a naphthyl radical having two points of attachment is called naphthylene. However, aryl does not include heteroaryl or overlaps in any way with heteroaryl, as defined separately below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring (e.g., heteroaryl as defined below), the resulting ring system is heteroaryl as defined herein, rather than aryl.

The term "halogen" herein refers to F, Cl, Br or I.

The term "heteroaryl" herein refers to a group selected from:

a 5-to 7-membered aromatic monocyclic ring, said 5-to 7-membered aromatic monocyclic ring comprising at least one (e.g., from 1 to 4, or in some embodiments, from 1 to 3 heteroatoms) heteroatom selected from, for example, N, O and S, the remaining ring atoms being carbon;

an 8-to 12-membered bicyclic ring comprising at least one (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) heteroatom selected from, for example, N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring, and the point of attachment is on any ring and on a carbon or heteroatom; and

an 11-to 14-membered tricyclic ring, said 11-to 14-membered tricyclic ring including at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from, for example, N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring, and the point of attachment is on any ring.

In some embodiments, the heteroaryl group comprises a 5-to 7-membered heterocyclic aromatic ring fused to a 5-to 7-membered cycloalkyl ring. For such fused bicyclic heteroaryl ring systems wherein only one ring includes at least one heteroatom, the point of attachment may be on the heteroaryl or cycloalkyl ring.

In some embodiments, the heteroaryl group comprises a 5-to 7-membered heterocyclic aromatic ring fused to a 5-to 7-membered aryl ring. For such fused bicyclic heteroaryl ring systems wherein only one ring includes at least one heteroatom, the point of attachment may be on the heteroaryl ring or the aryl ring. Non-limiting examples include quinolinyl and quinazolinyl.

In some embodiments, the heteroaryl group comprises a 5-to 7-membered heterocyclic aromatic ring fused to an additional 5-to 7-membered heterocyclic aromatic ring. Non-limiting examples include 1H-pyrazolo [3,4-b ] pyridyl and 1H-pyrrolo [2,3-b ] pyridyl.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no more than 1.

Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrrolinyl, pyrazinyl, pyrimidinyl, imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, dihydroindolyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (e.g., 1H-pyrrolo [2,3-b ] pyridin-3-yl), pyrazolopyridyl (e.g., 1H-pyrazolo [3,4-b ] pyridin-3-yl), benzoxazolyl (e.g., benzo [ d ] oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2, 3-oxadiazolyl, 1-oxa-2, 4-oxadiazolyl, 1-oxa-2, 5-oxadiazolyl, 1-oxa-3, 4-oxadiazolyl, 1-thia-2, 3-oxadiazolyl, 1-thia-2, 4-oxadiazolyl, 1-thia-2, 5-oxadiazolyl, 1-thia-3, 4-oxadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g. benzo [ d ] thiazol-6-yl), indazolyl (e.g. 1H-indazol-5-yl), and 5,6,7, 8-tetrahydroisoquinoline.

The terms "heterocycloalkyl", "heterocyclyl" or "heterocycle" herein refer to a ring selected from 4-to 12-membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings, said ring comprising at least one carbon atom and also at least one heteroatom (e.g., from 1-4 heteroatoms, further e.g., from 1-3 heteroatoms, or further e.g., 1 or 2 heteroatoms) selected from, for example, O, S and N. The point of attachment of the heterocyclyl group may be at a heteroatom or carbon. "heterocyclyl" herein also refers to 5-to 7-membered saturated or partially unsaturated carbocyclic rings that include at least one heteroatom selected from, for example, N, O and S (heterocyclic) fused to a 5-membered, 6-membered, and/or 7-membered cycloalkyl, heterocyclic ring, or carbocyclic aromatic ring, provided that when the heterocyclic ring is fused to the carbocyclic aromatic ring, the point of attachment is on the heterocyclic ring, and when the heterocyclic ring is fused to a cycloalkyl, the point of attachment may be on the cycloalkyl or heterocyclic ring. "Heterocyclyl" as used herein also refers to aliphatic spirocyclic rings that include at least one heteroatom selected from, for example, N, O and S. The ring may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocyclic ring may be substituted, for example, with oxo. The point of attachment may be carbon or a heteroatom. Heterocyclyl is not heteroaryl as defined herein.

Examples of heterocycles include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, dithianobutyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thiazalkyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepinyl, thiepanyl, oxathiahexyl, dioxacycloheptyl, oxathiepanyl, oxazepanyl, dithiacycloheptyl, thiazepanyl, and diazepan, dithianyl, azathiacyclohexane, piperidyl, piperidinyl, piperazinyl, pyranyl, thiazepanyl, and the likeRadical diazaThio-aza radicalA radical, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl, dioxanyl, pyrazolinyl, dithianylCyclopentylalkyl, pyrazolidinyl, imidazolinyl, oxopyrimidinyl, 1-dioxo-thiomorpholinyl, 3-azabicyclo [3.1.0]Hexane radical, 3-azabicyclo [4.1.0 ]]Heptylalkyl and azabicyclo [2.2.2]A hexyl group. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl.

The compounds disclosed herein may contain asymmetric centers and, thus, may exist as enantiomers. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader class of stereoisomers. It is well known in the art how to prepare optically active forms by resolution of the material or by asymmetric synthesis. All such possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers, are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless otherwise mentioned, reference to an isomer applies to any possible isomer. When the isomeric composition is not indicated, all possible isomers are included.

When the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to encompass both E and Z geometric isomers, unless otherwise specified.

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with X" includes both "alkyl not substituted with X" and "alkyl substituted with X". Those skilled in the art will appreciate that, for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is not sterically impractical, synthetically non-feasible, and/or inherently unstable.

In some embodiments, "substituted with at least one group" means that one hydrogen on the specified atom or group is replaced with one of the choices in the specified group from the substituent. In some embodiments, "substituted with at least one group" means that two hydrogens on the designated atom or group are independently replaced with two choices from the designated group of substituents. In some embodiments, "substituted with at least one group" means that three hydrogens on the designated atom or group are independently replaced with three choices from the designated group of substituents. In some embodiments, "substituted with at least one group" means that four hydrogens on the designated atom or group are independently replaced with the four choices from the designated group of substituents.

"pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids selected from, for example, hydrochloride, phosphate, hydrogen phosphate, hydrobromide, sulfate, sulfinate, and nitrate; and salts with organic acids selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, alkanoates (e.g. acetate), and with HOOC- (CH)₂) n-COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (such as a pharmaceutically acceptable addition salt) may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

By "treating" or "ameliorating" is meant administering at least one compound disclosed herein and/or at least one stereoisomer thereof (if any) and/or at least one pharmaceutically acceptable salt thereof to a subject identified as having, for example, cancer in need thereof.

The term "effective amount" refers to an amount of at least one compound disclosed herein and/or at least one stereoisomer thereof (if any) and/or at least one pharmaceutically acceptable salt thereof that is effective to "treat" a disease or disorder, as defined above, in a subject.

When the term "about" is used to modify a numerical value, it means a 5% change in the numerical value. When the term "about" is used to modify a numerical range, it means 5% change from the lower limit to the upper limit.

Formula I

Disclosed herein is a compound of formula I:

and/or a pharmaceutically acceptable salt thereof, wherein:

R₁is a hydrogen atom or an alkyl group,

R₂is aryl, heteroaryl, cycloalkyl, alkyl, alkoxy or heterocycloalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, alkyl, alkoxy and heterocycloalkyl is optionally substituted with at least one moiety selected from halogen, hydroxy, -CN, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄An oxo group, an alkyl group optionally substituted with at least one group selected from halogen and alkoxy, and an alkoxy group optionally substituted with at least one group selected from halogen and alkoxy,

L₁is that

Heterocycloalkyl, optionally substituted with at least one member selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy,

L₂is that

cycloalkyl optionally substituted with at least one substituent selected from halogen, -SO₂Of alkyl groups and of alkyl groupsSubstituted with at least one group selected from halogen, hydroxy and alkoxy,

WhereinIndicating the point of attachment to a neighboring group,

L₃is that

H，

with the proviso that (1) when AB is aryl and L₁When it is a heterocycloalkyl group, said heterocycloalkyl groupThe radical is pyrrolidinyl. In some embodiments, R₁Is H.

In some embodiments, R₂Is alkoxy substituted with alkoxy. In some embodiments, R₂Is aryl (e.g. phenyl or 2, 3-dihydrobenzo [ b ]][1,4]Dioxins) optionally substituted with at least one substituent selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo groups. In some embodiments, R₂Is heteroaryl (e.g. pyridyl, benzo [ d ]]Thiazole or imidazole) optionally with at least one hetero-aryl group selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo (e.g., selected from alkyl, alkoxy, and halogen). In some embodiments, R₂Is a heterocyclic group (e.g., piperidinyl, piperazinyl, or morpholinyl) optionally substituted with at least one substituent selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo (e.g., selected from alkyl, alkoxy, and halogen).

In some embodiments, the B ring is aryl (e.g., phenyl). In some embodiments, ring B is heteroaryl (e.g., furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl).

In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1,2 or 3, and R' and R" are independently selected from H and alkyl, said alkyl being optionally substituted with at least one group selected from hydroxy and halogen. In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1,2 or 3, one of R' and R" is H, and the other is alkyl, optionally substituted with at least one hydroxy and halogen group. In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1, one of R' and R" is H, and the other is alkyl, optionally substituted with hydroxy. In thatIn some embodiments, L₁Is (CR 'R ") n, wherein n is 1, one of R' and R" is H, and the other is methyl, optionally substituted with hydroxy. In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1, one of R' and R" is H, and the other is isopropyl, optionally substituted with hydroxy.

In some embodiments, L is₁Is a heterocycloalkyl radical (such as pyrrolidinyl, tetrahydrofuranyl or piperidinyl) optionally substituted with at least one halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy. In some embodiments, L is₁Is optionally substituted with alkyl (e.g. C)₁-C₄Alkyl, further such as methyl or ethyl) substituted pyrrolidinyl, said alkyl being optionally substituted with at least one group selected from halogen, hydroxy and alkoxy.

In some embodiments, L is₁Is cycloalkyl (e.g. cyclopropenyl or cyclopentyl), optionally substituted with at least one substituent selected from halogen, -SO₂Alkyl and alkyl group substitution.

In some embodiments, L is₂Is thatAnd L is₃Is heterocycloalkyl (such as pyrrolidinyl, piperazinyl or piperidinyl), optionally substituted with at least one substituent selected from halo; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from haloAnd an alkyl group and an alkoxy group, said heteroaryl group being optionally substituted with at least one group selected from halogen, alkyl and alkoxy.

In some embodiments, L is₂Is thatAnd L is₃Is piperazinyl substituted with aryl, wherein the aryl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, the aryl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, the cycloalkyl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, the heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, and the heteroaryl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy.

In some embodiments, L is₂Is thatAnd L is₃Is piperazinyl substituted with phenyl, wherein the phenyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, the aryl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, the cycloalkyl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, the heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, and the heteroaryl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy.

In some embodiments, L is₂Is thatAnd L is₃Is piperazinyl substituted with phenyl, wherein the phenyl is substituted with heteroaryl, which is optionally substituted with at least one group selected from halo, alkyl and alkoxy. In some embodimentsIn a table, L₂Is thatAnd L is₃Is piperazinyl substituted with phenyl, wherein the phenyl is substituted with pyrimidine.

In some embodiments, L is₂Is an aryl group (e.g., phenyl) optionally substituted with at least one group selected from halogen and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen and alkoxy. In some embodiments, L is₂Is phenyl optionally substituted with halogen (e.g., F) or trifluoromethyl.

In some embodiments, L is₃Is H. In some embodiments, L is₃Is heteroaryl (such as pyrazolyl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl), optionally substituted with at least one substituent selected from halo; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; a cycloalkyl group; and heterocycloalkyl; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, and said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy. In some embodiments, L is₃Is pyrazolyl optionally substituted with at least one group selected from alkyl and halogen. In some embodiments, L is₃Is pyridine optionally substituted with alkyl.

Formula II

In some embodiments, the compound of formula I and/or a pharmaceutically acceptable salt thereof is a compound of formula II and/or a pharmaceutically acceptable salt thereof:

wherein:

Z₁and Z₂Independently of each other is CH or N,

R₁is H or C₁-C₄An alkyl group, a carboxyl group,

L₁it is that,

a cycloalkyl group,said cycloalkyl group is optionally substituted with at least one group selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy, or

L₂is that

heterocycloalkyl, optionally substituted with at least one member selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy, or

WhereinIndicating the point of attachment to a neighboring group,

L₃is that

H，

Heterocycloalkyl, optionally substituted with at least one selected from halo; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, and said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy.

In some embodiments, Z₁Is N and Z₂Is CH, andto adjacent Z₁Or in Z₂Carbon (c) above. In some embodiments, Z₁Is CH and Z₂Is N, andis connected to Z₁And Z₂Carbon in between.

In some embodiments, R₁Is H.

In some embodiments, R₂Is alkoxy substituted with alkoxy. In some embodiments, R₂Is aryl (e.g. phenyl or 2, 3-dihydrobenzo [ b ]][1,4]Dioxins) optionally substituted with at least one substituent selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo groups. In some embodiments, R₂Is heteroaryl (e.g. pyridyl, benzo [ d ]]Thiazole or imidazole) optionally with at least one hetero-aryl group selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo groups. In some embodiments, R₂Is a heterocyclic group (e.g., piperidinyl, piperazinyl, or morpholinyl) optionally substituted with at least one substituent selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo groups.

In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1,2 or 3, and R' and R" are independently selected from H and alkyl, said alkyl being optionally substituted with at least one group selected from hydroxy and halogen. In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1,2 or 3, one of R' and R" is H, and the other is alkyl, optionally substituted with at least one hydroxy and halogen group. In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1, one of R' and R" is H, and the other is alkyl, optionally substituted with hydroxy. In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1, one of R' and R" is H, and the other is methyl, optionally substituted with hydroxy. In some embodiments, L is₁Is (CR 'R ") n, wherein n is 1, one of R' and R" is H, and the other is isopropyl, optionally substituted with hydroxy.

In some embodiments, L is₂Is thatAnd L is₃Is heterocycloalkyl (such as pyrrolidinyl, piperazinyl or piperidinyl), optionally substituted with at least one substituent selected from halo; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, and said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy.

In some embodiments, L is₂Is thatAnd L is₃Is piperazinyl substituted with aryl, wherein the aryl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, the aryl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, the cycloalkyl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, and the heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl, and alkoxyHalogen, alkyl and alkoxy, said heteroaryl being optionally substituted with at least one group selected from halogen, alkyl and alkoxy.

In some embodiments, L is₂Is thatAnd L is₃Is piperazinyl substituted with phenyl, wherein the phenyl is substituted with heteroaryl, which is optionally substituted with at least one group selected from halo, alkyl and alkoxy. In some embodiments, L is₂Is thatAnd L is₃Is piperazinyl substituted with phenyl, wherein the phenyl is substituted with pyrimidine.

In some embodiments, L is₃Is H. In some embodiments, L is₃Is heteroaryl (e.g. pyrazole)Aryl, pyrimidinyl, pyridinyl, pyridazinyl, or pyrazinyl), optionally substituted with at least one moiety selected from halo; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; cycloalkyl and heterocycloalkyl group substitution; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, and said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy. In some embodiments, L is₃Is pyrazolyl optionally substituted with at least one group selected from alkyl and halogen. In some embodiments, L is₃Is pyridine optionally substituted with alkyl.

Formula III

In some embodiments, the compound of formula I and/or a pharmaceutically acceptable salt thereof is a compound of formula III and/or a pharmaceutically acceptable salt thereof:

wherein:

R₁is H or C₁-C₄An alkyl group, a carboxyl group,

R₂is aryl, heteroaryl, cycloalkyl, alkyl, alkoxy or heterocycloalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, alkyl, alkoxy and heterocycloalkyl is optionally substituted with at least one moiety selected from halogen, hydroxy, -CN, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄An oxo group, an alkyl group optionally substituted with at least one group selected from halogen and an alkoxy group optionally substituted with at least one group selected from halogen and alkoxySubstituted with at least one group selected from halogen and alkoxy,

L₁it is that,

L₂is that

Heterocycloalkyl optionally substituted with at least oneIs selected from halogen, -SO₂Alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group selected from halogen, hydroxy and alkoxy, or

WhereinIndicating the point of attachment to a neighboring group,

L₃is that

H，

In some embodiments, R₂Is alkoxy substituted with alkoxy. In some embodiments, R₂Is aryl (e.g. phenyl or 2, 3-dihydrobenzo [ b ]][1,4]Dioxins), optionally with at least one alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl、-CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo groups. In some embodiments, R₂Is heteroaryl (e.g. pyridyl, benzo [ d ]]Thiazole or imidazole) optionally with at least one hetero-aryl group selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo groups. In some embodiments, R₂Is a heterocyclic group (e.g., piperidinyl, piperazinyl, or morpholinyl) optionally substituted with at least one substituent selected from alkyl, alkoxy, halogen, hydroxy, -CN, haloalkyl, -CO₂H、-CONR₃R₄、-SO₂NR₃R₄And oxo groups.

In some embodiments, L is₁Is a heterocycloalkyl radical (such as pyrrolidinyl, tetrahydrofuranyl or piperidinyl) optionally substituted with at least one halogen, -SO₂Alkyl and alkyl substituted with at least one group selected from halogen, hydroxy and alkoxyAnd (4) substitution. In some embodiments, L is₁Is optionally substituted with alkyl (e.g. C)₁-C₄Alkyl, further such as methyl or ethyl) substituted pyrrolidinyl, said alkyl being optionally substituted with at least one group selected from halogen, hydroxy and alkoxy.

In some embodiments, L is₂Is thatAnd L is₃Is piperazinyl substituted with aryl, wherein the aryl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, the aryl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, the cycloalkyl is optionally substituted with at least one group selected from halo, alkyl, and alkoxy, and the cycloalkyl is optionally substituted with at least one group selected from halo, alkoxy, and heteroaryl,Alkyl and alkoxy, said heterocycloalkyl being optionally substituted with at least one group selected from halogen, alkyl and alkoxy, said heteroaryl being optionally substituted with at least one group selected from halogen, alkyl and alkoxy.

In some embodiments，L₃Is H. In some embodiments, L is₃Is heteroaryl (such as pyrazolyl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl), optionally substituted with at least one substituent selected from halo; alkyl optionally substituted with at least one group selected from halogen and alkoxy; an aryl group; a heteroaryl group; a cycloalkyl group; and heterocycloalkyl; wherein the last four groups: each of aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with at least one group selected from alkyl, halo, aryl, cycloalkyl, heterocycloalkyl and heteroaryl, said aryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said cycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, said heterocycloalkyl is optionally substituted with at least one group selected from halo, alkyl and alkoxy, and said heteroaryl is optionally substituted with at least one group selected from halo, alkyl and alkoxy. In some embodiments, L is₃Is pyrazolyl optionally substituted with at least one group selected from alkyl and halogen. In some embodiments, L is₃Is pyridine optionally substituted with alkyl.

In some embodiments, the compound of formula I and/or pharmaceutically acceptable salt thereof is

(S) -N- (1- (3-chlorophenyl) -2-hydroxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(R) -N- (1- (3-chlorophenyl) -2-hydroxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(S) -and (R) -N- (1- (3-chlorophenyl) -2-hydroxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(R) -1- (3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -3- (1-phenylethyl) urea,

(S) -1- (3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -3- (1-phenylethyl) urea,

(R) -and (S) -1- (3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -3- (1-phenylethyl) urea,

n- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(S) -1- (3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) -3- (1-phenylethyl) urea,

(R) -1- (3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) -3- (1-phenylethyl) urea,

(S) -and (R) -1- (3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) -3- (1-phenylethyl) urea,

(R) -N- (1- (4-fluorophenyl) -2-hydroxy-2-methylpropyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(S) -N- (1- (4-fluorophenyl) -2-hydroxy-2-methylpropyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(R) -and (S) -N- (1- (4-fluorophenyl) -2-hydroxy-2-methylpropyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methoxyethoxy) -N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methoxyethoxy) -N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methoxyethoxy) -N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methoxyethoxy) -N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [4,3-c ] pyridine-6-amide,

n- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [4,3-c ] pyridine-6-amide,

a mixture of N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [4,3-c ] pyridine-6-amide and N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [4,3-c ] pyridine-6-amide,

(R) -3- (2-methylpyridin-4-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(S) -3- (2-methylpyridin-4-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(R) -and (S) -3- (2-methylpyridin-4-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3-morpholine-1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3-morpholine-1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3-morpholine-1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3-morpholine-1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -4- (3-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -4- (3-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -4- (3-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -4- (3-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-methyl-4- (3- (pyridin-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-methyl-4- (3- (pyridin-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -1-methyl-4- (3- (pyridin-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -1-methyl-4- (3- (pyridin-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-methyl-4- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-methyl-4- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -1-methyl-4- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -1-methyl-4- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methoxypyridin-4-yl) -N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methoxypyridin-4-yl) -N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methoxypyridin-4-yl) -N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methoxypyridin-4-yl) -N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

(R) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (pyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (pyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) - (S) -a mixture of (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (pyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (pyridin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (pyridin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (pyridin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3- (4-fluorophenyl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3- (4-fluorophenyl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3- (4-fluorophenyl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3-morpholine-N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3-morpholine-N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3-morpholine-N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3- (6-methoxypyridin-3-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3- (6-methoxypyridin-3-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3- (6-methoxypyridin-3-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (piperazin-1-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (piperazin-1-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (piperazin-1-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3- (6-hydroxypyridin-3-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3- (6-hydroxypyridin-3-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3- (6-hydroxypyridin-3-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -3- (pyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3- (2-methylbenzo [ d ] thiazol-6-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3- (2-methylbenzo [ d ] thiazol-6-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3- (2-methylbenzo [ d ] thiazol-6-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3- (1H-imidazol-1-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3- (1H-imidazol-1-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3- (1H-imidazol-1-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -N- (1- (4-fluorophenyl) -2-hydroxy-2-methylpropyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -N- (1- (4-fluorophenyl) -2-hydroxy-2-methylpropyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -N- (1- (4-fluorophenyl) -2-hydroxy-2-methylpropyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -3- (2-oxo-1, 2-dihydropyridin-4-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(S) -3- (2-oxo-1, 2-dihydropyridin-4-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

(R) -and (S) -3- (2-oxo-1, 2-dihydropyridin-4-yl) -N- (1- (2-oxo-2- (4- (4- (pyrimidin-2-yl) phenyl) piperazin-1-yl) ethyl) pyrrolidin-3-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

n- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

n- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide, or

A mixture of N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide and N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide,

3- (2-methoxypyrimidin-5-yl) -N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methoxypyrimidin-5-yl) -N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methoxypyrimidin-5-yl) -N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methoxypyrimidin-5-yl) -N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3R,4S) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3S,4R) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methylpyridin-4-yl) -N- ((3R,4S) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methylpyridin-4-yl) -N- ((3S,4R) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3R,4S) -1- (methylsulfonyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3S,4R) -1- (methylsulfonyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methylpyridin-4-yl) -N- ((3R,4S) -1- (methylsulfonyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methylpyridin-4-yl) -N- ((3S,4R) -1- (methylsulfonyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-isopropyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-isopropyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3S,4R) -1-isopropyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3R,4S) -1-isopropyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1- (2-methoxyethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1- (2-methoxyethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3S,4R) -1- (2-methoxyethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3R,4S) -1- (2-methoxyethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide, N- ((3S,4R) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

a mixture of N- ((3R,4S) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide and N- ((3S,4R) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

n- ((3R,4S) -4- (4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -4- (4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -4- (4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -4- (4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -4- (2, 4-difluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -4- (2, 4-difluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -4- (2, 4-difluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -4- (2, 4-difluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-ethyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-ethyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -1-ethyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -1-ethyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1- (2, 2-difluoroethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1- (2, 2-difluoroethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -1- (2, 2-difluoroethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -1- (2, 2-difluoroethyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -4- (2-chloro-4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -4- (2-chloro-4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -4- (2-chloro-4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -4- (2-chloro-4-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3R,4S) -1-propyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3S,4R) -1-propyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methylpyridin-4-yl) -N- ((3R,4S) -1-propyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methylpyridin-4-yl) -N- ((3S,4R) -1-propyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1- (2-hydroxy-2-methylpropyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1- (2-hydroxy-2-methylpropyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3R,4S) -1- (2-hydroxy-2-methylpropyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3S,4R) -1- (2-hydroxy-2-methylpropyl) -4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide, N- ((3S,4R) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

a mixture of N- ((3R,4S) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide and N- ((3S,4R) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

3- (2-methylpyridin-4-yl) -N- ((1S,2R) -2-phenylcyclopentyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((1R,2S) -2-phenylcyclopentyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methylpyridin-4-yl) -N- ((1S,2R) -2-phenylcyclopentyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methylpyridin-4-yl) -N- ((1R,2S) -2-phenylcyclopentyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3S,4R) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3R,4S) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3S,4S) -4-phenyltetrahydrofuran-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((3R,4R) -4-phenyltetrahydrofuran-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methylpyridin-4-yl) -N- ((3S,4S) -4-phenyltetrahydrofuran-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methylpyridin-4-yl) -N- ((3R,4R) -4-phenyltetrahydrofuran-3-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((1R,2S) -2-phenylcyclopropyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

3- (2-methylpyridin-4-yl) -N- ((1S,2R) -2-phenylcyclopropyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of 3- (2-methylpyridin-4-yl) -N- ((1R,2S) -2-phenylcyclopropyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and 3- (2-methylpyridin-4-yl) -N- ((1S,2R) -2-phenylcyclopropyl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide, N- ((3R,4S) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

a mixture of N- ((3S,4R) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide and N- ((3R,4S) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

n- ((3S,4R) -1-methyl-4-phenylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3R,4S) -1-methyl-4-phenylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((3S,4R) -1-methyl-4-phenylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3R,4S) -1-methyl-4-phenylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

n- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

n- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

a mixture of N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide and N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

n- ((1R,2S) -2- (2-chlorophenyl) cyclopropyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide, N- ((1S,2R) -2- (2-chlorophenyl) cyclopropyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

a mixture of N- ((1R,2S) -2- (2-chlorophenyl) cyclopropyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((1S,2R) -2- (2-chlorophenyl) cyclopropyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide,

and/or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of inhibiting the activity of Erk, comprising contacting the protein Erk with an effective amount of a compound of formula I (e.g., formula II and formula III) disclosed herein and/or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of treating a disease treatable by inhibition of Erk in a patient, the method comprising administering to a patient identified in need of such treatment an effective amount of a compound of formula I (formula II and formula III) disclosed herein and/or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of treating a disease treatable by inhibition of Erk in a patient, the method comprising administering to a patient identified in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of formula I (formula II and formula III) disclosed herein and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Also disclosed herein is a method of treating cancer in a patient, the method comprising administering to a patient identified as in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of formula I (formula II and formula III) disclosed herein and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the cancer is colon cancer, gastric cancer, leukemia, lymphoma, melanoma, or pancreatic cancer.

Also disclosed herein is a method of treating an inflammatory disease in a patient, comprising administering to a patient identified as in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of formula I (formula II and formula III) disclosed herein and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the inflammatory disease is rheumatoid arthritis, psoriasis, or eczema.

Also disclosed herein is the use of a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease responsive to the inhibition of Erk, such as cancer or an inflammatory disease. In some embodiments, the cancer is colon cancer, gastric cancer, leukemia, lymphoma, melanoma, or pancreatic cancer. In some embodiments, the inflammatory disease is rheumatoid arthritis, psoriasis, or eczema.

Also disclosed herein is a pharmaceutical composition comprising a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pharmaceutical compositions comprising a compound of formula I (e.g. formula II and formula III) and/or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, may be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation spray or via an implantable kit, although the most suitable route in any given case will depend on the particular host to which the active ingredient is being administered, and the nature and severity of the condition. As used herein, the term "parenteral" encompasses subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intracapsular, intralesional and intracranial injection or infusion techniques. The compositions disclosed herein may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art.

The compounds of formula I (e.g., formula II and formula III) and/or pharmaceutically acceptable salts thereof can be administered orally in solid dosage forms (e.g., capsules, tablets, lozenges, dragees, granules and powders) or in liquid dosage forms (e.g., elixirs, syrups, emulsions, dispersions and suspensions). The compounds of formula I (e.g., formula II and formula III) and/or pharmaceutically acceptable salts thereof may also be administered parenterally in sterile liquid dosage forms (e.g., dispersions, suspensions or solutions). Other dosage forms which may also be used for administration of a compound of formula I (e.g. formula II and formula III) and/or a pharmaceutically acceptable salt thereof, comprise ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspensions for ophthalmic administration, i.e. eyedrops, aerosol spray or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration.

Gelatin capsules containing a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof, and a powdered carrier (e.g., lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like) may also be used. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be made into sustained release products to provide continuous release of the drug over a period of time. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the environment, or enteric-coated to selectively disintegrate in the gastrointestinal tract.

Liquid dosage forms for oral administration may also include at least one auxiliary agent selected from coloring agents and flavoring agents to increase patient acceptance.

In general, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol may be examples of suitable carriers for injectable solutions. Solutions for parenteral administration may include a water-soluble salt of at least one compound disclosed herein, at least one suitable stabilizer, and at least one buffering substance, if desired. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, may be examples of suitable stabilizers. Citric acid and its salts and sodium edetate may also be used as examples of suitable stabilizers. In addition, the injection solution may further include at least one preservative selected from, for example, benzalkonium chloride, methyl and propyl parabens, and chlorobutanol.

The pharmaceutically acceptable carrier is selected, for example, from carriers that are compatible with (and in some embodiments capable of stabilizing) the active ingredient of the pharmaceutical composition and are not deleterious to the subject to be treated. For example, a solubilizing agent, such as cyclodextrin (which can form a specific more soluble complex with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein), can be used as a pharmaceutical excipient for delivery of the active ingredient. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (e.g., D & C yellow # 10). Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, a.

Compounds of formula I (e.g. formula II and formula III) and/or pharmaceutically acceptable salts thereof may be tested for efficacy in the treatment of cancer by in vivo testing. For example, a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof can be administered to an animal (e.g., a mouse model) having cancer and a therapeutic effect thereof can be obtained. A positive result in one or more such tests is sufficient to increase the scientific knowledge base and thus to demonstrate the utility of the tested compounds and/or salts. Based on the results, the appropriate dosage range and route of administration for the animal (e.g., human) can also be determined.

For administration by inhalation, the compounds of formula I (e.g., formula II and formula III) and/or pharmaceutically acceptable salts thereof may be conveniently delivered in the form of an aerosol spray from a pressurized pack or a nebulizer. The compounds of formula I (e.g., formula II and formula III) and/or pharmaceutically acceptable salts thereof may also be delivered in a powder, which may be formulated and the powder composition may be inhaled with the aid of an inhalation powder inhaler device. One exemplary delivery system for inhalation may be a Metered Dose Inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons.

For ophthalmic administration, an ophthalmic formulation may be formulated with an appropriate weight percentage of a solution or suspension of the compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof in an appropriate ophthalmic vehicle such that the compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof remains in contact with the viewing surface for a sufficient time to allow the compound to penetrate the cornea and interior regions of the eye.

Useful pharmaceutical dosage forms for administering a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

The dosage administered will depend on a variety of factors, such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment (if any), the frequency of the treatment, and the nature of the effect desired. In general, the daily dosage of the active ingredient may vary, for example from 0.1 to 2000 mg per day. For example, 10-500 mg per day or multiple times per day may be effective in achieving the desired results.

In some embodiments, the compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof may be present in an amount of 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 50mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 200mg, 250mg, 300mg, 400mg, and 500mg in a capsule.

In some embodiments, a large number of unit capsules can be prepared by filling each standard two-piece hard gelatin capsule with, for example, 100mg of a powder of a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof, 150mg of lactose, 50mg of cellulose, and 6mg of magnesium stearate.

In some embodiments, a mixture of a compound of formula I (such as formula II and formula III) and/or a pharmaceutically acceptable salt thereof and a digestible oil (such as soybean oil, cottonseed oil, or olive oil) may be prepared and injected into gelatin with the aid of a positive displacement pump to form soft gelatin capsules containing 75mg or 100mg of the active ingredient. The capsules are washed and dried.

In some embodiments, the compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof may be present in the tablet in an amount of 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 50mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 200mg, 250mg, 300mg, 400mg, and 500 mg.

In some embodiments, a plurality of tablets may be prepared by conventional methods such that a unit dose comprises, for example, 100mg of a compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof, 0.2 mg colloidal silicon dioxide, 5mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 mg lactose. Suitable coatings may for example be applied to increase palatability or delay absorption.

In some embodiments, parenteral compositions suitable for administration by injection may be prepared by stirring 1.5% by weight of a compound of formula I (such as formula II and formula III) and/or a pharmaceutically acceptable salt thereof in 10% by volume propylene glycol. The solution was made to the desired volume with water for injection and sterilized.

In some embodiments, aqueous suspensions may be prepared for oral administration. For example, an aqueous suspension comprising 100mg of a finely divided compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof, 100mg of sodium carboxymethylcellulose, 5mg of sodium benzoate, 1.0 g of a sorbitol solution (U.S. pharmacopoeia u.s.p.), and 0.025 ml of vanillin per 5ml can be used.

When the compound of formula I (e.g., formula II and formula III) and/or a pharmaceutically acceptable salt thereof is administered stepwise or in combination with at least one other therapeutic agent, the same dosage form may generally be used. When drugs are administered in physical combination, the dosage form and route of administration should be selected according to the compatibility of the drugs being combined. Thus, the term "co-administration" may be understood to encompass the simultaneous or sequential administration of at least two agents, or alternatively as a fixed-dose combination of at least two active ingredients.

The compound of formula I (e.g. formula II and formula III) and/or a pharmaceutically acceptable salt thereof may be administered as the sole active ingredient or in combination with at least one second active ingredient selected, for example, from other active ingredients known to be useful for treating a disease of interest in a patient, such as cancers comprising, for example, colon, gastric, leukemia, lymphoma, melanoma and pancreatic cancer.

Synthesis of Compounds

In the following examples, the following abbreviations are used:

DCM dichloromethane

DIPEA diisopropylethylamine

DMF dimethyl formamide

DMSO dimethyl sulfoxide

EDTA ethylene diamine tetraacetic acid

EtOAc ethyl acetate

HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridine 3-oxidohexafluorophosphate

MeOH methanol

Pd(dppf)Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

PE Petroleum Ether

TLC thin layer chromatography

TEA Triethylamine

TES Trivinylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

Xantphos 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene

Example 1:n- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b]Pyridine-5-amides

Step preparation of 15-bromo-3-iodo-1H-pyrazolo [3,4-b ] pyridine (II)

Iodine (64.1g, 252.5mmol, 10 equiv.) was added to 5-bromo-1H-pyrazolo [3,4-b]Pyridine (I) (5g, 25.25mmol, 1 equiv.) in a solution of 1, 4-dioxane (100mL) and 4N aqueous NaOH (100 mL). The mixture was stirred at 60 ℃ overnight and TLC showed the reaction was complete. The reaction mixture was extracted with EtOAc (100 ml. times.2). Combining the organics with saturated NaHSO₃Aqueous solution (100 mL. times.3) and brine (50mL) washed with Na₂SO₄Drying and concentrating to give the title compound 5-bromo-3-iodo-1H-pyrazolo [3,4-b as an off-white solid]Pyridine (II) (7.5g, yield: 91%)And the product is directly used in the next reaction step without further purification.

Step preparation of 25-bromo-1- (1-ethoxyethyl) -3-iodo-1H-pyrazolo [3,4-b ] pyridine

Ethoxyethylene (5.6g, 77.8mmol) and concentrated hydrochloric acid (0.5mL) were added to 5-bromo-3-iodo-1H-pyrazolo [3,4-b ]]Pyridine (6.3g, 19.4mmol) in toluene (120 mL). The mixture was stirred at room temperature overnight with EtOAc (200mL) and H₂Dilution with O (50 mL). The organic layer was collected, washed with brine (50mL) and washed with Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc ═ 15/1) to give the desired compound 5-bromo-1- (1-ethoxyethyl) -3-iodo-1H-pyrazolo [3,4-b]Pyridine (6.6g, yield: 87%).

Step preparation of 35-bromo-1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine

Reacting 5-bromo-1- (1-ethoxyethyl) -3-iodo-1H-pyrazolo [3,4-b]Pyridine (6.4g, 16.2mmol), 2-methylpyridin-4-ylboronic acid (2.4g, 17.8mmol), Pd (PPh)₃)₄(0.95g, 0.8mmol) and Na₂CO₃(3.4g, 32.4mmol) in dioxane/H₂The solution in O (100/20mL) was evacuated and backfilled with nitrogen (this process was repeated three times). The mixture was stirred at 90 ℃ for 4h, cooled slightly and concentrated. The residue was taken up in EtOAc (200mL) by H₂O (50 mL. times.2) and brine (50mL) in Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc. 8/1-3/1) to give the title compound 5-bromo-1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b]Pyridine (3.3g, yield: 56%).

Step 41 preparation of methyl 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-carboxylate

Pd (dppf) Cl₂(0.4g, 0.48mmol) and triethylamine (2.0g, 19.4mmol) were added 5-bromo-1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b]Pyridine (3.5g, 9.69mmol) in methanol (50 mL). The mixture was filled with CO to a pressure of 3atm and stirred at 70 ℃ for 18 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc. 5/1-2/1) to give the title compound 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b]Pyridine-5-carboxylic acid methyl ester (3.2g, yield: 97%).

Step preparation of 51- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-carboxylic acid

4N NaOH (10mL) was added to a solution of methyl 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-carboxylate (3.2g, 9.40mmol) in methanol (50 mL). The mixture was stirred at rt for 2h, concentrated under vacuum to remove methanol, cooled in an ice-water bath, and adjusted to PH 6-7 with 6N HCl. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-carboxylic acid (3.45g, yield: 100%).

Step 61 preparation of (1-ethoxyethyl) -N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide

1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b]A solution of pyridine-5-carboxylic acid (3.9g, 11.9mmol), 3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-amine (3.2g, 13.1mmol), HATU (6.8g, 17.9mmol) and DIPEA (4.6g, 35.7mmol) in DMF (70mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (500mL) by H₂O (100 mL. times.2) and brine (100mL) in Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (6.1g, yield: 93%).

Step 7 preparation of N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide

6N HCl (50mL) was added to 1- (1-ethoxyethyl) -N- (1-methyl-4- (3- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b]Pyridine-5-amide (6.1g, 0.011mol) in THF (50 mL). The mixture was stirred at room temperature for 18h and passed through saturated Na₂CO₃Adjusting the pH value of the aqueous solution to 7-8. The precipitate was collected by filtration and passed through H₂O (50mL) and acetone (50mL) and dried under vacuum to give the title compound N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b]Pyridine-5-amide (3.5g, yield: 66%).

Step 8 preparation of N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide and N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide

The method A comprises the following steps: the enantiomer of N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) -pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide (304mg, 0.631mmol) was separated by HPLC (column: CHIRALPAK ID 0.46 × 15cm, mobile phase: hexane/IPA/DEA ═ 50/50/0.1 (V/V), flow rate: 1 ml/min). The peak 1 fractions were collected and the solvent was evaporated in vacuo to yield 145mg of N- (3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide. The peak 2 fractions were collected and the solvent was evaporated in vacuo to yield 157mg of N- (3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide.

The method B comprises the following steps: the enantiomer of trans-1-methyl-4- (2- (trifluoromethyl) phenyl) -pyrrolidin-3-amine (64.0g, 0.262mol) was separated by HPLC (column: CHIRALPAK IE 0.46 × 15cm, mobile phase: hexane/EtOH/DEA 90/10/0.1 (V/V), flow rate: 1 ml/min). The peak 2 fractions were collected and the solvent was evaporated in vacuo to yield 27.9g of (3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-amine, which (3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-amine was used in the preparation of N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-5-amide (steps described in steps 6 and 7).

Example 2:n- (4, 3-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [4,3-c]Preparation of pyridine-5-amides

Step 1: preparation of 3- (2-methylpyridin-4-yl) -1-trityl-6-vinyl-1H-pyrazolo [4,3-c ] pyridine

Reacting 6-chloro-3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4, 3-c)]Pyridine (500mg, 1.02mmol), potassium trifluoro (vinyl) borate (166mg, 1.24mmol), Pd (dppf) Cl₂A solution of (82mg, 0.1mmol) and TEA (154mg, 1.54mmol) in n-BuOH (20mL) was stirred in a capped vial under nitrogen at 135 deg.C for 4 h. The mixture was cooled to room temperature, extracted with EtOAc (100mL), and passed through H₂O (20 mL. times.2) and brine (20mL) in Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc ═ 4:1) to give the title compound 3- (2-methylpyridin-4-yl) -1-trityl-6-vinyl-1H-pyrazolo [4,3-c]Pyridine (450mg, yield 65%).

Step 2: preparation of 3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4,3-c ] pyridine-6-carbaldehyde

Mixing OsO₄(2 mg/mL, 4mL in water) 3- (2-methylpyridin-4-yl) -1-trityl-6-vinyl-IH-pyrazolo [4, 3-c)]Pyridine (280mg, 0.585mmol) in dioxane (15 mL). The mixture was stirred at room temperature for 20min, and NaIO was added⁴(250mg, 1.17 mmol). The mixture was stirred at room temperature overnight, extracted with EtOAc (50mL), and passed through H₂O (15 mL. times.2) and brine (15mL) in Na₂SO₄Dried and concentrated to give the title compound 3- (2-methylpyridin-4-yl) -1-trityl-IH-pyrazolo [4,3-c]Pyridine-6-carbaldehyde (300mg, yield: 98%) which was used in the next step without further purification.

And step 3: preparation of 3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4,3-c ] pyridine-6-carboxylic acid

Adding NaClO₂(113mg, 1.248mmol) andNaH₂PO₄(195mg, 1.248mmol) in H₂To a solution of O (10mL) was added 3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4, 3-c)]Pyridine-6-carbaldehyde (300mg, 0.624mmol) and 2, 3-dimethylbut-2-ene (5mL) in t-BuOH (20 mL). The mixture was stirred at room temperature overnight, extracted with EtOAc (100mL), and passed through saturated NH₄Aqueous Cl (30mL) and brine (30mL) in Na₂SO₄Dried and concentrated to give the title compound 3- (2-methylpyridin-4-yl) -1-trityl-IH-pyrazolo [4,3-c]Pyridine-6-carboxylic acid (150mg, yield: 49%).

And 4, step 4: preparation of N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4,3-c ] pyridine-6-amide

Reacting 3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4, 3-c)]A solution of pyridine-6-carboxylic acid (50mg, 0.10mmol), 3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-amine (28mg, 0.12mmol), HATU (57mg, 0.15mmol) and DIPEA (39mg, 0.3mmol) in DMF (5mL) was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (50mL) through H₂O (15 mL. times.2) and brine (15mL) in Na₂SO₄Dried and concentrated. The residue was purified by preparative TLC (DCM/MeOH ═ 15/1) to give the title compound N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4, 3-c)]Pyridine-6-amide (38mg, yield: 53%).

And 5: preparation of N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [4,3-c ] pyridine-6-amide

Reacting TFA (1)mL) and TES (0.5mL) were added N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1-trityl-1H-pyrazolo [4, 3-c)]Pyridine-6-amide (38mg, 0.053mmol) in DCM (5 mL). The mixture was stirred at room temperature overnight, extracted with DCM/MeOH (10/1, 50mL), and purified by saturated NaHCO₃Aqueous solution (15mL) and brine (15mL) were washed in Na₂SO₄Dried and concentrated. The residue was purified by preparative TLC (DCM/MeOH ═ 10/1) to give the title compound N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo [4,3-c]Pyridine-6-amide (21mg, yield: 84%).

Example 3: preparation of trans-4-phenyltetrahydrofuran-3-amine

Step 1: preparation of trans-4-phenyltetrahydrofuran-3-ol

Phenylmagnesium bromide (7.7mL, 3N in EtOEt, 23.2mmol) was added dropwise to a suspension of CuI (265mg, 1.39mmol) in THF (10mL) cooled in an ice-water bath. The mixture was stirred at this temperature for 10min, and 3, 4-epoxytetrahydrofuran (2.0g, 23.2mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. With saturated NH₄The mixture was quenched with aqueous Cl (50mL) and extracted with EtOAc (50 mL. times.3). The combined organics were washed with brine (20mL) and Na₂SO₄Dried and concentrated. The obtained residue was purified by column chromatography (petroleum ether/EtOAc ═ 10/1) to give the desired compound as a colorless oil (2.5g, 67% yield).

Step 2: preparation of cis-4-phenyltetrahydrofuran-3-benzoic acid ester

DEAD (3.2g, 0.018mmol) was added to a solution of benzoic acid (2.2g, 0.018mol) in THF (15mL) cooled in an ice-water bath, followed by a solution of trans-4-phenyltetrahydrofuran-3-ol (2.5g, 0.015mmol) and PPh3(4.8g, 0.018mmol) in THF (15 mL). The mixture was stirred at 0 ℃ for 4h and diluted with EtOAc (100 mL). Subjecting the organic layer to H₂O (30 mL. times.2) and brine (30mL), Na₂SO₄Dried and concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 10/1-5/1) to give the desired compound as a colorless oil (2.8g, 69% yield).

And step 3: preparation of cis-4-phenyltetrahydrofuran-3-ol

Aqueous NaOH (4.0N, 10mL) was added to a solution of cis-4-phenyltetrahydrofuran-3-benzoate (1.05g, 3.9mmol) in MeOH (20 mL). The mixture was stirred at room temperature overnight and concentrated to remove most of the MeOH. The aqueous layer was extracted with EtOAc (30 mL. times.3), washed with brine (30mL), and Na₂SO₄Dried and concentrated to give the desired compound as a white solid (590mg, yield: 92%).

And 4, step 4: preparation of 2- (trans-4-phenyltetrahydrofuran-3-yl) isoindoline-1, 3-dione

DEAD (749mg, 4.3mmol) was added to a solution of isoindoline-1, 3-dione (634mg, 4.3mol) in THF (15mL) cooled in an ice-water bath, followed by cis-4-phenyltetrahydrofuran-3-ol (590mg, 3.6mmol) and PPh3(1.2g, 4.3mmol) in THF (15 mL). The mixture was stirred at 0 ℃ for 4h and diluted with EtOAc (100 mL). Passing the organic layer through H₂O(30mL×2)And brine (30mL), Na₂SO₄Dried and concentrated. The obtained residue was purified by column chromatography (petroleum ether/EtOAc: 10/1-5/1) to give the desired compound as a white solid (100mg, yield: 9%).

And 5: preparation of trans-4-phenyltetrahydrofuran-3-amine

85% hydrazine hydrate (5mL) was added to a solution of 2- (trans-4-phenyltetrahydrofuran-3-yl) isoindoline-1, 3-dione (100mg, 0.34mmol) in EtOH (10 mL). The mixture was stirred at 80 ℃ for 4h, cooled to room temperature, and diluted with EtOAc (50 mL). The organic layer was collected by NaHCO₃Washed (10mL) with brine (10mL) and Na₂SO₄Dried and concentrated to give crude compound as colorless oil (60mg, crude yield: 100%), which was used in the next step without further purification.

Table 1 lists the compounds of examples 1-3 above and the compounds prepared according to the procedures of examples 1-3 by using the corresponding intermediates and reagents under appropriate conditions that can be confirmed by those skilled in the art.

TABLE 1

Example 3:n- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c]Pyrazole-5-amides

Step 1: preparation of 3, 5-dibromo-1H-pyrazole-4-carbaldehyde

BuLi in hexane (2.5N, 57mL, 0.143mol) was added dropwise to N₂3,4, 5-tribromo-1H-pyrazole (21.8g, 0.072mol) cooled to-78 ℃ in Et₂O (300mL) while maintaining the temperature < -70 ℃. The mixture was stirred at-78 ℃ for 1.5h, followed by addition of DMF (26.3g, 0.36 mol). The mixture was stirred at-78 ℃ for 1h, warmed to room temperature and stirred for 4 h. TLC showed the reaction was complete. The mixture was cooled in an ice-water bath and washed with H₂O (200mL) quench. The organic phase was decanted and Et₂The aqueous phase was extracted with O (200 mL). The aqueous phase was collected, adjusted to PH3 by saturated aqueous citric acid solution, and treated with Et₂O (200 mL. times.3). The combined organic phases were washed with brine (30mL) over Na₂SO₄Dried and concentrated. The residue was dried under vacuum to give the title compound 3, 5-dibromo-1H-pyrazole-4-carbaldehyde (17.6g, yield: 96%) which was used in the next step without further purification.

Step 2: preparation of 3, 5-dibromo-1- (1-ethoxyethyl) -1H-pyrazole-4-carbaldehyde

Ethoxyethylene (6.8g, 0.0944mol) and 10 drops of concentrated hydrochloric acid were added to 3, 5-dibromo-1H-pyrazole-4-carbaldehyde (6.0g, 0.0236mol) in toluene (150mL)In the solution of (1). The mixture was stirred at room temperature overnight, diluted with toluene (200mL), and saturated NaHCO₃Aqueous solution (100mL) and brine (100mL) in Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc ═ 9/1) to give the title compound 3, 5-dibromo-1- (1-ethoxyethyl) -1H-pyrazole-4-carbaldehyde (4.76g, yield: 62%).

And step 3: preparation of methyl 3-bromo-1- (1-ethoxyethyl) -1H-thieno [2,3-c ] -pyrazole-5-carboxylate

Methyl 2-mercaptoacetate (1.14g, 10.7mmol) and Na₂CO₃(1.14g, 10.7mmol) was added to a solution of 3, 5-dibromo-1- (1-ethoxyethyl) -1H-pyrazole-4-carbaldehyde (3.5g, 10.7mmol) in EtOH (100 mL). The mixture was refluxed for 4h, cooled slightly and concentrated. The residue was taken up in DCM (150mL) and passed through H₂O (50 mL. times.2) and brine (50mL) in Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc ═ 8/1) to give the title compound 3-bromo-1- (1-ethoxyethyl) -1H-thieno [2,3-c]Pyrazole-5-carboxylic acid methyl ester (3.6g, yield: 75%).

And 4, step 4: preparation of methyl 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-carboxylate

Reacting 3-bromo-1- (1-ethoxyethyl) -1H-thieno [2,3-c]Pyrazole-5-carboxylic acid methyl ester (500mg, 1.50mmol), 2-methylpyridin-4-ylboronic acid (250mg, 1.80mmol), Pd (PPh3)₄(122mg, 0.15mmol) and Na₂CO₃(318mg, 3.0mmol) in dioxane/H₂A solution in O (10mL/2mL) was stirred at 80 ℃ for 4h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with EtOAc (100mL), and passed through H₂O (30 mL. times.2) and saltWashed with water (30mL) over Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc ═ 3/1) to give the title compound 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c]Pyrazole-5-carboxylic acid methyl ester (370mg, yield: 72%).

And 5: preparation of 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-carboxylic acid

4N NaOH (5mL) was added to 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ]]Pyrazole-5-carboxylic acid methyl ester (370mg, 1.07mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 2h, cooled in an ice-water bath and adjusted to PH 6-7 with 6N HCl. The suspension was extracted with EtOAc (50 mL. times.4). The combined organic layers were washed with brine (50mL) over Na₂SO₄Dried and concentrated to give the title compound 1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c]Pyrazole-5-carboxylic acid (360mg, yield: 100%) was used in the next step without further purification.

Step 6: preparation of 1- (1-ethoxyethyl) -N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide

1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c]A solution of pyrazole-5-carboxylic acid (50mg, 0.15mmol), 3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-amine (51mg, 0.18mmol), HATU (85mg, 0.23mmol) and DIPEA (97mg,0.75mmol) in DMF (5mL) was stirred at room temperature for 2 h. With EtOAc (100mL) and H₂The mixture was diluted O (30 mL). Collecting the organic layer with H₂O (30mL) and brine (20mL) in Na₂SO₄Dried and concentrated. The residue was purified by preparative TLC (DCM/MeOH ═ 15/1) to give the title compound 1- (1-ethoxyethyl) -N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c]Pyrazole-5-amide (52mg, yield: 63%).

And 7: preparation of N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide

6N HCl (2.0mL) was added to 1- (1-ethoxyethyl) -N- (1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ]]Pyrazole-5-amide (52mg, 0.093mmol) in THF (2 mL). The mixture was stirred at room temperature overnight and passed through NaHCO₃Adjusting the pH value to 7-8. The mixture was extracted with DCM/MeOH 10/1(20mL × 3). The combined organic layers were washed with brine (20mL) over Na₂SO₄Dried and concentrated. The residue was purified by preparative TLC (DCM/MeOH ═ 100/8) to give the title compound N- (3, 4-trans-1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c]Pyrazole-5-amide (21mg, yield: 47%).

Table 2 lists the compound of example 5 above and compounds prepared according to the procedure of example 5 by using the corresponding intermediates and reagents under appropriate conditions that can be confirmed by those skilled in the art.

TABLE 2

Example 4: enzymatic assay

Compounds tested Using LanthaScreen from Invitrogen^TMTime-resolved fluorescence energy transfer (TR-FRET) enzyme assay. The assay used human ERK2 (residues 19-96) recombinantly expressed as GST-tagged full-length protein purified from e.coli and activated in vitro with MAP2K1 (mitogen activated kinase 1, (Invitrogen, cat.pv3311). substrate is a recombinant truncated version of ATF2 fused to green fluorescent protein (Invitrogen, cat.pv4445). assay compounds were prepared and diluted 3-fold serially in DMSO to 100 x of final assay concentration and then further diluted to 4 x with kinase reaction buffer (Invitrogen, cat.pv3189) the enzymatic reaction for compound assay was carried out in white 384 well polypropylene plates (Packard, cat.6005214) in a total reaction volume of 10 μ l containing 20ng/ml ERK2, 400nM substrate and approximately K thereof_m5 μ M ATP. At the start of the assay 2.5. mu.l of ERK2 diluted in kinase reaction buffer was added to the wells, followed by an equal volume of 4 × compound and incubated for 15 min at room temperature for pretreatment. The enzymatic reaction was initiated by adding 5. mu.l of a mixture of substrate and ATP prepared in kinase reaction buffer. After 1 hour of reaction, a mixture of 10 μ l EDTA (final concentration 10mM) and terbium labeled anti-pATF 2(pThr71) antibody (final 2nM) (Invitrogen, cat.pv4451) prepared in TR-FRET antibody dilution buffer (Invitrogen, cat.pv3574) was added to stop the enzymatic reaction and generate TR-FRET signal. After incubation for 30 minutes at room temperature, with the following settings: excitation: tecan Infinite F200 Pr at 340nm (30)/1495 nm (10)/2520 nm (25)o read plate. The TR-FRET value is a dimensionless number calculated as the ratio of acceptor (green fluorescent protein) signal to donor (terbium) signal. The percentage of control was calculated as the percentage of DMSO of the treated compound relative to 1% of the blank treatment. Dose-response curves were generated and IC was calculated by nonlinear sigmoidal curve fitting using GraphPad Prism₅₀。

ERK2 enzymatic inhibition IC of compounds disclosed herein₅₀Values range from about 0.1nM to 10. mu.M.

Example 5: colo205 cell proliferation assay

The inhibition of ERK2 by the compounds disclosed herein was tested by the Colo205 cell proliferation assay by the MTT method. In this test, complete media was prepared by adding 10% fetal bovine serum to RPMI-1640 medium (Life technology). Colon cancer cells (Colo205 cell line) were added to each of 88 wells of a 96-well plate at a seeding density of 5,000 cells/well/90 μ L. Cells were attached to the plate by incubation at 37 ℃ for 24 hours. Compounds were dissolved in dmso (sigma). Solutions of the test compounds were prepared in whole culture media by serial dilution to obtain the following concentrations: 500. mu.M, 150. mu.M, 50. mu.M, 15. mu.M, 5. mu.M, 1.5. mu.M, 0.5. mu.M, 0.15. mu.M and 0.05. mu.M. A solution of test compound (10. mu.L) was added to each of 80 wells containing cells. The final concentrations of the compounds were as follows: 50. mu.M, 15. mu.M, 5. mu.M, 1.5. mu.M, 0.5. mu.M, 0.15. mu.M, 0.05. mu.M, 0.015. mu.M and 0.005. mu.M. The final concentration of DMSO is 0.5%. Only the complete medium (containing 0.5% DMSO) was added to the 8 remaining wells containing cells to form a control group in order to measure the maximum proliferation. The complete medium was added to the remaining 8 empty wells to form a blank control for background measurement. The plates were incubated at 37 ℃ for 72 hours. mu.L of WST-8 solution (DOJINDO, Cell Counting KIT-8) was added to each well. The plates were further incubated at 37 ℃ for 2 hours and then absorbance was read at 450nM using a microplate reader. ERK2 enzymatic inhibition IC of compounds disclosed herein₅₀Values ranged from 0.1nM to 10. mu.M.

Colo205 cell growth inhibition IC of compounds 1-4, 9, 10, 13-26, 28, 29, 31-42, 55₅₀Values range from 0.052 μ M to 10.0 μ M.

Claims

1. A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

n- ((3R,4S) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

n- ((3S,4R) -4- (2-fluorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

n- ((3R,4S) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

n- ((3S,4R) -4- (2-chlorophenyl) -1-methylpyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide,

a mixture of N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide and N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-indazole-5-amide.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

3. A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

A mixture of N- ((3R,4S) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide and N- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, selected from:

n- ((3S,4R) -1-methyl-4- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) -3- (2-methylpyridin-4-yl) -1H-thieno [2,3-c ] pyrazole-5-amide, and

5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a patient, the treatment comprising administering to the patient identified as in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The use of claim 6, wherein the cancer is selected from the group consisting of colon cancer, gastric cancer, leukemia, lymphoma, melanoma, and pancreatic cancer.