WNK1 inhibitors

Abstract

The present invention relates to novel compounds of formulae (la) and (lb), pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases or disorders relating to the activity of WNK1.

Description

[0001] WNK1 inhibitors

[0002] Technical field

[0003] The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases and disorders related to the activity of WNK1 . The invention further relates to methods of treating, alleviating and / or preventing diseases and disorders related to the activity of WNK1.

[0004] Background

[0005] WNK1 (WNK lysine deficient protein kinase 1) belongs to a subfamily of atypical serine-threonine kinases, characterised by the lack of a conserved catalytic lysine in the kinase subdomain II (WNK1-4).

[0006] WNK1 is known to play an important role in ion transport through WNK1 -mediated phosphorylation and activation of OSR1 (oxidative-stress response kinase 1) and STK39 / SPAK (STE20 / SPS1 -related proline-alanine-rich protein kinase) kinases. Following activation by WNK1 , OSR1 and STK39 / SPAK catalyze the phosphorylation of ion cotransporters of the SLC12 family of cation-coupled chloride co-transporters, thereby activating the Na+ / K+-coupled Cl’ importers SLC12A1(NKCC1), SLC12A2 (NKCC2) and SLC12A3 (NCC)11-17, whilst inhibiting the K+-coupled Cl' exporters SLC12A4-SLC12A7 (KCC1-KCC4).

[0007] WNK1 is known to be involved in various processes, both as ion transport as stated above, but also cell volume regulation, sodium reabsorption, potassium secretion, response to hypertonic stress, autophagy and regulation of blood pressure. Moreover increased WNK1 activity has been associated with different diseases and disorders, including hypertension and cancers such as breast cancer, colon cancer, pancreatic ductal adenocarcinoma and blood cancers, including leukemia and multiple myeloma.

[0008] WNK1 and hypertension

[0009] Hypertension is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. Hypertension is a risk factor for many disabling and often fatal diseases, including stroke, myocardial infarction, arrhythmia, congestive heart failure, renal failure and retinopathy. WNK1 has a well-described role in inherited hypertension. Mutations which result in the overexpression of WNK1 have been associated with different types of hypertension, including familial hyperkalemic hypertension (FHHt), an inherited form of hypertension characterized by increased salt reabsorption and impaired K+and H+excretion in the kidney, and pseudohypoaldosteronism type II (PHAII), which is an autosomal dominant disorder featuring hypertension, hyperkalemia and renal tubular acidosis.

[0010] WNK1 and cancer

[0011] It is known that the WNK1-4 kinases are dysregulated in various types of cancer, and moreover it is has been established that the dysregulation contributes to tumor growth, metastasis, and angiogenesis through complex mechanisms, including phosphorylation of kinase substrates SPS1 -related proline / alanine-rich kinase (STK39 / SPAK) and oxidative stress-responsive kinase 1 (OSR1).

[0012] WNK1 specifically has been associated with different types of cancer, including breast cancer, colon cancer and blood cancers such as leukaemia and multiple myeloma.

[0013] US 2008 / 0286809 A1 discloses that the rate of autophosphorylation of endogenously expressed WNK1 is increased ~ 5-fold by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines.

[0014] WO 2021 / 028438 A1 discloses that inhibition of WNK1 is toxic to cells of leukemic and myeloma origin, and moreover it is disclosed that conditional knockdown of WNK1 results in increased lifespan of acute myeloid leukemia (AML) mice.

[0015] WNK1 inhibition

[0016] Inhibition of WNK1 presents a promising target for treatment of such diseases and disorders, due to the role of WNK1 in various diseases as described above.

[0017] An ongoing interest in developing inhibitors to the WNK1-4 kinases, have resulted in a variety of WNK1 inhibitors (Ishigami-Yuasa et al., 2017; Yamada et al., 2017; Yamada et al., 2016a; Yamada et al., 2016b). Nonetheless, there is a need for novel, effective WNK1 inhibitors, allowing for effective modulation of WNKI . Summary

[0018] This invention concerns a series of compounds which are inhibitors of WNK1.

[0019] The compounds constitute a new group of potential drugs that can be used to treat or ameliorate diseases and disorder related to dysregulation of WNK1 , including hypertension and cancers, such as breast cancer, pancreatic cancer, colon cancer and blood cancers such as leukemia and multiple myeloma.

[0020] In one major aspect, the present invention concerns a compound of Formula (I): wherein

[0021] W is C(H)2or C(D)2;

[0022] Y is C(H) or N;

[0023] Z is C or N;

[0024] R1is H or CH3;

[0025] R2is H;

[0026] R3is H or OCH3;

[0027] A is selected from the group consisting of H, C1.3 alkoxy, CF3, and a group of formula (II):

[0028] Formula (II) wherein

[0029] X is C(H) or N;

[0030] R6is H or C1-4 alkyl optionally substituted with phenyl; and

[0031] Rsis selected from the group consisting of C1.6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1-6 alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);

[0032] R7is individually selected from C1.3 alkoxy optionally substituted with one or more F; - o

[0033] OH; -O-benzyl; C1-3 alkyl optionally substituted with OH; N(CH3)2; N(H)2; ; and or when two R7are linked together to form a ring, then said two R7are individually selected from Ci-2alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said Ci-2alkanediyl is optionally replaced with -O-; or

[0034] R5and R5are linked together to form a ring and

[0035] R5is a bond or C1.5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); and

[0036] R6is a bond or C1.5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0037] R8is individually selected from C1.3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1-3 alkanediyl optionally substituted with one or two substituents selected from F, OH and NH2, and one or two methylene(s) of said C1-3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(0H3)-; and

[0038] R9is H, C1-3 alkyl, oxetanyl, provided that when Y is N, then Z is C(H), and when Z is N, then Y is C(H), or a pharmaceutically acceptable salt thereof. In another main aspect, the present invention concerns a compound of Formula (la) or Formula (lb): wherein

[0039] W is C(H)2or C(D)2;

[0040] R1is H or CH3;

[0041] R2is H;

[0042] R3is H or OCH3;

[0043] A is selected from the group consisting of H, C1-3 alkoxy, CF3, and a group of formula (II):

[0044] Formula (II) wherein

[0045] X is C(H) or N;

[0046] R6is H or C1-4 alkyl optionally substituted with phenyl; and

[0047] R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C-i-e alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s); R7is individually selected from C1-3 alkoxy optionally substituted with one or more F; -OH; -O-benzyl; C1.3 alkyl optionally substituted with OH; N(CH3)2; or when two R7are linked together to form a ring, then said two R7are individually selected from C1.2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said C1-2 alkanediyl is optionally replaced with -O-; or

[0048] R5and R6are linked together to form a ring and

[0049] R5is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); and

[0050] Rsis a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1-5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0051] R8is individually selected from C1-3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1.3 alkanediyl optionally substituted with one or two substituents selected from F, OH and NH2, and one or two methylene(s) of said C1.3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or - N(CH3)-; and

[0052] R9is H, C1.3 alkyl, oxetanyl, or a pharmaceutically acceptable salt thereof.

[0053] In a third aspect, the invention concerns a composition comprising a compound as defined herein. In a fourth aspect, the invention concerns a method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1 comprising administration of a compound as herein described to a subject in need thereof.

[0054] In a fifth aspect, the invention concerns a method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1-4 comprising administration of a compound as herein described to a subject in need thereof.

[0055] Detailed description

[0056] Definitions

[0057] The term ‘WNKT as used herein refers to ‘WNK lysine deficient protein kinase T.

[0058] Other names for WNK1 includes ‘With-No-lysine(K) kinase T,

[0059] The term ‘WNK2’ as used herein refers to ‘WNK lysine deficient protein kinase 2’. Other names for WNK2 includes ‘With-No-lysine(K) kinase 2’,

[0060] The term ‘WNK3’ as used herein refers to ‘WNK lysine deficient protein kinase 3’. Other names for WNK3 includes ‘With-No-lysine(K) kinase 3’,

[0061] The term ‘WNK4’ as used herein refers to ‘WNK lysine deficient protein kinase 4’. Other names for WNK4 includes ‘With-No-lysine(K) kinase 4’,

[0062] The term ‘WNK1-4’ as used herein refers to ‘WNK lysine deficient protein kinases 1-4’.

[0063] The term ’WNK1 inhibitor’ as used herein refers to a chemical compound, which binds to the WNK1 kinase, and which moreover has the ability to reduce, slow, halt or prevent activity the WNK1 kinase. The binding interaction itself, as well as the binding activity can be confirmed by any conventional method for testing binding affinity, known by the skilled person, e.g. those described in the working examples.

[0064] The term ’WNK1-4 inhibitor’ as used herein refers to a chemical compound, which binds to a WNK1-4 kinase, and which moreover has the ability to reduce, slow, halt or prevent activity the WNK1-4 kinase. The binding interaction itself, as well as the binding activity can be confirmed by any conventional method for testing binding affinity, known by the skilled person, e.g. those described in the working examples.

[0065] The terms ‘Ci-6 alkyl’, ‘C1.4 alkyl’, and ‘C1.3 alkyl’ refers to a branched or unbranched alkyl group having from one to three, one to four or one to five carbon atoms respectively, including but not limited to methyl, ethyl, prop-1-yl, prop-2-yl, / so-propyl, tert-butyl, but-1-yl, but-2-yl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methylbut-1-yl, 3- methylbut-1-yl), hex-1 -yl or 2,3-dimethylbut-1-yl.

[0066] The term ‘C3-6 cycloalkyl’ refers to a group having three to six carbon atoms including a monocyclic or bicyclic carbocycle, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0067] The term ‘C1-3 alkoxy’ refers to an C1-3 alkyl group, linear or branched, bonded to an oxygen atom. Examples of C1.3 alkoxy groups includes methoxy, ethoxy, n-propoxy, and isopropoxy.

[0068] The term ‘wherein two Rxare optionally linked together to form a ring together with the intervening atom(s)’ refers to an optionally substituted 3-6-membered (hetero)cyclic ring formed by two Rxsubstituents, together with their intervening atom(s).

[0069] The term ‘intervening atom(s)’ refers to the atom(s) between the two Rxsubstituents. The intervening atom(s) may for example be carbon, nitrogen, or oxygen.

[0070] The terms ’C1.5 alkanediyl’, ‘C1-3 alkanediyl’, and ‘C1-2 alkanediyl’ refers to branched or unbranched alkanediyl group having from one to two, one to three or one to five carbon atoms. The alkanediyl groups are derived by the removal of two hydrogen atoms from a single carbon atom of a parent alkane. Typical alkanediyl groups include, but are not limited to, methanediyl; ethanediyl; propanediyl, butanediyl, or pentanediyl.

[0071] The term “C=O” as well as the term 'C(O)’ refers to a carbonyl group.

[0072] The term “treatment” refers to the combating of a disease or disorder. “Treatment” or “treating,” as used herein, includes any desirable effect on the symptoms or pathology of a disease or condition as described herein, and may include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated. “Treatment” or “treating” does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof. In some embodiments, the term “treatment” encompasses amelioration and prevention.

[0073] The term “alleviating” refers to moderation in the severity of the symptoms of a disease or condition. Improvement in a patient's condition, or the activity of making an effort to correct, or at least make more acceptable, conditions that are difficult to endure related to patient's conditions is considered “ameliorative” treatment.

[0074] The term “prevent” or “preventing” refers to precluding, alleviating, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.

[0075] Compounds

[0076] It is within the scope of the present invention to provide a compound for use in treating, alleviating and / or preventing diseases and disorders characterized in that the WNK1 activity is dysregulated. The compounds of the present invention comprise compounds capable of inhibiting WNK1, thereby reducing or normalising the activity of WNK1.

[0077] In a main aspect, the present invention is a compound of Formula (I):

[0078] Formula (I) wherein

[0079] W is C(H)2or C(D)2;

[0080] Y is C(H) or N;

[0081] Z is C or N;

[0082] R1is H or CH3;

[0083] R2is H;

[0084] R3is H or OCH3; A is selected from the group consisting of H, C1.3 alkoxy, CF3, and a group of formula (II):

[0085] Formula (II) wherein

[0086] X is C(H) or N;

[0087] R6is H or C1-4 alkyl optionally substituted with phenyl; and

[0088] Rsis selected from the group consisting of C1.6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1-6 alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);

[0089] R7is individually selected from C1.3 alkoxy optionally substituted with one or more F; -

[0090] OH; -O-benzyl; C1-3 alkyl optionally substituted with OH; N(CH3)2; N(H)2; or when two R7are linked together to form a ring, then said two R7are individually selected from C1-2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said C1.2 alkanediyl is optionally replaced with -O-; or

[0091] R5and R5are linked together to form a ring and

[0092] R5is a bond or C1.5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); and

[0093] Rsis a bond or C1.5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s); R8is individually selected from C1.3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1-3 alkanediyl optionally substituted with one or two substituents selected from F,OH and NH2, and one or two methylene(s) of said C1-3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-; and

[0094] R9is H, C1-3 alkyl, oxetanyl, provided that when Y is N, then Z is C(H), and when Z is N, then Y is C(H), or a pharmaceutically acceptable salt thereof.

[0095] In another main aspect, the compound of the present invention is a compound of Formula (la) of Formula (lb): wherein

[0096] W is C(H)2or C(D)2;

[0097] R1is H or CH3;

[0098] R2is H;

[0099] R3is H or OCH3;

[0100] A is selected from the group consisting of H, C1-3 alkoxy, CF3, and a group of formula (II):

[0101] Formula (II) wherein

[0102] X is C(H) or N;

[0103] Rsis H or C1- alkyl optionally substituted with phenyl; and R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said Ci-6 alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);

[0104] R7is individually selected from C1-3 alkoxy optionally substituted with one or more F; -OH; -O-benzyl; C1.3 alkyl optionally substituted with OH; N(CH3)2; or when two R7are linked together to form a ring, then said two R7are individually selected from C1.2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said C1-2 alkanediyl is optionally replaced with -O-; or

[0105] R5and R6are linked together to form a ring and

[0106] R5is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); and

[0107] Rsis a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0108] R8is individually selected from C1-3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1.3 alkanediyl optionally substituted with one or two substituents selected from F, OH and NH2, and one or two methylene(s) of said Ci-3alkanediyl is optionally and individually replaced with -O-, -N(H)- or - N(CH3)-; and

[0109] R9is H, C1.3 alkyl, oxetanyl, or a pharmaceutically acceptable salt thereof.

[0110] In one embodiment the compound of the present invention is of Formula (la).

[0111] In one embodiment the compound of the present invention is of Formula (lb).

[0112] In one embodiment W is C(H)2. In one embodiment W is C(D)2.

[0113] In one embodiment R1is H. In one embodiment R1is CH3.

[0114] In one embodiment R3is H. In one embodiment R3is OCH3.

[0115] In one embodiment R1is H, and R2is H. In one embodiment R1is H, R2is H, and R3is H. In one embodiment R1is H, R2is H, and R3is OCH3.

[0116] In one embodiment A is H.

[0117] In one embodiment A is of Formula (II):

[0118] Formula (II) wherein

[0119] X is N;

[0120] R6is H or C1-4 alkyl optionally substituted with phenyl; and

[0121] R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said Ci-e alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s); R7is individually selected from C1-3 alkoxy optionally substituted with one or more F; -OH; -O-benzyl; C1.3 alkyl optionally substituted with OH; N(CH3)2; or when two R7are linked together to form a ring, then said two R7are individually selected from C1.2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said C1-2 alkanediyl is optionally replaced with -O-.

[0122] In one embodiment R6is H. In one embodiment R6is benzyl. In one embodiment R6is C1-4 alkyl. In one embodiment R6is CH3.

[0123] In one embodiment R5is C1.6 alkyl substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1.6 alkyl is optionally and individually replaced with -O- or C=O. In one embodiment R5is -C(O)-Ci-s alkyl. In one embodiment R5is -C(O)C(CH3)3. In one embodiment R5is -C(O)CH2C(CH3)3. In one embodiment R5is C(O)O-Ci-4 alkyl. In one embodiment R5is C(O)OC(CH3)3. In one embodiment R5is C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7. In one embodiment R5is C5 cycloalkyl substituted with one or more, identical or different, substituents R7. In one embodiment R5is Cs cycloalkyl. In one embodiment R5is C5 cycloalkyl substituted with OH. In one embodiment R5is Ce cycloalkyl substituted with one or more, identical or different, substituents R7. In one embodiment R5is Ce cycloalkyl substituted with OH. In one embodiment R5is Ce cycloalkyl substituted with -O-benzyl. In one embodiment R5is Ce cycloalkyl. In one embodiment R7is OH. In one embodiment R7is -O-benzyl.

[0124] In one embodiment A is of Formula (II):

[0125] Formula (II) wherein

[0126] X is N;

[0127] R6is H or C1-4 alkyl optionally substituted with phenyl; and R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said Ci-6 alkyl is optionally and individually replaced with -O- or C=O; or C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; wherein R7is individually selected from -OH; -O-benzyl; C1.3 alkyl.

[0128] In one embodiment A is of Formula (II):

[0129] Formula (II) wherein

[0130] X is N;

[0131] R6is H, CH3, or benzyl; and

[0132] R5is C1-6 alkyl substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1-6 alkyl is optionally and individually replaced with -O- or C=O.

[0133] In one embodiment A is of Formula (II):

[0134] R5> s

[0135] Formula (II) wherein

[0136] X is N;

[0137] R5is H, CH3, or benzyl; and

[0138] R5is C(O)C(CH3)3, C(O)CH2C(CH3)3, C(O)OC(CH3)3, C5cycloalkyl substituted with OH or Ce cycloalkyl substituted with -O-benzyl.

[0139] In one embodiment A is selected from the group consisting of:

[0140] In one embodiment A is of Formula (II):

[0141] R5) R6

[0142] Formula (II) wherein

[0143] X is N;

[0144] R5and R6are linked together to form a ring, and

[0145] R5is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); and

[0146] R6is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0147] R8is individually selected from C1-3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1.3 alkanediyl optionally substituted with one or two substituents selected from F, OH and NH2, and one or two methylene(s) of said C1.3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or - N(CH3)-; and

[0148] R9is H, C-i-3 alkyl, oxetanyl, In one embodiment A is of Formula (II), wherein X is N; R5and R6are linked together to form a ring; and -R5-R6- is C3-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8.

[0149] In one embodiment R8is F.

[0150] In one embodiment, A is of Formula (III):

[0151] Formula (III) wherein

[0152] X1is N or C(H);

[0153] X2is C(R1D)(R11) or absent;

[0154] R10is H or C1.3 alkyl;

[0155] R11is H or C1.3 alkyl;

[0156] X3is C(R12)(R13), O or N(R14);

[0157] R12is H, OH, NH2or C1.3 alkyl optionally substituted with OH; and R13is H or Ci- 3 alkyl optionally substituted with OH; or

[0158] R12and R13are linked together to form a ring together with the intervening atom, and R12- R13is C3-5 alkanediyl wherein one or two methylenes of said alkanediyl is optionally replaced with O, C(H)(NH2) or N(R17);

[0159] R17is H or C1.3 alkyl;

[0160] R14is H, C1.3 alkyl, oxetanyl

[0161] X4is C(R15)(R16) or absent;

[0162] R15is H; OH; C1-3 alkyl optionally substituted with OH; or OC1-3 alkyl optionally substituted with one or more F; and R16is H.

[0163] In one embodiment, A is pyrrolidinyl optionally substituted with one or more individually selected R8, wherein two R8are optionally linked together to form a ring together with the intervening atom(s); R8is individually selected from C1.3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1-3 alkanediyl optionally substituted with one or two substituents selected from F,OH and NH2, and one or two methylene(s) of said C1-3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-.

[0164] In one embodiment the pyrrolidinyl is attached to Formula (I) in position 1 of the pyrrolidinyl. In one embodiment the pyrrolidinyl is attached to Formula (la) or Formula (lb) in position 1 of the pyrrolidinyl.

[0165] In one embodiment A is

[0166] In one embodiment A is H.

[0167] In one embodiment the compound is of formula (la) or formula (lb); W is C(H)2; R1is H or CHs; R2is H; R3is H or OCHs; A is H, C1-3 alkoxy, CF3, or a group of formula (II):

[0168] RsxA A

[0169] R6

[0170] Formula (II).

[0171] In one embodiment the compound is of formula (la) or formula (lb); W is C(H)2; R1is H or CH3; R2is H; R3is H or OCH3; and A is H, or a group of formula (II).

[0172] In one embodiment the compound is of formula (la) or formula (lb); W is C(H)2; R1is H or CH3; R2is H; R3is H or OCH3; and A is H, C1.3 alkoxy, CF3, or a group of formula (II), wherein X is N; R6is H, CH3, or benzyl; and R5is C(O)C(CH3)3, C(O)CH2C(CH3)3, C(O)OC(CH3)3, CB cycloalkyl substituted with OH or CB cycloalkyl substituted with -O- benzyl.

[0173] In one embodiment the compound is of formula (la) or formula (lb); W is C(H)2; R1is H;

[0174] R2is H; R3is H or OCH3; and A is H,

[0175] In one embodiment the compound of the present invention is selected from the group consisting of:

[0176] N-(1 H-indol-4-ylmethyl)imidazo[1 ,2-a]pyridine-3-carboxamide, tert-butyl N-{3-[( 1 H-indol-4-ylmethyl)carbamoyl]pyrazolo[1 , 5-a] py ri di n-5- yl}carbamate, 5-(2,2-dimethylpropanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1 ,5-a]pyridine-3- carboxamide,

[0177] 5-(3,3-dimethylbutanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1,5-a]pyridine-3- carboxamide, N-[(7-methoxy-1 H-indol-4-yl)methyl]imidazo[1 ,2-a]pyridine-3-carboxamide,

[0178] 6-(3,3-difluoropyrrolidin-1-yl)-N-[(7-methoxy-1 H-indol-4-yl)methyl]imidazo[1,2- a]pyridine-3-carboxamide, 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1 ,2-a]pyridine-3-carboxamide, 6-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1 ,2-a]pyridine-3-carboxamide, 6-{[(1S,3S)-3-hydroxycyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1 ,2-a]pyridine-3-carboxamide, 5-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1 ,5-a]pyridine-3-carboxamide, and 5-{[(1S,3S)-3-hydroxycyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1 ,5-a]pyridine-3-carboxamide.

[0179] In one embodiment the compound of the present invention is selected from the group consisting of:

[0180]

[0181] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1 H- and 3H- imidazole, 1 H-, 2H- and 4H- 1 ,2,4-triazole, 1 H- and 2H- isoindole, and 1 H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Tautomeric forms can also include methyltropic tautomers, which result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a methyl group. All compounds described herein, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates).

[0182] In one aspect, the present invention is directed to an intermediate compound, or a pharmaceutically acceptable salt thereof, which can be used in the synthesis of the compounds of the present invention. For example, said intermediate compound is in some embodiments one of the intermediate compounds, or a pharmaceutically acceptable salt thereof, of Example 1 disclosed herein. In some embodiments the compound of the present invention is selected from any of the intermediate compounds, or a pharmaceutically acceptable salt thereof, disclosed in example 1 herein.

[0183] The compounds of the present invention may contain, for example, one or more asymmetric carbon atoms, and therefore may exist as stereoisomers, enantiomers and diastereomers. Accordingly, the scope of the instant invention is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form and stereoisomeric mixtures of any chemical structures disclosed herein, unless the stereochemistry is specifically identified. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated.

[0184] The term “stereoisomer” or “stereoisomerically pure” compound as used herein refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.

[0185] In some embodiments, the compound as defined herein is stereoisomerically pure.

[0186] Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents, for example as outlined in the example section.

[0187] Preparation of compounds

[0188] Compounds according to the present invention may be prepared according to any conventional methods of chemical synthesis known by the skilled person, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods known by the skilled artisan from commercially available chemicals.

[0189] The end products of the reactions described herein may be isolated by conventional technique such as extraction, crystallisation, distillation, chromatography etc.

[0190] The compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

[0191] Pharmaceutically Acceptable Salts

[0192] The chemical compound of the invention may be provided in any form suitable for the intended administration, including pharmaceutically (i.e. physiologically) acceptable salts. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, and the like. Such salts may be formed by procedures well known and described in the art. Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.

[0193] Examples of pharmaceutically acceptable cationic salts of a compound of Formula (I), Formula (la) or Formula (lb) of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the zinc, the aluminium, the lithium, the choline, the lysinium, and the ammonium salt, and the like, of a compound of Formula (I), Formula (la) or Formula (lb) of the invention containing an anionic group. Such cationic salts may be formed by procedures well known and described in the art. In the context of this invention the "onium salts" of A / -containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

[0194] Labelled Compounds

[0195] The chemical compound of the present invention may be used in its labelled or unlabelled form. In the context of this invention the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling will allow easy quantitative detection of said compound.

[0196] The labelled compounds of the invention may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging. The labelled isomer of the invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is preferably selected from2H (deuterium),3H (tritium),13C,14C,131l,125l,123l, and18F.

[0197] The physical method for detecting the labelled isomer of the present invention may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof. Pharmaceutical compositions

[0198] The present invention also relates to a pharmaceutical composition comprising, for example as an active ingredient, a pharmaceutically effective amount of a compound of Formula (I), Formula (la) or Formula (lb), as defined above. In one embodiment, said pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (I), Formula (la) or Formula (lb), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0199] In one embodiment, the present invention is a pharmaceutical composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0200] In one embodiment, the present invention is a pharmaceutical composition comprising a compound of Formula (lb), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0201] While the compound of Formula (I), Formula (la) or Formula (lb), of the present invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0202] In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0203] A therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, e.g. ED5o, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by ratio between plasma levels resulting in therapeutic effects and plasma ratios resulting in toxic effects. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.

[0204] The dose administered may be adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage can be determined by the practitioner.

[0205] The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 0.1 to about 10.000 mg of active ingredient per individual dose are suitable for therapeutic treatments. In some embodiments, the subject is administered a dose of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the range of 0.001 - 100 mg / kg.

[0206] In one embodiment, a compound of Formula (I) is administered in combination with one or more additional therapeutically active ingredient. In one embodiment, the additional therapeutically active ingredient is known for treating hypertension or cancer.

[0207] WNK1 inhibition

[0208] The series of compounds of Formula (I), including the compounds of Formula (la) or Formula (lb), bind to WNK1. By virtue of this binding interaction, the compounds are capable of modulating WNK1.

[0209] WNK463 (A / -(terf-butyl)-1-(1-(5-(5-(trifluoromethyl)-1 ,3,4-oxadiazol-2-yl)pyridin-2- yl)piperidin-4-yl)-1 / 7-imidazole-5-carboxamide) is known to be an inhibitor of WNK1 catalytic activity (Yamada et al., 2016). As demonstrated in Example 2, the compounds of the present invention compete for the same site of WNK1 kinase as WNK463. Hence, the compounds of the present invention are inhibitors of WNK1 catalytic activity.

[0210] In one embodiment the compound of Formula (I) is a WNK lysine deficient protein kinase 1 (WNK1) inhibitor. In one embodiment the compound of Formula (la) is a WNK lysine deficient protein kinase 1 (WNK1) inhibitor.

[0211] In one embodiment the compound of Formula (lb) is a WNK lysine deficient protein kinase 1 (WNK1) inhibitor.

[0212] To further test that compounds are WNK1 inhibitors, their capability of inhibiting in vitro phosphorylation of myelin basic protein (MBP) by purified recombinant human WNK1 may be tested as described in Yamada et al., 2016a. Furthermore, the capability of inhibiting phosphorylation of the native substrate OSR1 by purified recombinant WNK1 kinase domain in vitro, and exogenously expressed OSR1 in HEK293 cells following sorbitol-induced osmotic stress may also be tested as described in Yamada et al., 2016a.

[0213] In one aspect, the present invention relates to a method of inhibiting WNK1 , said method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0214] WNK1-4 inhibition

[0215] The series of compounds of Formula (I), including the compounds of Formula (la) or Formula (lb), bind to WNK1-4. By virtue of this binding interaction, the compounds are capable of modulating WNK1-4.

[0216] In one embodiment, the compound of Formula (I) is a WNK lysine deficient protein kinase 1-4 (WNK1-4) inhibitor.

[0217] In one aspect, the present invention relates to a method of inhibiting WNK1-4, said method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0218] In one embodiment, the compound of Formula (I) is a WNK lysine deficient protein kinase 2 (WNK2) inhibitor.

[0219] In one aspect, the present invention relates to a method of inhibiting WNK2, said method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is a WNK lysine deficient protein kinase 3 (WNK3) inhibitor.

[0220] In one aspect, the present invention relates to a method of inhibiting WNK3, said method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0221] In one embodiment, the compound of Formula (I) is a WNK lysine deficient protein kinase 4 (WNK4) inhibitor.

[0222] In one aspect, the present invention relates to a method of inhibiting WNK4, said method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0223] Treatment

[0224] Being ligands for WNK1 , compound of Formula (I), including the compounds of respectively Formula (la) or Formula (lb), are of use in the treatment, prevention, and / or alleviation of disorders of a living body, including human. As used herein, the term “treatment” also includes prevention, and / or alleviation of diseases and disorders. In one aspect, the compound of formula (I) as described herein is for use in medicine.

[0225] In one aspect, the present invention concerns a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0226] In one embodiment, the present invention is a compound of Formula (la), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0227] In one embodiment, the present invention concerns a compound of Formula (lb), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0228] In one aspect, the present invention concerns a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating, alleviating or preventing diseases and disorders related to the activity of WNK1. In another aspect, the present invention concerns a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating, alleviating or preventing diseases and disorders related to the activity of WNK1-4, such as WNK1 , WNK2, WNK3 and / or WNK4.

[0229] In one embodiment, the present invention concerns a compound of Formula (la), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating, alleviating or preventing diseases and disorders related to the activity of WNK1.

[0230] In one embodiment, the present invention concerns a compound of Formula (lb), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating, alleviating or preventing diseases and disorders related to the activity of WNK1.

[0231] In one aspect, the present invention concerns a method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1 , said method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0232] In another aspect, the present invention concerns a method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1-4, such as WNK1 , WNK2, WNK3 and / or WNK4, said method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0233] In one embodiment, the present invention concerns a method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1 , said method comprising administering a compound of Formula (la), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0234] In one embodiment, the present invention concerns a method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1 , said method comprising administering a compound of Formula (lb), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0235] In one aspect, the present invention concerns the use of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating, alleviating or preventing diseases and disorders related to the activity of WNK1.

[0236] In one aspect, the present invention concerns the use of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating, alleviating or preventing diseases and disorders related to the activity of WNK1-4, such as WNK1, WNK2, WNK3 and / or WNK4.

[0237] In one embodiment, the present invention concerns the use of a compound of Formula

[0238] (la), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating, alleviating or preventing diseases and disorders related to the activity of WNK1.

[0239] In one embodiment, the present invention concerns the use of a compound of Formula

[0240] (lb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating, alleviating or preventing diseases and disorders related to the activity of WNK1.

[0241] Treatment of hypertension

[0242] WNK1 inhibitors have been demonstrated to be effectful in the treatment or prevention of various diseases and disorders associated with increased WNK1 activity, including hypertension. Being ligands for WNK1 , the compounds of Formula (I), Formula (la) or of Formula (lb), are of use in the treatment, prevention, and / or alleviation of different types of hypertension, including familial hyperkalemic hypertension (FHHt and pseudohypoaldosteronism type II (PHAII) disorders of a living body, including human.

[0243] In one aspect, the present invention relates to a compound of formula (I) as described herein for use in the treatment, alleviation and / or prevention of hypertension. In one aspect, the present invention relates to a compound of formula (I) as described herein for use in the treatment, alleviation and / or prevention of inherited hypertension.

[0244] In one aspect, the present invention relates to a method for treating and / or preventing hypertension, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0245] Preferably, the subject is a mammal, such as a human. In some embodiments, the subject is suffering from hypertension.

[0246] In some embodiments, the subject is having, is suspected of having, or at risk of developing hypertension. In some embodiments, the subject is a human subject having, suspected of having, or at risk of developing hypertension.

[0247] In one aspect, the present invention concerns a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of hypertension.

[0248] In one embodiment, the present invention concerns a compound of Formula (la), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of hypertension.

[0249] In one embodiment, the present invention concerns a compound of Formula (lb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of hypertension.

[0250] In one aspect, the present invention concerns a method for treatment of hypertension, comprising administering a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0251] In one embodiment, the present invention concerns a method for treatment of hypertension, comprising administering a compound of Formula (la), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof. In one embodiment, the present invention concerns a method for treatment of hypertension, comprising administering a compound of Formula (lb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0252] In one aspect, the present invention concerns the use of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of hypertension.

[0253] In one embodiment, the present invention concerns the use of a compound of Formula

[0254] (la), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of hypertension.

[0255] In one embodiment, the present invention concerns the use of a compound of Formula

[0256] (lb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of hypertension.

[0257] Treatment of cancer

[0258] WNK1 inhibitors have been demonstrated to be effectful in the treatment or prevention of various diseases and disorders associated with increased WNK1 activity, including cancer. Being ligands for WNK1, the compounds of Formula (I), Formula (la) or of Formula (lb), are of use in the treatment, prevention, and / or alleviation of different types of cancer, including breast cancer, colon cancer, pancreatic cancer, such as pancreatic ductal adenocarcinoma and blood cancers, such as leukemia, including acute myeloid leukemia, lymphoma and myeloma, including multiple myeloma.

[0259] In one aspect, the present invention relates to a compound of formula (I) as described herein for use in the treatment, alleviation and / or prevention of cancer.

[0260] In one aspect, the present invention relates to a method for treating and / or preventing cancer the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0261] Preferably, the subject is a mammal, such as a human. In some embodiments, the subject is suffering from cancer. In one aspect, the present invention concerns a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0262] In one embodiment, the present invention concerns a compound of Formula (la), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0263] In one embodiment, the present invention concerns a compound of Formula (lb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0264] In one aspect, the present invention concerns a method for treatment of cancer, comprising administering a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0265] In one embodiment, the present invention concerns a method for treatment of cancer, comprising administering a compound of Formula (la), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0266] In one embodiment, the present invention concerns a method for treatment of cancer, comprising administering a compound of Formula (lb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0267] In one aspect, the present invention concerns the use of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer.

[0268] In one embodiment, the present invention concerns the use of a compound of Formula (la), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer. In one embodiment, the present invention concerns the use of a compound of Formula (lb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer.

[0269] In one embodiment, the cancer is selected from the group consisting of Adenoid cystic carcinoma, Anal cancer, Appendix cancer and PMP, Bile duct cancer (cholangiocarcinoma), Bladder cancer, Blood cancer, Bone cancer (Primary), Bone cancer (Secondary), Bowel cancer, Brain tumours, Breast cancer, Cancer of the uterus, Cancer of unknown primary, Cervical cancer, Connective tissue cancer, Endocrine cancer, Gall bladder (bile duct) cancer, Head, neck and throat cancers, Kaposi sarcoma, Kidney cancer, Leukaemia, Liver cancer (Primary), Liver cancer (Secondary), Lung cancer, Lymphoma, Melanoma, Mesothelioma, Myeloma, Neuroendocrine tumours (NETs), Ocular (uveal) melanoma, Ovarian cancer, Pancreatic cancer, Penile cancer, Peritoneal cancer, Prostate cancer, Skin cancer, Small bowel cancer, Soft tissue sarcoma, Stomach and oesophageal cancers, Testicular cancer, Thymus cancer, Thyroid cancer, Upper tract urothelial cancer, Vaginal cancer and Vulvar cancer.

[0270] In one embodiment, the cancer is selected from the group consisting of Acute Myeloid Leukemia (LAML), Adrenocortical carcinoma (ACC), Bladder Urothelial Carcinoma (BLCA), Brain Lower Grade Glioma (LGG), Breast invasive carcinoma (BRCA), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Cholangiocarcinoma (CHOL), Chronic Myelogenous Leukemia (LCML), Colon adenocarcinoma (COAD), Esophageal carcinoma (ESCA), Glioblastoma multiforme (GBM), Head and Neck squamous cell carcinoma (HNSC), Kidney Chromophobe (KICH), Kidney renal clear cell carcinoma (KIRC), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC), Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC), Mesothelioma (MESO), Ovarian serous cystadenocarcinoma (OV), Pancreatic adenocarcinoma (PAAD), Pheochromocytoma and Paraganglioma (PCPG), Prostate adenocarcinoma (PRAD), Rectum adenocarcinoma (READ), Sarcoma (SARC), Skin Cutaneous Melanoma (SKCM), Stomach adenocarcinoma (STAD), Testicular Germ Cell Tumors (TGCT), Thymoma (THYM), Thyroid carcinoma (THCA), Uterine Carcinosarcoma (UCS), Uterine Corpus Endometrial Carcinoma (UCEC), and Uveal Melanoma (UVM). In one embodiment, the cancer is selected from the group consisting of leukemia, including acute myeloid leukemia, lymphoma and myeloma, including multiple myeloma.

[0271] Items

[0272] 1 . A compound of formula

[0273] Formula (I) wherein

[0274] W is C(H)2or C(D)2;

[0275] Y is C(H) or N;

[0276] Z is C or N;

[0277] R1is H or CH3;

[0278] R2is H;

[0279] R3is H or OCH3;

[0280] A is selected from the group consisting of H, C1-3 alkoxy, CF3, and a group of formula (II):

[0281] Formula (II) wherein

[0282] X is C(H) or N;

[0283] Rsis H or C1-4 alkyl optionally substituted with phenyl; and

[0284] R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1.6 alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);

[0285] R7is individually selected from C1-3 alkoxy optionally substituted with one or more F; -OH; -O-benzyl; C1.3 alkyl optionally substituted with OH; or when two R7are linked together to form a ring, then said two R7are individually selected from C1-2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said Ci-2 alkanediyl is optionally replaced with -O-; or

[0286] R5and R6are linked together to form a ring and

[0287] R5is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1-5 alkanediyl is optionally replaced with -O- or N(R9); and

[0288] Rsis a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1-5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0289] R8is individually selected from C1-3 alkyl optionally substituted with OH; - OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1-3 alkanediyl optionally substituted with one or two substituents selected from F, OH and NH2, and one or two methylene(s) of said C1-3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-; and

[0290] R9is H, C1-3 alkyl, oxetanyl, provided that when Y is N, then Z is C(H), and when Z is N, then Y is C(H), or a pharmaceutically acceptable salt thereof. A compound of formula (la) or formula (lb):

[0291] Formula (la) Formula (lb) wherein

[0292] W is C(H)2or C(D)2;

[0293] R1is H or CH3;

[0294] R2is H;

[0295] R3is H or OCH3;

[0296] A is selected from the group consisting of H, C1-3 alkoxy, CF3, and a group of formula (II):

[0297] Formula (II) wherein

[0298] X is C(H) or N;

[0299] R6is H or C1-4 alkyl optionally substituted with phenyl; and

[0300] R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said Ci-e alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);

[0301] R7is individually selected from C1-3 alkoxy optionally substituted with one or more F; -OH; -O-benzyl; C1.3 alkyl optionally substituted with OH; or when two R7are linked together to form a ring, then said two R7are individually selected from C1-2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said C1.2 alkanediyl is optionally replaced with -O-; or

[0302] R5and R6are linked together to form a ring and

[0303] R5is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1-5 alkanediyl is optionally replaced with -O- or N(R9); and

[0304] R6is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1-5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0305] R8is individually selected from C1-3 alkyl optionally substituted with OH; - OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1-3 alkanediyl optionally substituted with one or two substituents selected from F,OH and NH2, and one or two methylene(s) of said C1-3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-; and

[0306] R9is H, C1-3 alkyl, oxetanyl, or a pharmaceutically acceptable salt thereof. compound of formula

[0307] Formula (I) wherein

[0308] W is C(H)2or C(D)2;

[0309] Y is C(H) or N;

[0310] Z is C or N; R1is H or CH3;

[0311] R2is H;

[0312] R3is H or OCH3;

[0313] A is a group of formula (III):

[0314] Formula (III) wherein

[0315] X1is N or C(H);

[0316] X2is C(R10)(R11) or absent;

[0317] R10is H or C1.3 alkyl;

[0318] R11is H or C1.3 alkyl;

[0319] X3is C(R12)(R13), O or N(R14);

[0320] R12is H, OH, NH2 or C1-3 alkyl optionally substituted with OH; and R13is H or C1-3 alkyl optionally substituted with OH; or

[0321] R12and R13are linked together to form a ring together with the intervening atom, and R12- R13is C3-5 alkanediyl wherein one or two methylenes of said alkanediyl is optionally replaced with O, C(H)(NH2) or N(R17);

[0322] R17is H or C1.3 alkyl;

[0323] R14is H, C1.3 alkyl, oxetanyl

[0324] X4is C(R15)(R16) or absent;

[0325] R15is H; OH; C1.3 alkyl optionally substituted with OH; or OC1-3 alkyl optionally substituted with one or more F; and

[0326] R16is H.

[0327] 4. A compound of formula

[0328] Formula (I) wherein

[0329] W is C(H)2or C(D)2;

[0330] Y is C(H) or N;

[0331] Z is C or N;

[0332] R1is H or CH3;

[0333] R2is H;

[0334] R3is H or OCH3;

[0335] A is piperidinyl, pyrrolidi nyl , azetidinyl, piperazinyl, or morpholinyl, wherein said piperidinyl, pyrrolidinyl, or azetidinyl, is optionally substituted with one or more individually selected R18, wherein two R18are optionally linked together to form a ring together with the intervening atom(s); wherein said piperazinyl is optionally substituted with R14; and wherein said morpholinyl is optionally substituted with one or more, identical or different, substituents R19;

[0336] R18is individually selected from Ci-3alkyl optionally substituted with OH; - OH; F; N(H)2; and -OCi-3alkyl optionally substituted with one or more F, or when two R18are linked together to form a ring, then said two R18are individually selected from Ci-3alkanediyl optionally substituted with one or two substituents selected from F, OH, and NH2, and one or two methylene(s) of said Ci-3alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-;

[0337] R14is Ci.3alkyl, oxetanyl

[0338] R19is individually selected from Ci-3alkyl and Ci-3alkyl substituted with OH. The compound according to item 1 , wherein the compound is of formula

[0339] (la). The compound according to item 1 , wherein the compound is of formula

[0340] (lb). The compound according to anyone of the preceding items, wherein W is C(H)2. 8. The compound according to anyone of the preceding items, wherein W is C(D)2.

[0341] 9. The compound according to anyone of the preceding items, wherein R1is H.

[0342] 10. The compound according to anyone of the preceding items, wherein R1is CH3.

[0343] 11 . The compound according to anyone of the preceding items, wherein R3is H.

[0344] 12. The compound according to anyone of the preceding items, wherein R3is OCH3.

[0345] 13. The compound according to anyone of the preceding items, wherein R1is H, and R2is H.

[0346] 14. The compound according to anyone of the preceding items, wherein R1is H, R2is H, and R3is H.

[0347] 15. The compound according to anyone of the preceding items, wherein R1is H, R2is H, and R3is OCH3.

[0348] 16. The compound according to anyone of the preceding items, wherein A is of Formula (II):

[0349] Formula (II) wherein

[0350] X is N;

[0351] R6is H or C1-4 alkyl optionally substituted with phenyl; and

[0352] R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1.6 alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);

[0353] R7is individually selected from C1-3 alkoxy optionally substituted with one or more F; -OH; -O-benzyl; C1.3 alkyl optionally substituted with OH; or when two R7are linked together to form a ring, then said two R7are individually selected from C1-2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said Ci-2 alkanediyl is optionally replaced with -O-. The compound according to anyone of the preceding items, wherein A is of Formula (II):

[0354] Formula (II) wherein

[0355] X is N;

[0356] Rsis H or C1-4 alkyl optionally substituted with phenyl; and

[0357] R5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1.6 alkyl is optionally and individually replaced with -O- or C=O; or C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; wherein R7is individually selected from -OH; -O-benzyl; C1.3 alkyl. The compound according to anyone of the preceding items, wherein A is of Formula (II):

[0358] Formula (II) wherein

[0359] X is N;

[0360] R6is H, CH3, or benzyl; and

[0361] R5is C1-6 alkyl substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1-6 alkyl is optionally and individually replaced with -O- or C=O.

[0362] 19. The compound according to anyone of the preceding items, wherein A is of Formula (II):

[0363] Formula (II) wherein

[0364] X is N;

[0365] Rsis H, CH3, or benzyl; and

[0366] 20. R5is C(O)C(CH3)3, C(O)CH2C(CH3)3, C(O)OC(CH3)3, C6cycloalkyl substituted with OH or Ce cycloalkyl substituted with -O-benzyl.The compound according to anyone of the preceding items, wherein R6is H.

[0367] 21 . The compound according to anyone of the preceding items, wherein R6is benzyl.

[0368] 22. The compound according to anyone of the preceding items, wherein R6is C1-4 alkyl.

[0369] 23. The compound according to anyone of the preceding items, wherein R6is CH3.

[0370] 24. The compound according to anyone of the preceding items, wherein R5is

[0371] C1-5 alkyl substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1-6 alkyl is optionally and individually replaced with -O- or C=O.

[0372] 25. The compound according to anyone of the preceding items, wherein R5is - C(O)-Ci-5alkyl.

[0373] 26. The compound according to anyone of the preceding items, wherein R5is - C(O)C(CH3)3.

[0374] 27. The compound according to anyone of the preceding items, wherein R5is - C(O)CH2C(CH3)3.

[0375] 28. The compound according to anyone of the preceding items, wherein R5is C(O)O-Ci-4alkyl.

[0376] 29. The compound according to anyone of the preceding items, wherein R5is C(O)OC(CH3)3.

[0377] 30. The compound according to anyone of the preceding items, wherein R5is C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R7.

[0378] 31 . The compound according to anyone of the preceding items, wherein R5is Cs cycloalkyl substituted with one or more, identical or different, substituents R7.

[0379] 32. The compound according to anyone of the preceding items, wherein R5is C5 cycloalkyl substituted with OH.

[0380] 33. The compound according to anyone of the preceding items, wherein R5is Ge cycloalkyl substituted with one or more, identical or different, substituents R7.

[0381] 34. The compound according to anyone of the preceding items, wherein R5is Ge cycloalkyl substituted with OH. 35. The compound according to anyone of the preceding items, wherein R5is Ge cycloalkyl substituted with -O-benzyl.

[0382] 36. The compound according to anyone of the preceding items, wherein R5is Ge cycloalkyl.

[0383] 37. The compound according to anyone of the preceding items, wherein R7is OH.

[0384] 38. The compound according to anyone of the preceding items, wherein R7is - O-benzyl.

[0385] 39. The compound according to anyone of the preceding items, wherein A is selected from the group consisting of:

[0386] 40. The compound according to any one of the preceding items, wherein A is of Formula (II):

[0387] Formula (II) wherein

[0388] X is N;

[0389] R5and R6are linked together to form a ring, and

[0390] R5is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); and R6is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1.5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0391] R8is individually selected from C1-3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1.3 alkanediyl optionally substituted with one or two substituents selected from F,OH and NH2, and one or two methylene(s) of said C1.3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or - N(CH3)-; and

[0392] R9is H, C1.3 alkyl, oxetanyl,

[0393] 41 . The compound according to any one of the preceding items, wherein A is of Formula (II), wherein X is N; R5and R6are linked together to form a ring; and -R5-R6- is C3-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8.

[0394] 42. The compound according to any one of the preceding items, wherein R8is F.

[0395] 43. The compound according to anyone of the preceding items, wherein A is of Formula (III):

[0396] Formula (III) wherein

[0397] X1is N or C(H);

[0398] X2is C(R10)(R11) or absent;

[0399] R10is H or C1.3 alkyl;

[0400] R11is H or C1.3 alkyl; X3is C(R12)(R13), O or N(R14);

[0401] R12is H, OH, NH2 or C1.3 alkyl optionally substituted with OH; and R13is H or Ci. 3 alkyl optionally substituted with OH; or

[0402] R12and R13are linked together to form a ring together with the intervening atom, and R12- R13is C3-5 alkanediyl wherein one or two methylenes of said alkanediyl is optionally replaced with O, C(H)(NH2) or N(R17);

[0403] R17is H or C1.3 alkyl;

[0404] R14is H, C1.3 alkyl, oxetanyl

[0405] X4is C(R15)(R16) or absent;

[0406] R15is H; OH; C1-3 alkyl optionally substituted with OH; or OC1-3 alkyl optionally substituted with one or more F; and

[0407] R16is H.

[0408] 44. The compound according to anyone of the preceding items, wherein A is piperidinyl, pyrrolidi nyl , azetidinyl, or piperazinyl, wherein said piperidinyl, pyrrolidinyl, azetidinyl, or piperazinyl is optionally substituted with one or more individually selected R18, wherein R18is -CH3, -CH2OH, -OH, N(H)2, o H N . .U J ' -1"1' OCHF2, -F, oxetanyl or

[0409] 45. The compound according to anyone of the preceding items, wherein A is piperidinyl, pyrrolidinyl, azetidinyl or piperazinyl, wherein said piperidinyl, pyrrolidinyl, azetidinyl, or piperazinyl is substituted with two or more R18, wherein two R18are linked together to form a ring together with the intervening atom(s), and wherein the two R18linked together to form a ring are individually selected from C1.3 alkanediyl optionally substituted with one or two substituents selected from F, OH and -NH2, and wherein one or two methylene(s) of said C1.3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-.

[0410] 46. The compound according to anyone of the preceding items, wherein A is morpholinyl, wherein said morpholinyl optionally substituted with one or more, identical or different, substituents R19, wherein R19is -CH3, or - CH2OH. The compound according to anyone of the preceding items, wherein A is pyrrolidinyl optionally substituted with one or more individually selected R8, wherein two R8are optionally linked together to form a ring together with the intervening atom(s);

[0411] R8is individually selected from C1-3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1.3 alkanediyl optionally substituted with one or two substituents selected from F,OH and NH2, and one or two methylene(s) of said C1.3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-. The compound according to anyone of the preceding items, wherein A is pyrrolidinyl optionally substituted with one or more individually selected R8, wherein R8is selected from C1.3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F. The compound according to anyone of the preceding items, wherein the pyrrolidinyl is attached to Formula (I) in position 1 of the pyrrolidinyl. The compound according to anyone of the preceding items, wherein A is

[0412] F\Z'^

[0413] F' J The compound according to anyone of the preceding items, wherein A is H. The compound according to anyone of the preceding items, wherein the compound is of formula (la) or formula (lb); W is C(H)2; R1is H or CH3; R2is H; R3is H or OCH3; A is H, C1-3 alkoxy, CF3, or a group of formula (II):

[0414] Formula (II). The compound according to anyone of the preceding items, wherein the compound is of formula (la) or formula (lb); W is C(H)2; R1is H or CH3; R2is H; R3is H or OCHs; and A is H, C1.3 alkoxy, CF3, or a group of formula (II):

[0415] R5

[0416] R6

[0417] Formula (II). The compound according to anyone of the preceding items, wherein the compound is of formula (la) or formula (lb); W is C(H)2; R1is H or CHs; R2is H; R3is H or OCHs; and A is H, C1.3 alkoxy, CF3, or a group of formula (II):

[0418] R5XR- 6

[0419] Formula (II) wherein

[0420] X is N;

[0421] R6is H, CH3, or benzyl; and

[0422] R5is C(O)C(CH3)3, C(O)CH2C(CH3)3, C(O)OC(CH3)3, C6cycloalkyl substituted with OH or Ce cycloalkyl substituted with -O-benzyl. The compound according to anyone of the preceding items, wherein the compound is of formula (la) or formula (lb); W is C(H)2; R1is H; R2is H; R3is H or OCH3; and A is H, The compounds according to anyone of the preceding items, wherein the compound is selected from the group consisting of:

[0423] N-(1 H-indol-4-ylmethyl)imidazo[1 ,2-a]pyridine-3-carboxamide, tert-butyl N-{3-[(1 H-indol-4-ylmethyl)carbamoyl]pyrazolo[1 ,5-a]pyridin-5- yl}carbamate,

[0424] 5-(2,2-dimethylpropanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1 ,5- a] py ri d i ne-3-ca rboxa m i d e ,

[0425] 5-(3,3-dimethylbutanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1,5- a]pyridine-3-carboxamide,

[0426] N-[(7-methoxy-1 H-indol-4-yl)methyl]imidazo[1 ,2-a]pyridine-3- carboxamide,

[0427] 6-(3,3-difluoropyrrolidin-1-yl)-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide,

[0428] 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide,

[0429] 6-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide,

[0430] 6-{[(1S,3S)-3-hydroxycyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide,

[0431] 5-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1 ,5-a]pyridine-3-carboxamide, and

[0432] 5-{[(1S,3S)-3-hydroxycyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1 ,5-a]pyridine-3-carboxamide. he compounds according to anyone of the preceding items, wherein the compound is selected from the group consisting of: The compound according to any one of the preceding items, wherein the compound is a WNK lysine deficient protein kinase 1 (WNK1) inhibitor. The compound according to any one of the preceding items, wherein the compound is a WNK lysine deficient protein kinase 2 (WNK2) inhibitor. The compound according to any one of the preceding items, wherein the compound is a WNK lysine deficient protein kinase 3 (WNK3) inhibitor. The compound according to any one of the preceding items, wherein the compound is a WNK lysine deficient protein kinase 4 (WNK4) inhibitor. A pharmaceutical composition comprising a compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents. The compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for use as a medicament. The compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for use in treating, alleviating or preventing diseases and disorders related to the activity of WNK1 . The compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for use in treating, alleviating or preventing diseases and disorders related to the activity of WNK1-4, such as WNK1, WNK2, WNK3 and / or WNK4. A method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1 , said method comprising administering a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, to a subject in need thereof. A method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1-4, said method comprising administering a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, to a subject in need thereof. Use of a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for the manufacture of a medicament for treating, alleviating or preventing diseases and disorders related to the activity of WNK1. Use of a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for the manufacture of a medicament for treating, alleviating or preventing diseases and disorders related to the activity of WNK1-4. The compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for use in the treatment of hypertension. 71 . A method for treatment of hypertension, comprising administering a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, to a subject in need thereof.

[0433] 72. Use of a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for the manufacture of a medicament for the treatment of hypertension.

[0434] 73. The compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for use in the treatment of cancer.

[0435] 74. A method for treatment of cancer, comprising administering a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, to a subject in need thereof.

[0436] 75. Use of a compound according to any one of items 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 62, for the manufacture of a medicament for the treatment of cancer.

[0437] 76. The compound or pharmaceutical composition for use according to item 68, the method according to 71 , or the use according to 72, wherein the cancer is selected from the group consisting of Adenoid cystic carcinoma, Anal cancer, Appendix cancer and PMP, Bile duct cancer (cholangiocarcinoma), Bladder cancer, Blood cancer, Bone cancer (Primary), Bone cancer (Secondary), Bowel cancer, Brain tumours, Breast cancer, Cancer of the uterus, Cancer of unknown primary, Cervical cancer, Connective tissue cancer, Endocrine cancer, Gall bladder (bile duct) cancer, Head, neck and throat cancers, Kaposi sarcoma, Kidney cancer, Leukaemia, Liver cancer (Primary), Liver cancer (Secondary), Lung cancer, Lymphoma, Melanoma, Mesothelioma, Myeloma, Neuroendocrine tumours (NETs), Ocular (uveal) melanoma, Ovarian cancer, Pancreatic cancer, Penile cancer, Peritoneal cancer, Prostate cancer, Skin cancer, Small bowel cancer, Soft tissue sarcoma, Stomach and oesophageal cancers, Testicular cancer, Thymus cancer, Thyroid cancer, Upper tract urothelial cancer, Vaginal cancer and Vulvar cancer. The compound or pharmaceutical composition for use according to item 68, the method according to 71 , or the use according to 75, wherein the cancer is selected from the group consisting of Acute Myeloid Leukemia (LAML), Adrenocortical carcinoma (ACC), Bladder Urothelial Carcinoma (BLCA), Brain Lower Grade Glioma (LGG), Breast invasive carcinoma (BRCA), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Cholangiocarcinoma (CHOL), Chronic Myelogenous Leukemia (LCML), Colon adenocarcinoma (COAD), Esophageal carcinoma (ESCA), Glioblastoma multiforme (GBM), Head and Neck squamous cell carcinoma (HNSC), Kidney Chromophobe (KICH), Kidney renal clear cell carcinoma (KIRC), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC), Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC), Mesothelioma (MESO), Ovarian serous cystadenocarcinoma (OV), Pancreatic adenocarcinoma (PAAD), Pheochromocytoma and Paraganglioma (PCPG), Prostate adenocarcinoma (PRAD), Rectum adenocarcinoma (READ), Sarcoma (SARC), Skin Cutaneous Melanoma (SKCM), Stomach adenocarcinoma (STAD), Testicular Germ Cell Tumors (TGCT), Thymoma (THYM), Thyroid carcinoma (THCA), Uterine Carcinosarcoma (UCS), Uterine Corpus Endometrial Carcinoma (UCEC), and Uveal Melanoma (UVM). The compound or pharmaceutical composition for use according to item 68, the method according to 71 , or the use according to 75, wherein the cancer is selected from the group consisting of leukemia, including acute myeloid leukemia, lymphoma and myeloma, including multiple myeloma. Examples

[0438] Example 1 : Synthetic protocols

[0439] General Synthetic Remarks:

[0440] Abbreviations aq aqueous

[0441] DCM methylene chloride

[0442] DIPEA N,N-diisopropylethylamine

[0443] DMF N,N-dimethylformamide eq equivalent

[0444] Et ethyl

[0445] EtOAc ethyl acetate

[0446] EtOH ethanol

[0447] HATU 1-[Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0448] HFIP 1 ,1 ,1,3,3,3-hexafluoro-2-propanol

[0449] Me methyl

[0450] MeCN acetonitrile

[0451] MeOH methanol

[0452] MTBE methyl tert-butyl ether

[0453] N2nitrogen(g) rt room temperature

[0454] RT retention time

[0455] TBAF tetrabutyl ammonium fluoride

[0456] TEA triethylamine

[0457] THF tetra hydrofuran

[0458] Reagents

[0459] All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

[0460] The reactions were monitored using LCMS and / or TLC. Thin layer chromatography was conducted with 5 cm x 10 cm plates coated with Merck Type 60 F254 silica-gel. Microwave heating was performed in an Anton Parr MonoWave or CEM Discover® instrument. Photochemistry was performed in a Hepatochem Lucent 360™ Advanced Photoreactor. Reductions via hydrogenation were conducted under hydrogen at atmospheric pressure, using an apparatus that includes burettes of hydrogen(g) displaced by water and sealing Rodavis® glassware joints, which were supported and agitated under an atmosphere of hydrogen on a Heidolph shaker. Hydrogen was generated via electrolysis of water using a Domnick Hunter® NITROX ™ UHP Hydrogen Generator. Scavenging agents were used to quench coupling reaction, such as SiliaBond Carbonate (R66030B) supplied by SiliCycle Inc. Evaporation and drying of compounds were performed using Buchi rotary evaporators and / or Biotage® V-10 Touch Evaporation Systems. Lyophilisation of compounds from aqueous mixtures resultant of preparative reverse phase chromatography were performed using a LABCONCO FreeZone 4.5 Litre -84° C freeze drier.

[0461] Purification

[0462] Compounds were purified using either flash chromatography or reverse phase preparative chromatography, or a combination of both techniques.

[0463] Flash chromatography was performed on ISCO CombiFlash Rf 200, Rf 200i Rf 300+ and Rf+ Lumen™ with pre-packed silica-gel cartridges (RediSep® Rf Normal-phase Silica Flash Columns (35-70pm, 60 A), RediSep Rf Gold® Normal-phase Silica High Performance Columns (20-40pm, 60 A), RediSep® Rf Reversed-phase C18 Columns (40-63 Dm, 60 A), or RediSep Rf Gold® Reversed-phase C18 High Performance Columns (20-40 Dm, 100 A).

[0464] Reverse phase prep-chromatography was performed by the following methods: AccQPrep HP125 (Teledyne ISCO) system, with a Gemini® NX 5 pm C18(2), 150 mm x 21.2 mm i d. column from Phenomenex, running at a flow rate of 20 mL min-1or Gemini® NX 5 pm C18(2), 250 mm x 30 mm i.d. column from Phenomenex, running at a flow rate of 40 mL min-1with UV (214 and 254 nm) and ELS detection. pH4 eluents: Solvent A: water + 0.08% (v / v) formic acid; solvent B: MeCN + 0.08% (v / v) formic acid. pH9 eluents: Solvent A: water + 0.08% (v / v) cc. aq. NH3 solution; solvent B: MeCN + 0.08% (v / v) cc. aq. NH3 solution. Neutral eluents: Solvent A: water; Solvent B: MeCN. Analytical methods

[0465] Analytical LC-MS: The compounds of the present invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) using the following instruments and methods:

[0466] LCMS (method A): Agilent 1260 LC coupled with an Agilent InfinityLab LC / MSD XT single quadrupole, operating in both positive and negative ion electrospray ionisation modes. Molecular weight scan range is 100 to 1350 m / z. Parallel UV detection was performed at 210 nm 254 nm and 270 nm. Samples were supplied as a 1 mM solution in MeCN, or in THF / water (1:1) with 5 pL loop injection. Column specification ZORBAX Eclipse XDB-C18, 1.8 pm, 50 mm x 4.6 mm i.d. operated at 40° C, at a flow rate of 1 mL min-1 using 0.02% V / V aq. Formic acid solution (Solvent A) and 0.02% V / V formic acid solution in MeCN (Solvent B) with a gradient starting from 100% Solvent A and finishing at 100% Solvent B over various duration of time.

[0467] LCMS (method B): Agilent 1290 Infinity II UHPLC series connected to a TOF 6230 with an ES ionisation source (positive or negative mode ionisation). The LCMS was configured with a buffered mobile phase - polar: Water / 10 mM ammonium formate / 0.08% (v / v) formic acid pH = 3.3; apolar: acetonitrile 15.3 % (v / v) ammonium formate / 0.08% (v / v) formic acid. The mobile phase passed through a Phenomenex Kinetex C18 column, 2.6 microns, 50 x 2 mm, temperature: 55°C at a flow rate of 1.3 mL / min. A 1 pL sample was injected and purified using a 5 to 95% gradient in 1.18 min, total run time 1.95 min.

[0468] 1H-NMR measurements were performed on a Bruker Avance NEO 400 MHz spectrometer, using DMSO-de or CDCh as solvent.1H NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-ds and 7.26 ppm for CDCh) as internal standard. Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), app s (apparent singlet), br s (broad singlet), br d (broad doublet), br t (broad triplet), br m (broad multiplet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), qd (quartet of doublets), ddd (doublet of doublet of doublets), dm (doublet of multiplets). Exemplification 1 : N-(1 H-indol-4-ylmethyl)imidazo[1 ,2-a]pyridine-3-carboxamide

[0469] Intermediate 1a: imidazo[1 ,2-a]pyridine-3-carbonyl chloride

[0470] To a stirred suspension of imidazo[1 ,2-a]pyridine-3-carboxylic acid (250 mg, 1.54 mmol, 1 eq) in DCM (5 mL) under N2was slowly added oxalyl chloride, (1.54 mL, 2M in DCM, 3.08 mmol, 2 eq) followed by catalytic DMF (a few drops). The reaction was stirred at rt for approximately 40 min. The reaction mixture was concentrated under reduced pressure and the crude residue used immediately without further analysis.

[0471] Compound 1 : N-(1 H-indol-4-ylmethyl)imidazo[1 ,2-a]pyridine-3-carboxamide

[0472] To a suspension of (1a) imidazo[1,2-a]pyridine-3-carbonyl chloride (55 mg, 0.3 mmol) in DCM (1 mL) under N2was added 4-aminomethylindole (53 mg, 0.37 mmol, 1.2 eq) followed by TEA (0.13 mL, 0.91 mmol, 3 eq), before leaving to stir at rt for 16 h. The reaction was then partitioned between DCM and water. The organic layer was subsequently washed with brine, dried over anhydrous MgSCU, filtered, and concentrated in vacuo. The resultant residue was purified by automated flash chromatography (Combiflash 300+, Gold RediSep Silica, 12 g column) eluting with 0 to 12% MeOH in DCM. The resultant gum was transferred to a submission vial using DCM, solvent was then removed under a stream of N2before drying further at 45° C under vacuum over the weekend to afford title compound 1 (65 mg, 0.23 mmol, 74%) as a pink solid. LC-HRMS (method B); RT 0.74 min; target mass 290.1168; found mass ion [M+H]+291.1246; found empirical formula C17 H14 N4 O.1H NMR (400 MHz, DMSO) 5 ppm 11.13 (app s, 1 H), 9.54 (dt, J = 7.0, 1.2 Hz, 1 H), 8.99 (t, J = 5.9 Hz, 1 H), 8.41 (s, 1H), 7.72 (dt, J = 9.0, 1.2 Hz, 1 H), 7.46 (ddd, J = 9.0, 6.8, 1.4 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.13 (td, J = 6.9, 1.3 Hz, 1H), 7.12 - 7.01 (m, 1H), 6.98 (dd, J = 7.2, 1.0 Hz, 1H), 6.61 (ddd, J = 3.0, 1.9, 0.9 Hz, 1 H), 4.78 (d, J = 5.8 Hz, 2H). ,5- a]pyridin-5-yl}carbamate

[0473] To a stirred solution of 5-{[(tert-butoxy)carbonyl]amino}pyrazolo[1 ,5-a]pyridine-3- carboxylic acid (100 mg, 0.36 mmol) in DMF (3 ml_) was added 4-aminomethylindole (79 mg, 0.54 mmol, 1.5 eq) followed by DIPEA (0.18 mL, 1.08 mmol, 3 eq) and then HATU (206 mg, 0.54 mmol, 1.5 eq). The reaction was then stirred at rt for 16 h. The reaction was diluted with EtOAc then washed with water followed by brine. The organic extract was dried over anhydrous MgSC , filtered, and then absorbed on to ISOLUTE HM-N. Material was then purified by automated flash chromatography (Combiflash 300+, RediSep Silica, 12 g column) eluting with 0 to 15% MeOH in DCM. The main product fraction gave impure title compound 2 (153 mg, 0.38 mmol, qaunt.) as a pink gum to be used impure in later syntheses. The second product fraction gave less impure material as a pink gum (16 mg). This was dissolved in DMSO and purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) at pH 9 to afford title compound 2 (2.4 mg, 0.01 mmol, 15%) as a pink solid. LC-HRMS (method B); RT 1.06 min; target mass 405.1801; found mass ion [M+H]+406.1873; found empirical formula C22 H23 N5 03.1H NMR (400 MHz, DMSO) 5 ppm 11.09 (app s, 1 H), 9.85 (s, 1 H), 8.60 (dd, J = 7.5, 0.8 Hz, 1 H), 8.57 - 8.47 (m, 3H), 7.34 - 7.26 (m, 2H), 7.07 - 6.98 (m, 2H), 6.98 - 6.92 (m, 1 H), 6.58 (ddd, J = 3.0, 2.0, 0.9 Hz, 1 H), 4.72 (d, J = 5.8 Hz, 2H), 1.51 (s, 9H).

[0474] Exemplification 3: 5-(2,2-dimethylpropanamido)-N-(1 H-indol-4-ylmethyl)pyrazolori ,5- alpyridine-3-carboxamide Intermediate 3a: 5-amino-N-(1 H-indol-4-ylmethyl)pyrazolo[1 ,5-a]pyridine-3- carboxamide

[0475] A solution of (2) tert-butyl N-{3-[(1 H-indol-4-ylmethyl)carbamoyl]pyrazolo[1 ,5-a]pyridin- 5-yl}carbamate (176 mg, 0.43 mmol) in HFIP (2 mL) was microwaved at 100° C for 20 min. The reaction solvent was removed in vacuo. The resultant residue was absorbed on to ISOLUTE HM-N and purified by automated flash reverse phase chromatography (Combiflash Rf, RediSep C18, 13 g column) eluting with 10 to 100% MeCN in water to give title compound 3a (45.7 mg, 0.15 mmol, 34%) as a white solid. LCMS (method B); RT 0.682 min, [M+H]+306.136.1H NMR (400 MHz, DMSO) 5 ppm 11.09 (app s, 1 H), 8.31 (d, J = 7.5 Hz, 2H), 8.25 (t, J = 6.0 Hz, 1 H), 7.34 - 7.26 (m, 2H), 7.17 (d, J = 2.5 Hz, 1H), 7.12 - 6.99 (m, 1 H), 6.97 - 6.91 (m, 1H), 6.59 (ddd, J = 3.0, 1.9, 0.8 Hz, 1 H), 6.43 (dd, J = 7.4, 2.5 Hz, 1 H), 6.04 (s, 2H), 4.71 (d, J = 5.9 Hz, 2H).

[0476] Compound 3: 5-(2,2-dimethylpropanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1 ,5- a]pyridine-3-carboxamide

[0477] A solution of (3a) 5-amino-N-(1 H-indol-4-ylmethyl)pyrazolo[1,5-a]pyridine-3- carboxamide (46 mg, 0.15 mmol, 1 eq), pivaloyl chloride (0.02 mL, 0.18 mmol, 1.2 eq) and TEA (0.06 mL, 0.45 mmol, 3 eq) in DCM (2 mL) was stirred at rt for 16 h. The reaction was partitioned between water and DCM. The organic extract was dried over anhydrous MgSCU, filtered and concentrated. The resultant residue was dissolved in DMSO and purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) eluting with 5 to 95% MeCN in water to afford title compound 3 (4.3 mg, 0.01 mmol, 7%) as a white solid. LC-HRMS (method B); RT 0.99 min; target mass 389.1852; found mass ion [M+H]+390.1926; found empirical formula C22 H23 N5 02.1H NMR (400 MHz, DMSO) 5 ppm 11.09 (app s, 1 H), 9.64 (s, 1 H), 8.69 - 8.61 (m, 2H), 8.53 (d, J = 13.4 Hz, 2H), 7.43 (dd, J = 7.6, 2.4 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.03 (t, J = 7.6 Hz, 1 H), 6.96 (dd, J = 7.2, 1.0 Hz, 1 H), 6.60 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H), 4.74 (d, J = 5.8 Hz, 2H), 1.25 (s, 9H). Exemplification 4: 5-(3,3-dimethylbutanamido)-N-(1 H-indol-4-ylmethyl)pyrazolon,5- alpyridine-3-carboxamide

[0478] Intermediate 4a: ethyl 5-(3,3-dimethylbutanamido)pyrazolo[1,5-a]pyridine-3- carboxylate

[0479] To a stirred solution of ethyl 5-aminopyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, 0.97 mmol, 1 eq) and TEA (0.41 ml_, 0.73 g / mL, 2.92 mmol, 3 eq) in DCM (5 mL) was added tert-butylacetyl chloride (0.16 mL, 1.17 mmol, 1.2 eq) was added. The reaction was stirred at rt for 16 h. The reaction was diluted with DCM then washed with sat. NaHCOs (aq) solution followed by brine. The organic extract was dried over anhydrous MgSCu, filtered, and concentrated to dryness. The resultant residue was purified by automated flash chromatography (Combiflash 300+, RediSep Silica, 12 g column) eluting with 0 to 7% MeOH in DCM to give title compound 4a (250 mg, 0.82 mmol, 85%) as a brown gum. LCMS (method A); RT 1.163 min, [M+H]+304.4.1H NMR (400 MHz, DMSO) 3 ppm 10.35 (s, 1 H), 8.74 (dd, J = 7.5, 0.8 Hz, 1 H), 8.57 (dd, J = 2.4, 0.8 Hz, 1H), 8.33 (s, 1H), 7.24 (dd, J = 7.5, 2.4 Hz, 1 H), 4.28 (q, J = 7.1 Hz, 2H), 2.27 (s, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.05 (s, 9H).

[0480] Intermediate 4b: 5-(3,3-dimethylbutanamido)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid A solution of (4a) ethyl 5-(3,3-dimethylbutanamido)pyrazolo[1 ,5-a]pyridine-3- carboxylate (250 mg, 0.82 mmol, 1 eq) and sodium hydroxide (1.65 mL, 2 M in water , 3.3 mmol, 4 eq) in methanol (6 mL) was heated to 60° C, where it was maintained for 4 h. The MeOH was removed in vacuo then the residual aqueous was acidified to pH 1 with 2N HCI (aq). The aqueous was extracted with 3:1 DCM / IPA three times. The combined organic extracts were then dried over anhydrous MgSO4, filtered, and concentrated to yield title compound 4b (265 mg, 0.96 mmol, quant.) as a yellow gum. LCMS (method A); RT 0.958 min, [M+H]+276.2.1H NMR (400 MHz, DMSO) 6 ppm 12.22 (s, 1 H), 10.32 (s, 1H), 8.72 (dd, J = 7.5, 0.8 Hz, 1 H), 8.54 (dd, J = 2.4, 0.8 Hz, 1 H), 8.29 (s, 1 H), 7.24 (dd, J = 7.5, 2.4 Hz, 1 H), 2.26 (s, 2H), 1.04 (s, 9H).

[0481] Compound 4: 5-(3,3-dimethylbutanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1 ,5- a]pyridine-3-carboxamide

[0482] To a stirred solution of (4b) 5-(3,3-dimethylbutanamido)pyrazolo[1,5-a]pyridine-3- carboxylic acid (88 mg, 0.32 mmol, 1 eq) in DMF (2 mL) was added 4- aminomethylindole (70.09 mg, 0.48 mmol, 1.5 eq) followed by DIPEA (0.16 mL, 0.78 g / mL, 0.96 mmol, 3 eq) and then HATU (183 mg, 0.48 mmol, 1.5 eq). The reaction was stirred at rt for 16 h. The reaction was diluted with EtOAc then washed with sat.

[0483] NaHCOs (aq) solution followed by brine. The organic extract was dried over anhydrous MgSCU, filtered, and then concentrated. The resultant residue was purified by automated flash chromatography (Combiflash 300+, Gold RediSep Silica, 12 g column) eluting with 0 to 12% MeOH in DCM. Product was then dissolved in DMSO and further purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) eluting with 5 to 95% MeCN in water to give title compound 4 (33.2 mg, 0.08 mmol, 26%) as an off-white solid. LC-HRMS (method B); RT 1.03 min; target mass 403.2008; found mass ion [M+H]+404.2083; found empirical formula C23 H25 N5 02.1H NMR (400 MHz, DMSO) 5 ppm 11.11 (app s, 1 H), 10.24 (s, 1H), 8.69 - 8.61 (m, 2H), 8.55 (d, J = 13.5 Hz, 2H), 7.35 - 7.27 (m, 2H), 7.23 (dd, J = 7.5, 2.4 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 7.00 - 6.93 (m, 1 H), 6.63 - 6.57 (m, 1H), 4.75 (d, J = 5.8 Hz, 2H), 2.25 (s, 2H), 1.05 (s, 9H). Exemplification 5: N-[(7-methoxy-1 H-indol-4-yl)methyHimidazo[1 ,2-alpyridine-3- carboxamide

[0484] Intermediate 5a: (7-methoxy-1 H-indol-4-yl)methanamine

[0485] A solution of 7-methoxy-1 H-indole-4-carbonitrile (150 mg, 0.87 mmol, 1 eq) in THF (5 mL) and water (5 mL) was cooled in an ice bath then cobalt (II) chloride (226 mg, 1.74 mmol, 2 eq) was added. The reaction was stirred until the cobalt chloride had fully dissolved (~5 min) then sodium borohydride (330 mg, 8.71 mmol, 10 eq) was added in 3 portions (care: gas evolved). The reaction was allowed to slowly warm to rt, where it was stirred for a total of 5 h. The reaction was filtered through a 2.5 g Celite 545 cartridge, washing with MeOH. Solvent was then removed in vacuo. The resultant residue absorbed on to ISOLUTE HM-N and purified by automated flash reverse phase chromatography (Combiflash Rf, RediSep C18, 13 g column) eluting with 10 to 100% MeON in water to afford title compound 5a (99 mg, 0.56 mmol, 65%) as a cream solid. LCMS (method A); RT 0.452 min, [M+H]+160.2.1H NMR (400 MHz, DMSO) 6 ppm 11.14 (app s, 1 H), 7.20 (t, J = 2.8 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 6.57 (d, J = 7.8 Hz, 1 H), 6.48 (dd, J = 3.0, 2.0 Hz, 1 H), 3.88 (d, J = 2.4 Hz, 5H), 1 .66 (s, 2H).

[0486] Compound 5: N-[(7-methoxy-1 H-indol-4-yl)methyl]imidazo[1 ,2-a]pyridine-3- carboxamide

[0487] To a stirred suspension of imidazo[1 ,2-a]pyridine-3-carboxylic acid (40 mg, 0.25 mmol, 1 eq) in DCM (2 mL) was added oxalyl chloride (0.5 mL, 2 M in DCM, 0.98 mmol, 4 eq). The reaction as stirred at rt for 90 min before being concentrated under reduced pressure. The resultant residue was re-suspended in DCM (2 mL) and then (5a) (7- methoxy-1 H-indol-4-yl)methanamine (43 mg, 0.25 mmol, 1 eq) and TEA (0.1 mL, 0.74 mmol, 3 eq) were added before leaving to stir at rt for 16 h. The reaction was diluted with DCM then washed with sat. NaHCOs (aq) solution followed by brine. The organic extract was dried over anhydrous MgSC , filtered and concentrated. The resultant residue was dissolved in DMSO and purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) eluting with 5 to 95% MeCN in water to give title compound 5 (17.2 mg, 0.05 mmol, 22%) as a white solid. LC-HRMS (method B); RT 0.83 min; target mass 320.1273; found mass ion [M+H]+321.135; found empirical formula C18 H16 N4 02.1H NMR (400 MHz, DMSO) 6 ppm 11.22 (app s, 1 H), 9.54 (dt, J = 6.9, 1.3 Hz, 1 H), 8.89 (t, J = 5.9 Hz, 1 H), 8.37 (s, 1 H), 7.70 (dt, J = 9.1, 1.2 Hz, 1 H), 7.45 (ddd, J = 9.1 , 6.8, 1.4 Hz, 1 H), 7.22 (t, J = 2.8 Hz, 1 H), 7.12 (td, J = 6.9, 1.3 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1 H), 6.63 - 6.53 (m, 2H), 4.70 (d, J = 5.8 Hz, 2H), 3.89 (s, 3H).

[0488] Exemplification 6: 6-(3,3-difluoropyrrolidin-1-yl)-N-[(7-methoxy-1 H-indol-4- yl)methyl1imidazo[1,2-alpyridine-3-carboxamide

[0489] Intermediate 6a: ethyl 6-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3- carboxylate

[0490] To a 30 mL sealed tube was added sequentially ethyl 6-bromoimidazo[1 ,2-a]pyridine-3- carboxylate (100 mg, 0.37 mmol, 1 eq), 3,3-Difluoropyrrolidine hydrochloride (69 mg, 0.48 mmol, 1.3 eq), cesium carbonate (3 g, 0.93 mmol, 2.5 eq), Bl NAP (s)-(-)-2,2 - bis(diphenylphosphino)-1 ,1'-binaphthyl (21 mg, 0.03 mmol, 0.09 eq), palladium^ I) acetate (5 mg, 0.02 mmol, 0.06 eq) and toluene (6 mL). The mixture was degassed with N2for 5 min, the vessel sealed, and then heated to 120° C for 16 h. The reaction was cooled to rt, diluted with EtOAc (15 mL), ISOLUTE HM-N was added and then the mixture concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 12 g column) eluting with 0 to 50% EtOAc in heptane to afford title compound 6a (23.1 mg, 0.08 mmol, 21%) as a cream solid. LCMS (method A); RT 1.010 min, [M+H]+296.2.1H NMR (400 MHz, DMSO) 6 ppm 8.46 (d, J = 2.4 Hz, 1 H), 8.15 (s, 1 H), 7.73 (dd, J = 9.7, 0.8 Hz, 1H), 7.35 (dd, J = 9.7, 2.5 Hz, 1 H), 7.30 - 7.19 (m, OH), 4.35 (q, J = 7.1 Hz, 2H), 3.77 (t, J = 13.2 Hz, 2H), 3.52 (t, J = 7.2 Hz, 2H), 2.59 (tt, J = 14.6, 7.2 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).19F NMR (376 MHz, DMSO) 6 -96.95.

[0491] Intermediate 6b: 6-(3,3-difluoropyrrolidin-1-yl)imidazo[1 ,2-a]pyridine-3-carboxylic acid To a suspension of (6a) ethyl 6-(3,3-difluoropyrrolidin-1-yl)imidazo[1 ,2-a]pyridine-3- carboxylate (23 mg, 0.08 mmol, 1 eq) in methanol (5 ml_) was added sodium hydroxide (0.2 ml_ (2 M in water), 0.39 mmol, 5 eq). The reaction was stirred at rt for 16 h before concentrating under reduced pressure. The residue was diluted with water and acidified by addition of 2 M HCI (aq) solution. Product was extracted with EtOAc, dried over MgSO4, filtered, and concentrated to dryness on a Biotage V10 at 50° C to give title compound 6b (15.6 mg, 0.06 mmol, 75%) as a beige solid. LCMS (method A); RT 0.581 min, [M+H]+268.2.1H NMR (400 MHz, DMSO) 5 ppm 8.64 - 8.55 (m, 1 H), 7.68 (d, J = 9.7 Hz, 1 H), 7.42 - 7.05 (m, 1 H), 4.34 - 4.07 (m, 1 H), 3.75 (t, J = 13.3 Hz, 1 H), 3.70 - 3.40 (m, 2H), 3.20 - 2.87 (m, 3H), 2.68 - 2.53 (m, 1 H), 1.41 - 1.01 (m, 1H).19F NMR (376 MHz, DMSO) 6 -97.33.

[0492] Compound 6: 6-(3,3-difluoropyrrolidin-1-yl)-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide

[0493] To a stirred solution of (6b) 6-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-a]pyridine-3- carboxylic acid (16 mg, 0.06 mmol, 1 eq) , (5a) (7-methoxy-1 H-indol-4-yl)methanamine (10 mg, 0.06 mmol, 1 eq) and DIPEA (31 pL, 0.18 mmol, 3 eq) in DMF (1 ml_) was added HATU (33.29 mg, 0.09 mmol, 1.5 eq) before stirring at rt for 16 h . The reaction was diluted with EtOAc and washed with sat. NaHCOs (aq) solution followed by brine. The organic extract was dried over anhydrous MgSC , filtered and then concentrated to dryness. The resultant residue was purified by automated flash chromatography (Combiflash 300+, Gold RediSep Silica, 4 g column) eluting with 0 to 100% EtOAc in heptane. Product was further purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) at pH 4 followed by pH 9 to give title compound 6 (0.4 mg, 0.89 pmol, 1.5%) as a cream solid. LC-HRMS (method B); RT 0.88 min; target mass 425.1663; found mass ion [M+H]+426.1746; found empirical formula C22 H21 F2 N5 02.1H NMR (400 MHz, DMSO) 5 pp 11.22 (app s, 1 H), 8.86 (d, J = 2.3 Hz, 1 H), 8.79 (t, J = 5.8 Hz, 1 H), 8.27 (s, 1 H), 7.62 (d, J = 9.7 Hz, 1 H), 7.25 (dd, J = 9.7, 2.4 Hz, 1 H), 7.23 (t, J = 2.8 Hz, 1 H), 6.89 (d, J = 7.8 Hz, 1 H), 6.60 (d, J = 7.8 Hz, 1 H), 6.56 (dd, J = 3.0, 2.0 Hz, 1 H), 4.69 (d, J = 5.8 Hz, 2H), 3.90 (s, 3H), 3.73 (t, J = 13.2 Hz, 2H), 3.49 (t, J = 7.2 Hz, 2H), 2.62 - 2.53 (m, 1H), 1.24 (s, 1H).19F NMR (376 MHz, DMSO) 5 -60.72, -96.47.

[0494] Exemplification 7: 6-{benzyl[3-(benzyloxy)cyclohexyllamino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazon,2-alpyridine-3-carboxamide

[0495] Intermediate 7a: 3-[(6-nitropyridin-3-yl)amino]cyclohexan-1-ol

[0496] To a 30 mL microwave vial was added 5-fluoro-2-nitropyridine 500 mg, 3.52 mmol), 3- aminocyclohexanol (608 mg, 5.28 mmol, 1.5 eq), DMA (8 mL) and then finally DIPEA (0.8 mL, 4.57 mmol, 1.3 eq) . The vial was sealed and heated to 180° C for 15 min in a microwave reactor. The reaction mixture was then diluted with EtOAc (20 mL), ISOLUTE HM-N was added and then the mixture concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 24 g column) eluting with 0 to 100% EtOAc in heptane to give title compound 7a (1.38 g, 5.83 mmol, quant.) as a brown oil. Despite rigorous drying, analysis showed residual DMA still present, material was used in the subsequent step without further purification. LCMS (method A); RT 0.737 min, [M+H]+238.2.1H NMR (400 MHz, DMSO) 5 ppm 8.11 (dd, J = 9.1 , 4.0 Hz, 1 H), 7.89 (dd, J = 5.4, 2.9 Hz, 1 H), 7.28 (d, J = 7.8 Hz, OH), 7.06 (ddd, J = 10.8, 9.2, 2.9 Hz, 1 H), 4.56 (d, J = 3.4 Hz, OH), 4.00 - 3.92 (m, OH), 3.82 - 3.69 (m, 1H), 2.95 (s, 1H), 2.79 (s, 1 H), 1.96 (s, 1 H), 1.94 - 1.77 (m, 2H), 1.70 (tt, J = 13.3, 5.1 Hz, OH), 1.59 - 1.42 (m, 2H), 1.30 (tdd, J = 12.6, 8.3, 3.6 Hz, 1 H), 1.19 - 0.97 (m, 1 H).

[0497] Intermediate 7b: N-benzyl-N-[3-(benzyloxy)cyclohexyl]-6-nitropyridin-3-amine

[0498] To a solution of (7a) 3-[(6-nitropyridin-3-yl)amino]cyclohexan-1-ol (835 mg, 3.52 mmol) in DMF (15 mL) cooled to 0° C under N2was added sodium hydride (211 mg (60% suspension in mineral oil), 5.28 mmol, 1.5 eq) portion-wise. The reaction mixture was stirred at 0° C for 15 min before benzyl bromide (1.05 mL, 8.8 mmol, 2.5 eq) was added dropwise over the course of a minute. Once addition was complete the cooling bath was removed, and the reaction was stirred at rt for 4 h. The reaction was cooled again to 0° C and quenched by the addition of MeOH (10 mL). The reaction was diluted with EtOAc and washed with brine, the organic layer was then dried over anhydrous MgSO4, filtered and ISOLUTE HM-N was added. The mixture was concentrated to dryness and then and purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 24 g column) eluting with 0 to 100% EtOAc in heptane to give title compound 7b (0.57 g, 1.36 mmol, 39%) as a yellow gum. LCMS (method A); RT 1.324 min, [M+H]+418.2.1H NMR (400 MHz, DMSO) 6 ppm 8.12 (dd, J = 9.3, 5.1 Hz, 1 H), 8.01 (d, J = 3.1 Hz, 1 H), 7.48 - 7.17 (m, 9H), 4.75 (s, 1 H), 4.81 - 4.66 (m, 1H), 4.61 - 4.45 (m, 2H), 4.18 (tq, J = 10.9, 3.8 Hz, 1 H), 3.58 (tt, J = 10.7, 3.9 Hz, 1H), 2.25 - 2.11 (m, 1 H), 2.09 (s, 1 H), 2.11 - 1.86 (m, 1H), 1.78 (s, 1 H), 1.86 - 1.67 (m, 2H), 1.67 - 1.29 (m, 2H), 1.44 (s, 1 H), 1.26 - 1.08 (m, 1 H).

[0499] Intermediate 7c: 5-N-benzyl-5-N-[3-(benzyloxy)cyclohexyl]pyridine-2,5-diamine

[0500] To a solution of (7b) N-benzyl-N-[3-(benzyloxy)cyclohexyl]-6-nitropyridin-3-amine (568 mg, 1.36 mmol, 1 eq) in methanol (10 mL) was added ammonium chloride (363.87 mg, 6.8 mmol, 5 eq), followed then by zinc (889.62 mg, 13.6 mmol, 10 eq) portion wise. The reaction mixture was stirred at room temperature under N2for 16 h before it was filtered through a 2.5 g Celite 545 cartridge, washing with MeOH. ISOLUTE HM-N was added to the filtrate and the whole concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 40 g column) eluting with 0 to 100% EtOAc in heptane to give title compound 7c (837 mg, 2.16 mmol, quant.) as a purple gum. Residual DMF still present, material was used in the subsequent step without further drying. LCMS (method A); RT 1.120 min, [M+H]+388.4.1H NMR (400 MHz, DMSO) 6 ppm 7.96 (s, 1 H), 7.55 - 7.46 (m, 1 H), 7.45 - 7.20 (m, 8H), 7.22 - 7.12 (m, 1H), 7.16 - 7.01 (m, 1H), 6.33 (d, J = 8.8 Hz, 1H), 5.43 - 5.32 (m, 1 H), 4.61 - 4.40 (m, 2H), 4.23 (d, J = 13.5 Hz, 2H), 3.46 - 3.34 (m, OH), 2.90 (s, 3H), 2.74 (d, J = 0.6 Hz, 2H), 2.30 - 2.18 (m, 1 H), 2.11 - 1.94 (m, 1H), 1.83 - 1.67 (m, 1 H), 1.38 - 1.11 (m, 2H), 1.19 (s, 1 H).

[0501] Intermediate 7d: ethyl 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}imidazo[1,2- a]pyridine-3-carboxylate

[0502] To a mixture of (7c) 5-N-benzyl-5-N-[3-(benzyloxy)cyclohexyl]pyridine-2,5-diamine (527 mg, 1.36 mmol) in ethanol (15 ml_) was added ethyl-2-chloro-2-formylacetate (307 mg, 2.04 mmol, 1.5 eq) before heating at 75° C for 16 h under N2. The reaction mixture was then cooled to rt, diluted with EtOAc, ISOLUTE HM-N was added, and the crude mixture concentrated to dryness. Crude material was then then purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 24 g column) eluting with 0 to 50% EtOAc in heptane to afford title compound 7d (734 mg, 1.52 mmol, quant.) as a purple solid. Residual solvent present, material was used in the subsequent step without further drying. LCMS (method A); RT 1.416 min, [M+H]+484.4.1H NMR (400 MHz, DMSO) 5 ppm 8.58 (d, J = 2.5 Hz, 1 H), 8.09 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 9.8, 5.2 Hz, 1 H), 7.46 (dd, J = 9.9, 2.5 Hz, 1 H), 7.43 - 7.15 (m, 10H), 4.53 (d, J = 2.4 Hz, 2H), 4.53 - 4.39 (m, 2H), 4.29 (qd, J = 7.0, 1.7 Hz, 2H), 4.22 - 3.99 (m, 1 H), 3.83 - 3.71 (m, 1 H), 3.54 (s, 1 H), 3.59 - 3.45 (m, 1H), 2.33 - 2.17 (m, 1 H), 2.12 - 1.96 (m, 1 H), 1.99 (s, 1 H), 1.78 (s, 2H), 1.94 - 1 .65 (m, 1 H), 1.65 - 1 .41 (m, 1 H), 1.41 - 1.06 (m, 4H), 1.09 (s, 2H). Intermediate 7e: 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}imidazo[1 ,2-a]pyridine-3- carboxylic acid

[0503] To a suspension of (7d) ethyl 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}imidazo[1 ,2- a]pyridine-3-carboxylate (329 mg, 0.68 mmol, 1 eq) in methanol (15 mL) was added sodium hydroxide (1.7 mL (2 M in water), 3.4 mmol, 5 eq). The reaction was then stirred at rt for 3 days. The reaction was concentrated under reduced pressure, the residue was then diluted with water and acidified by the addition of 2 M HCI (aq). Product was then extracted with DCM, dried over anhydrous MgSC , filtered and concentrated to dryness. Crude material was loaded onto ISOLUTE HM-N and purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 12 g column) eluting with 0 to 100% EtOAc in heptane to afford title compound 7e (101 mg, 0.22 mmol, 33%) as a cream gum. LCMS (method A); RT 1.079 min, [M+H]+ 456.4.1H NMR (400 MHz, DMSO) 5 ppm 8.78 - 8.63 (m, 1H), 8.04 (d, J = 3.4 Hz, 1H), 7.69 - 7.56 (m, 1 H), 7.50 - 7.36 (m, 1H), 7.37 (s, 1H), 7.40 - 7.23 (m, 8H), 7.27 - 7.13 (m, 1 H), 4.58 - 4.40 (m, 4H), 3.95 - 3.69 (m, 1 H), 3.51 (tt, J = 10.8, 4.1 Hz, 1 H), 3.32 (d, J = 16.0 Hz, 1 H), 2.33 - 2.24 (m, 1H), 2.15 - 1.94 (m, 1 H), 1.94 - 1.04 (m, 7H).

[0504] Compound 7: 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide

[0505] To a stirred solution of (7e) 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}imidazo[1 ,2- a]pyridine-3-carboxylic acid (68 mg, 0.15 mmol, 1 eq) , (5a) (7-methoxy-1 H-indol-4- yl)methanamine (26 mg, 0.15 mmol, 1 eq) and DIPEA (78 pL, 0.45 mmol, 3 eq) in DMF (3 mL) was added HATU (85 mg, 0.22 mmol, 1.5 eq). The reaction was stirred at rt for 16 h. SiliaBond carbonate scavenging agent (0.5 g) was added, and the mixture stirred for a further hour at rt. The reaction was then diluted with EtOAc, ISOLUTE HM-N was added, and the mixture concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash 300+, RediSep Silica, 12 g column) eluting with 0 to 100% EtOAc in heptane. Product was then further purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) at pH 9 to give title product 7 (23 mg, 0.04 mmol, 26%) as a cream solid. LC-HRMS (method B); RT 1.23 min; target mass 613.3053; found mass ion [M+H]+614.3132; found empirical formula C38 H39 N5 03.1H NMR (400 MHz, DMSO) 6 ppm 11.14 (app s, 1 H), 9.00 (d, J = 2.3 Hz, 1 H), 8.62 (t, J = 5.8 Hz, 1 H), 8.14 (s, 1 H), 7.43 (d, J = 9.8 Hz, 1H), 7.31 - 7.07 (m, 12H), 6.79 (d, J = 7.8 Hz, 1 H), 6.51 (d, J = 7.9 Hz, 1H), 6.46 (dd, J = 3.1 , 2.0 Hz, 1H), 4.60 (dd, J = 5.8, 1.8 Hz, 2H), 4.45 (s, 2H), 4.34 (s, 2H), 3.82 (s, 3H), 3.58 (td, J = 10.6, 5.0 Hz, 1H), 3.42 (tt, J = 10.7, 4.0 Hz, 1 H), 2.27 - 2.17 (m, 1 H), 2.01 - 1.92 (m, 1 H), 1.79 - 1.65 (m, 2H), 1.45 - 1.31 (m, 1 H), 1.31 - 1.17 (m, 1H), 1.12 - 0.94 (m, 1 H).

[0506] Exemplification 8: 6-{f(1S,3S)-3-hydroxycyclopentyllamino)-N-[(7-methoxy-1 H-indol-4- yl)methyl1imidazo[1,2-alpyridine-3-carboxamide

[0507] Intermediate 8a: (1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentan-1 -amine

[0508] A solution of (1S,3S)-3-Aminocyclopentanol hydrochloride (200 mg, 1.45 mmol, 1 eq), triisopropylsilyl trifluoromethanesulfonate (0.78 ml_, 2.91 mmol, 2 eq) and DI PEA (0.96 ml_, 5.81 mmol, 4 eq) in DCM (8 ml_) was stirred at rt for 16 h. The reaction was diluted with DCM and then washed with sat. NaHCCh (aq) solution followed by brine. The organic layer was dried over anhydrous MgSC , filtered, and concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash 300+, RediSep Silica, 24 g column) eluting with 0 to 20% MeOH in DCM to yield target compound 8a (234 mg, 0.91 mmol, 63%) as a white solid.1H NMR (400 MHz, DMSO) 6 ppm 7.67 (s, 3H), 4.47 (tt, J = 5.3, 3.6 Hz, 1 H), 3.63 (qd, J = 7.6, 5.8 Hz, 1 H), 2.16 - 1.94 (m, 2H), 1.94 - 1.84 (m, 1H), 1.77 (ddd, J = 13.2, 7.0, 5.6 Hz, 1 H), 1.66 - 1.40 (m, 2H), 1.03 (d, J = 3.7 Hz, 21 H).

[0509] Intermediate 8b: 6-nitro-N-[(1S,3S)-3-{[tris(propan-2-yl)silyl]oxy}cyclopentyl]pyridin-3- amine To a 30 mL microwave vial was added 5-fluoro-2-nitropyridine (85 mg, 0.6 mmol, 1 eq) , (8a) (1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentan-1 -amine (231 mg, 0.9 mmol, 1.5 eq) , DMA (6 mL) , then DIPEA (0.14 mL, 1.3 eq). The vial was sealed and heated at 180° C for 15 min in a microwave reactor. The reaction was diluted with EtOAc, ISOLUTE HM-N was added, and the mixture concentrated to dryness. Crude material was purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 12 g column) eluting with 0 to 100% EtOAc in heptane to give title compound 8b (335 mg, 0.88 mmol, quant.) as a yellow gum. Analysis showed residual DMA still present, material was used in the subsequent step without further purification. LCMS (method A); RT 1.487 min, [M+H]+380.4.1H NMR (400 MHz, DMSO) 5 ppm 8.12 (d, J = 9.0 Hz, 1 H), 7.86 (d, J = 2.9 Hz, 1H), 7.45 (d, J = 6.6 Hz, 1 H), 7.04 (dd, J = 9.1, 2.9 Hz, 1 H), 4.49 (ddd, J = 9.9, 5.9, 4.0 Hz, 1 H), 4.08 - 3.97 (m, 1 H), 2.95 (s, 4H), 2.79 (s, 4H), 2.21 (dq, J = 12.8, 7.4 Hz, 1H), 2.01 (ddd, J = 12.9, 7.6, 4.9 Hz, 1 H), 1.96 (s, 4H), 1.79 (dt, J = 13.4, 6.0 Hz, 1 H), 1.64 - 1.54 (m, 1 H), 1.54 - 1.41 (m, 1 H), 1.14 - 0.99 (m, 14H).

[0510] Intermediate 8c: 5-N-[(1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentyl]pyridine-2,5-diamine To a solution of (8b) 6-nitro-N-[(1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentyl]pyridin-3- amine (227 mg, 0.6 mmol, 1 eq) in methanol (15 mL) cooled to 0° C under N2was added ammonium chloride (160 mg, 2.99 mmol, 5 eq) followed by zinc (391 mg, 5.98 mmol, 10 eq) portion wise. The mixture was then stirred at rt under N2for 4 h. The reaction mixture was filtered through a 2.5 g Celite 545 cartridge, washing with MeOH. ISOLUTE HM-N was added to the filtrate and the whole was then concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 12 g column) eluting with 0 to 50% EtOAc in heptane to yield title compound 8c (115 mg, 0.33 mmol, 55%) as a purple solid. LCMS (method A); RT 1.282 min, [M+H]+350.4.1H NMR (400 MHz, DMSO) 5 ppm 8.00 (t, J = 2.7 Hz, 1 H), 7.67 - 7.60 (m, OH), 7.04 (dd, J = 9.0, 2.9 Hz, 1 H), 6.78 (s, 1H), 4.54 - 4.45 (m, 1 H), 4.08 - 3.95 (m, 1 H), 2.21 (dq, J = 12.5, 7.3 Hz, 1H), 2.08 - 1.88 (m, 2H), 1.84 - 1.75 (m, 1 H), 1.76 (s, 1 H), 1.70 - 1.42 (m, 2H), 1.15 - 0.96 (m, 23H).

[0511] Intermediate 8d: ethyl 6-{[(1S,3S)-3- [(triisopropylsilyl)oxy]cyclopentyl]amino}imidazo[1 ,2-a]pyridine-3-carboxylate To a solution of (8c) 5-N-[(1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentyl]pyridine-2,5- diamine (115 mg, 0.33 mmol, 1 eq) in ethanol (15 mL) was added ethyl-2-chloro-2- formylacetate (75 mg, 0.49 mmol, 1.5 eq). The reaction was stirred at 75° C for 2 days under N2. The reaction mixture was cooled to rt, diluted with EtOAc and washed with sat. NaHCOs (aq). The layers were separated and the aqueous extracted twice with 10% MeOH in DCM. The combined organic layers were dried over anhydrous MgSC , filtered and concentrated to dryness. Crude material was then loaded onto ISOLUTE HM-N and purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 12 g column) eluting with 0 to 100% EtOAc in heptane to yield title product 8d (311 mg (70%), 0.70 mmol, quant) as a red gum. Analysis showed residual solvent present, material was used in the subsequent step without further purification. LCMS (method B); RT 1.496 min.

[0512] Intermediate 8e: 6-{[(1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentyl]amino}imidazo[1,2- a]pyridine-3-carboxylic acid

[0513] In a 30 mL microwave vial, to a suspension of (8d) ethyl 6-{[(1S,3S)-3- [(triisopropylsilyl)oxy]cyclopentyl]amino}imidazo[1 ,2-a]pyridine-3-carboxylate (146 mg, 0.33 mmol, 1 eq) in methanol (15 mL) was added sodium hydroxide (1.64 mL (2 M in water), 3.28 mmol, 10 eq). The vial was sealed and heated at 80° C for 45 min in a microwave reactor. The reaction was concentrated under reduced pressure, the residue was diluted with water and then neutralised to pH 7 by the addition of 2 M HCI (aq). Product was then extracted with DCM, dried over anhydrous gSO4, filtered, and concentrated to dryness. Crude material was loaded onto ISOLUTE HM-N and purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 12 g column) eluting with 5 to 100% EtOAc in heptane to give title compound 8e (44 mg, 0.11 mmol, 32%) as a pink gum. LCMS (method B); RT 1.147 min, [M+H]+418.253.

[0514] Intermediate 8f: N-[(7-methoxy-1 H-indol-4-yl)methyl]-6-{[(1S,3S)-3- [(triisopropylsilyl)oxy]cyclopentyl]amino}imidazo[1 ,2-a]pyridine-3-carboxamide To a stirred solution of (5a) (7-methoxy-1 H-indol-4-yl)methanamine (19 mg, 0.11 mmol, 1 eq), (8e) 6-{[(1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentyl]amino}imidazo[1,2- a]pyridine-3-carboxylic acid (44 mg, 0.11 mmol, 1 eq) and DIPEA (56 pL, 0.32 mmol, 3 eq) in DMF (3 mL) was added HATU (61 mg, 0.16 mmol, 1.5 eq). The reaction was then stirred at rt for 16 h. SiliaBond carbonate scavenging agent (0.5 g) was added, and the reaction stirred for a further hour at rt. The reaction mixture was then diluted with EtOAc, ISOLUTE HM-N was added, and concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash 300+, Gold RediSep Silica, 4 g column) eluting with 0 to 100% EtOAc in heptane to give title product 8f (26.6 mg, 0.05 mmol, 43%) as a brown gum. LCMS (method A); RT 1.444 min, [M+H]+576.4.1H NMR (400 MHz, MeOD) 6 ppm 7.29 (dt, J = 2.9, 1.3 Hz, 1 H), 7.02 - 6.93 (m, 1H), 6.70 - 6.58 (m, 1H), 6.41 (dd, J = 3.1 , 1.8 Hz, 1 H), 4.57 (s, 1H), 3.97 (s, 2H), 3.98 - 3.90 (m, 1H), 3.73 (hept, J = 6.6 Hz, 3H), 3.23 (q, J = 7.4 Hz, 3H), 3.14 - 2.97 (m, 4H), 2.97 - 2.82 (m, 3H), 1.41 - 1.28 (m, 20H), 1.12 (d, J = 2.4 Hz, 2H).

[0515] Compound 8: 6-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide

[0516] To a solution of (8f) N-[(7-methoxy-1 H-indol-4-yl)methyl]-6-{[(1S,3S)-3- [(triisopropylsilyl)oxy]cyclopentyl]amino}imidazo[1 ,2-a]pyridine-3-carboxamide (27 mg, 0.05 mmol, 1 eq) in DCM (3 mL) was added HCI (46.16 pL (4 M in dioxane), 0.18 mmol, 4 eq), before stirring at rt for 16 h . The reaction mixture was diluted with DCM and washed with sat. Na2CC>3 (aq) followed by brine. The organic layer was then dried over anhydrous MgSC , filtered, ISOLUTE HM-N was added, and the mixture concentrated to dryness. Crude material was then purified by automated flash chromatography (Combiflash Rf, RediSep Silica, 4 g column) eluting with 0 to 100% EtOAc in heptane followed by 0 to 60% MeOH in EtOAc. Product was then further purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) at pH 9 to afford title product 8 (0.28 mg, 0.67 mol, 1.4%) as a cream solid. LC-HRMS (method B); RT 0.68 min; target mass 419.1957; found mass ion [M+H]+420.2035; found empirical formula C23 H25 N5 03.1H NMR (400 MHz, DMSO) 5 ppm 11.29 (app s, 1 H), 8.75 (d, J = 2.2 Hz, 1 H), 8.68 (t, J = 6.0 Hz, 1 H), 8.15 (s, 1H), 7.44 (d, J = 9.6 Hz, 1H), 7.22 (t, J = 2.7 Hz, 1 H), 7.01 (dd, J = 9.6, 2.3 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 6.68 - 6.46 (m, 2H), 5.70 (d, J = 6.1 Hz, 1H), 4.67 (d, J = 5.8 Hz, 1 H), 4.56 (d, J = 3.9 Hz, 1 H), 3.89 (s, 3H), 3.74 (q, J = 6.6 Hz, 1 H), 2.16 (dt, J = 14.8, 7.3 Hz, 1 H), 2.03 - 1.81 (m, 2H), 1.64 (dt, J = 12.8, 6.1 Hz, 2H), 1.56 - 1.39 (m, 2H), 1.23 (s, 1 H).

[0517] Exemplification 9: 6-{[(1S,3S)-3-hydroxycvclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazon,2-alpyridine-3-carboxamide

[0518] Compound 9 was made using a route analogous to example 8, starting with (1S,3S)-3- aminocyclohexan-1-ol: HCI to give title compound 9 (3.2 mg, 0.01 mmol) as a cream solid. LC-HRMS (method B); RT 0.74 min; target mass 433.2114; found mass ion [M+H]+ 434.2184; found empirical formula C24 H27 N5 03.1H NMR (400 MHz, DMSO) 6 11.30 (app s, 1 H), 8.81 (d, J = 2.3 Hz, 1 H), 8.67 (t, J = 5.9 Hz, 1 H), 8.16 (s, 1 H), 7.45 (dd, J = 9.6, 0.7 Hz, 1 H), 7.23 (t, J = 2.8 Hz, 1H), 7.07 (dd, J = 9.6, 2.3 Hz, 1 H), 6.88 (d, J = 7.9 Hz, 1 H), 6.66 - 6.51 (m, 2H), 5.48 (d, J = 7.8 Hz, 1 H), 4.68 (d, J = 5.8 Hz, 2H), 4.48 (d, J = 3.7 Hz, 1 H), 3.97 - 3.82 (m, 2H), 3.90 (s, 3H), 3.52 (td, J = 7.6, 3.9 Hz, 1 H), 2.15 - 2.06 (m, 1 H), 1.89 - 1.71 (m, 2H), 1.71 - 1.41 (m, 2H), 1.36 - 1.22 (m, 2H), 1.15 (s, 1 H). Exemplification 10: 5-{r(1S,3S)-3-hvdroxycyclopentyl1amino}-N-((7-methoxy-1 H-indol-4- yl)methyllpyrazolori,5-alpyridine-3-carboxamide

[0519] Intermediate 10a: 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid

[0520] To a suspension of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 g, 3.72 mmol, 1 eq) in methanol (30 mL) was added sodium hydroxide (7.4 mL, 2 M in water, 14.9 mmol, 4 eq). The reaction was then heated to 50° C for 16 h before cooling to rt and removing the methanol under reduced pressure. The residual aqueous was then acidified by the addition of 2 M HCI (aq), the resultant precipitate was collected by filtration, washing with water followed by diethyl ether. The sample was dried for 16 h under vacuum at 40° C to give title product 10a (785 mg, 2.83 mmol, 76%) as a white solid. LCMS (method A); RT 0.798 min, [M+H]+ 241.0.1H NMR (400 MHz, DMSO) 5 12.65 (s, 1 H), 8.84 (dd, J = 7.3, 0.8 Hz, 1 H), 8.43 (s, 1 H), 8.22 (dd, J = 2.3, 0.8 Hz, 1 H), 7.31 (dd, J = 7.3, 2.2 Hz, 1 H).

[0521] Intermediate 10b: 5-bromo-N-[(7-methoxy-1 H-indol-4-yl)methyl]pyrazolo[1 ,5- a]pyridine-3-carboxamide

[0522] To a solution of (10a) 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (300 mg, 1.08 mmol, 1 eq) in DMF (10 mL) was added DIPEA (0.54 mL, 3.24 mmol, 3 eq), HATU (617 mg, 1.62 mmol, 1.5 eq) and finally (5a) (7-methoxy-1 H-indol-4-yl)methanamine (227 mg, 1.3 mmol, 1.2 eq). The reaction was stirred at rt for 4.5 h before the solvent was removed on a Biotage V10. The residue was partitioned between EtOAc and water, the aqueous layer was then back extracted with EtOAc twice. The combined organics were washed with brine, dried over anhydrous MgSO4, filtered, and then concentrated to dryness. Crude material was loaded onto ISOLUTE HM-N and purified by automated flash chromatography (Combiflash 300+, RediSep Silica, 40 g column) eluting with 0 to 100% EtOAc in Heptane. Product was then triturated with MTBE, the filtrate was concentrated to afford title product 10b (85 mg, 0.21 mmol, 20%) as a yellow solid. LCMS (method A); RT 1.072 min, [M+H]+399.2.

[0523] Compound 10: 5-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1,5-a]pyridine-3-carboxamide

[0524] To a microwave vial was added (10b) 5-bromo-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1,5-a]pyridine-3-carboxamide (90 mg, 0.23 mmol, 1 eq), (8a) (1S,3S)-3-[(triisopropylsilyl)oxy]cyclopentan-1 -amine (87 mg, 0.34 mmol, 1.5 eq), sodium tert-butoxide (65 mg, 0.68 mmol, 3 eq) and 2-dicyclohexylphosphino-2’-(N,N- dimethylamino)biphenyl (18 mg, 0.05 mmol, 0.2 eq) and 1,4-dioxane (2 ml_). The solution was sparged with N2 before tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol, 0.05 eq) was added. The vial was sealed and heated at 125° C for 1 h in a microwave reactor. The reaction was diluted with EtOAc and then washed with sat. NaHCCh (aq) followed by brine. The organic layer was dried over anhydrous MgSCU, filtered, and then concentrated to dryness. Crude intermediate was then purified by automated flash chromatography (Combiflash 300+, Gold RediSep Silica, 12 g column) eluting with 0 to 13% MeOH in DCM. Impure intermediate was then loaded onto ISOLUTE HM-N and further purified by automated flash chromatography (Combiflash Rf, RediSep C18, 13 g column) at pH 4. Product fractions were combined and the MeCN removed under reduced pressure, the residual aqueous was basified by addition of sat. NaHCOs (aq) and product was extracted with EtOAc twice. The organic extract was washed with brine, dried over anhydrous MgSO4 and the solvent removed in vacuo. The protected intermediate was dissolved in THF (1 mL), TBAF (0.45 mL, 1 M in THF, 0.45 mmol, 2 eq) was added and the reaction was left to stir at rt for 16 h. The reaction mixture was diluted with EtOAc and then washed with sat. NaHCOs (aq) followed by brine. The organic layer was dried over anhydrous MgSO4, filtered, and then concentrated to dryness. Crude product was then purified by preparative HPLC automated chromatography (ISCO AccQPrep HP150) at pH 9 to give title product 10 (0.86 mg, 2.05 pmol, 0.9%) as a white solid. LC-HRMS (method B); RT 0.78 min; target mass 419.1957; found mass ion [M+H]+420.2034; found empirical formula C23 H25 N5O3.1H NMR (400 MHz, DMSO) 6 ppm 11.17 (apps, 1H), 8.31-8.25 (m, 2H), 8.19 (t, J = 5.8 Hz, 1H), 7.21 (t, J = 2.8 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.61 -6.50 (m, 3H), 6.43 (dd, J = 7.5, 2.5 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H), 4.59 (d, J = 3.9 Hz, 1H), 4.23 (dt, J = 9.3, 4.2 Hz, 1H), 3.94-3.85 (m, 1H), 3.88 (s, 3H), 2.24-2.11 (m, 1H), 2.02- 1.92 (m, 1H), 1.91 - 1.83 (m, 1H), 1.64 (dt, J = 12.9, 6.2 Hz, 1H), 1.55 (d, J = 12.6 Hz, 1H), 1.55-1.37 (m, 1H).

[0525] Exemplification 11: 5-{((1S,3S)-3-hydroxycyclohexyl1amino}-N-r(7-methoxy-1H-indol-4- yl)methyl]pyrazolon,5-alpyridine-3-carboxamide

[0526] Intermediate 11a: (1S,3S)-3-[(triisopropylsilyl)oxy]cyclohexan-1 -amine

[0527] Intermediate 11a was made using a method analogous to intermediate 8a, using (1S,3S)-3-aminocyclohexan-1-ol: HCI, instead to give title compound 11a (370 mg, 1.36 mmol, 69%) as a beige gum.1H NMR (400 MHz, DMSO) 5 ppm 6.59 (s, 2H), 4.24 (dq, J = 5.7, 2.7 Hz, 1H), 3.23-3.11 (m, 1H), 1.95-1.79 (m, 2H), 1.72- 1.30 (m, 5H), 1.29-1.16 (m, 1H), 1.11 -0.96 (m, 21H).

[0528] Compound 11: 5-{[(1S,3S)-3-hydroxycyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1,5-a]pyridine-3-carboxamide

[0529] Compound 11 was made using a route analogous to example 10, using (11a) (1S,3S)- 3-[(triisopropylsilyl)oxy]cyclohexan-1-amine instead to yield title compound 11 (2.2 mg, 4.96 pmol, 1.3%) as a white solid. LC-HRMS (method B); RT 0.85 min; target mass 433.2114; found mass ion [M+H]+ 434.2188; found empirical formula C24 H27 N503.1H NMR (400 MHz, DMSO) 5 ppm 11.17 (d, J = 2.9 Hz, 1H), 8.28 (t, J = 3.8 Hz, 2H), 8.18 (t, J = 5.9 Hz, 1H), 7.20 (t, J = 2.8 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H), 6.54 (dd, J = 3.1, 2.0 Hz, 1H), 6.48 (dd, J = 7.6, 2.6 Hz, 1 H), 6.37 (d, J = 7.8 Hz, 1 H), 4.62 (d, J = 5.8 Hz, 2H), 4.53 (d, J = 3.6 Hz, 1H), 4.00 - 3.91 (m, 1H), 3.88 (s, 3H), 3.75 - 3.57 (m, 1H), 1.96 - 1.40 (m, 7H), 1.26 (q, J =

[0530] 8.7 Hz, 1 H).

[0531] Example 2: WNK1 TR-FRET binding assay

[0532] The binding activity of compounds was determined by in-vitro assay

[0533] The WNK1 TR-FRET binding assays were performed in a 40 pL volume in white 384- well plates (corning #3574) using in-house Terbium labelled phosphorylated or dephosphorylated WNK1 protein, Tb-8His-Halo-TEV-WNK1 (210-482) (UniProtKB® primary accession number Q9H4A3) having an amino acid sequence MHHHHHHHHAEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYVW RNIIPHVAPTHRCIAPDLIGMGKSDKPDLGYFFDDHVRFMDAFIEALGLEEVVLVIHDW GSALGFHWAKRNPERVKGIAFMEFIRPIPTWDEWPEFARETFQAFRTTDVGRKLIIDQ NVFIEGTLPMGVVRPLTEVEMDHYREPFLNPVDREPLWRFPNELPIAGEPANIVALVE EYMDWLHQSPVPKLLFWGTPGVLIPPAEAARLAKSLPNCKAVDIGPGLNLLQEDNPDL IGSEIARWLSTLEISGGGSENLYFQCKAVGMSNDGRFLKFDIEIGRGSFKTVYKGLDTE TTVEVAWCELQDRKLTKSERQRFKEEAEMLKGLQHPNIVRFYDSWESTVKGKKCIVL VTELMTSGTLKTYLKRFKVMKIKVLRSWCRQILKGLQFLHTRTPPIIHRDLKCDNIFITG PTGSVKIGDLGLATLKRASFAKSVIGTPEFMAPEMYEEKYDESVDVYAFGMCMLEMA TSEYPYSECQNAAQIYRRVTSGVKPASFDKVAIPEVKEIIEGCIRQNKDERYSIKDLLNH AFFQEE (SEQ ID No. 1).

[0534] The Terbium labelled WNK1 proteins were coupled with a fluorescein labelled ATP competitive probe, VER-00540269. The design of VER-00540269 was based on literature inhibitor WNK463 (Yamada et al., 2016a), replacing the t-butyl amide with a flexible linker to tether a fluorescein label. The addition of WNK463 (MCE® Cat. No.: HY- 100626), competitively to the same site as the inhibitor probe, results in a decrease in the TR-FRET signal due to displacement of the probe. WNK463 was demonstrated to dose dependently inhibit the phosphorylation of OSR1 in HEK293 cells (Yamada et al., 2016a).

[0535] Compounds were screened in n=2 11 point 3-fold titrations. The assay consisted of 1nM Terbium labelled WNK1 , 2 nM or 150 nM VER-00540269 probe, 50 mM HEPES (4-(2- hydroxyethyl)-l-piperazine-ethanesulfonic acid) pH 7.5, 150 mM NaCI, 0.01% Tween-20, 1 mM dithiothreitol and 5% DMSO. Assays were incubated for 2 h at 23° C. TR-FRET measurements were performed on a BioTek Synergy Neo2 plate reader. TR- FRET was measured by excitation of the terbium-donor with 340 nm light and then, after a delay time 100 (is, measurement of terbium and fluorescein emission at 495 nm and 520 nm, using a time window of 300 |is. This measurement was repeated 20 times for both emissions (495 nm and 520 nm) with a 300 .s time window between repeat reads. The TR-FRET signal was calculated as an emission ratio of 520 nm over 495 nm signals.

[0536] The TR-FRET signal for test compound was normalized against 0% inhibition control wells and 100% inhibition control wells and % inhibition of test compound calculated. Test compound potency (IC50) was estimated by nonlinear regression using the sigmoidal dose-response (variable slope) using Xlfit 4 (I DBS, Guildford, Surrey, UK, model 205).y= (A+((B-A) / (1+((C / x)AD)))) where y is the normalized TR-TRET signal measurement for a given concentration of test compound, x is the concentration of test compound, A is the estimated efficacy (% inhibition) at infinite compound dilution, and B is the maximal efficacy (% inhibition). C is the IC50 value and D is the Hill slope coefficient.

[0537] The Ki values were determined from the IC50 values according to Cer et al, Nucleic Acids Res, 2009, 37(WebServer issue): W441-W445. Inhibition constants (Ki) are determined from complete binding inhibition curves (cKi).

[0538] The c values were determined from the IC50 values as follows;

[0539] And PTis total protein, LTis total probe, IC50is concentration giving 50% inhibition and KM(probe Kd) is determined experimentally. I50is the free inhibitor concentration at the ICso.Lso is the free probe concentration at the IC50 The compounds of the invention were screened in the above-mentioned assay and the cKj values of the compounds are set forth in Table 1 below wherein “A” refers to a c of less than 100 nM, “B” refers to cKj value in the range of 100 nM to 1000 nM and “C” refers to cKi value in the range of greater than 1000 nM to 2000 nM.

[0540] Table 1. cKj values.

[0541] References

[0542] Ishigami-Yuasa M et al.: Development of WNK signaling inhibitors as a new class of antihypertensive drugs. Bioorg Med Chem. 2017, 25(14):3845-3852.

[0543] Yamada K et al.: Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol. 2016,12:896-898. (Yamada et al., 2016a)

[0544] Yamada K, et al.: Discovery and Characterization of Allosteric WNK Kinase Inhibitors.

[0545] ACS Chem Biol. 2016, 11(12):3338-3346. (Yamada et al., 2016b)

[0546] Yamada K et al.: Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models. J Med Chem. 2017 Aug 24;60(16):7099- 7107.

[0547] Xiu, M., Li, L, Li, Y. et al. An update regarding the role of WNK kinases in cancer. Cell Death Dis 13, 795 (2022).

Claims

Claims1 . A compound of formula (la) or formula (lb):whereinW is C(H)2or C(D)2;R1is H or CH3;R2is H;R3is H or OCH3;A is selected from the group consisting of H, C1-3 alkoxy, CF3, and a group of formula (II):Formula (II) whereinX is C(H) or N;R6is H or C1-4 alkyl optionally substituted with phenyl; andR5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said Ci-e alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);R7is individually selected from C1-3 alkoxy optionally substituted with one or more F; -OH; -O-benzyl; C1.3 alkyl optionally substituted with OH;N(CH3)2; N(H)2;or when two R7are linked together to form a ring, then said two R7are individually selected from C1-2 alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said C1.2 alkanediyl is optionally replaced with -O-; orR5and R6are linked together to form a ring andR5is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1-5 alkanediyl is optionally replaced with -O- or N(R9); andR6is a bond or C1-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8, and one methylene of the C1-5 alkanediyl is optionally replaced with -O- or N(R9); wherein two R8are optionally linked together to form a ring together with the intervening atom(s);R8is individually selected from C1-3 alkyl optionally substituted with OH; - OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F; or when two R8are linked together to form a ring, then said two R8are individually selected from C1-3 alkanediyl optionally substituted with one or two substituents selected from F, OH and NH2, and one or two methylene(s) of said C1-3 alkanediyl is optionally and individually replaced with -O-, -N(H)- or -N(CH3)-; andR9is H, C1-3 alkyl, oxetanyl,or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1is H, R2is H, and R3is H or OCH3.

3. The compound according to claim 1, wherein R1is H, R2is H, and R3is OCH3.

4. The compound according to anyone of the preceding claims, wherein A is H, or of Formula (II):Formula (II) whereinX is N;R6is H or C1-4 alkyl optionally substituted with phenyl; andR5is selected from the group consisting of C1-6 alkyl optionally substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1.6 alkyl is optionally and individually replaced with -O- or C=O; C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R7; and tetrahydropyranyl; wherein two R7are optionally linked together to form a ring together with the intervening atom(s);R7is individually selected from Ci-3alkoxy optionally substituted with one or more F; -OH; -O-benzyl; Ci-3alkyl optionally substituted with OH;or when two R7are linked together to form a ring, then said two R7are individually selected from Ci-2alkanediyl optionally substituted with one or two substituents selected from F and OH, and one of the methylene of said Ci-2alkanediyl is optionally replaced with -O-.

5. The compound according to anyone of the preceding claims, wherein R5is C1-6 alkyl substituted with one or more, identical or different, substituents R7, wherein one or more methylene(s) of said C1-6 alkyl is optionally and individually replaced with -O- or C=O.

6. The compound according to anyone of the preceding claims, wherein R5is C(O)-Ci-5alkyl, C(O)C(CH3)3, C(O)CH2C(CH3)3, C(O)O-Ci-4alkyl, or C(O)OC(CH3)3.

7. The compound according to anyone of the preceding claims, wherein R5is Cs cycloalkyl substituted with one or more, identical or different, substituents R7.

8. The compound according to anyone of the preceding claims, wherein R5is Cs cycloalkyl, Cs cycloalkyl substituted with OH, Ce cycloalkyl substituted with OH, Ce cycloalkyl, or Ce cycloalkyl substituted with -O-benzyl.

9. The compound according to anyone of the preceding claims, wherein R6is H or benzyl.

10. The compound according to anyone of the preceding claims, wherein R7is OH, O-benzyl.11 . The compound according to any one of the preceding claims, wherein A is of Formula (II), wherein X is N; R5and R5are linked together to form a ring; and -R5-R6- is C3-5 alkanediyl optionally substituted with one or more, identical or different, substituents R8.

12. The compound according to anyone of the preceding claims, wherein A is pyrrolidinyl optionally substituted with one or more individually selected R8, wherein R8is selected from C1.3 alkyl optionally substituted with OH; -OH; F; N(H)2; and -OC1-3 alkyl optionally substituted with one or more F.

13. The compound according to any one of the preceding claims, wherein R8is F.

14. The compound according to anyone of the preceding claims, wherein A is selected from the group consisting of:

15. The compound according to anyone of the preceding claims, wherein the compound is selected from the group consisting of:N-(1 H-indol-4-ylmethyl)imidazo[1 ,2-a]pyridine-3-carboxamide, tert-butyl N-{3-[(1 H-indol-4-ylmethyl)carbamoyl]pyrazolo[1 , 5-a]pyridin-5- yl}carbamate, 5-(2,2-dimethylpropanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1 ,5- a] py ri d i ne-3-ca rboxa m i d e ,5-(3,3-dimethylbutanamido)-N-(1 H-indol-4-ylmethyl)pyrazolo[1,5- a]pyridine-3-carboxamide,N-[(7-methoxy-1 H-indol-4-yl)methyl]imidazo[1 ,2-a]pyridine-3- carboxamide,6-(3,3-difluoropyrrolidin-1-yl)-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide, 6-{benzyl[3-(benzyloxy)cyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide, 6-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide, 6-{[(1S,3S)-3-hydroxycyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]imidazo[1,2-a]pyridine-3-carboxamide, 5-{[(1S,3S)-3-hydroxycyclopentyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1 ,5-a]pyridine-3-carboxamide, and 5-{[(1S,3S)-3-hydroxycyclohexyl]amino}-N-[(7-methoxy-1 H-indol-4- yl)methyl]pyrazolo[1 ,5-a]pyridine-3-carboxamide.

16. The compound according to anyone of the preceding claims, wherein the compound of Formula (I) is a WNK lysine deficient protein kinase 1 (WNK1) inhibitor.

17. A pharmaceutical composition comprising a compound according to claims 1-16, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

18. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, for use as a medicament.

19. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, for use in treating, alleviating or preventing diseases and disorders related to the activity of WNK1.

20. The compound for use according to claim 19, wherein the disease or disorder related to the activity of WNK1 is hypertension.21 . The compound for use according to claim 19, wherein the disease or disorder related to the activity of WNK1 is cancer.

22. The compound for use according to claim 21 , wherein the cancer is selected from leukemia, lymphoma and myeloma.

23. Use of a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, for the manufacture of a medicament for treating, alleviating or preventing diseases and disorders related to the activity of WNK1.

24. A method for treating, alleviating or preventing diseases and disorders related to the activity of WNK1 , said method comprising administering a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, to a subject in need thereof.

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