FOXN1 activators

Abstract

The present disclosure provides compounds that are FOXN1 activators useful for promoting thymus regeneration, immune reconstitution, promoting skin wound healing, and / or augmenting hair growth in a subject in need thereof.

Description

- 1 - FOXN1 ACTIVATORS BACKGROUND Field

[0001] The present disclosure provides compounds that are FOXN1 activators. FOXN1 activators are useful for promoting thymus regeneration, immune reconstitution, promoting skin wound healing, and / or augmenting hair growth in a subject in need thereof. Background

[0002] The thymus is a specialized primary lymphoid organ of the immune system that facilitates maturation of T cells, which play a central role in the adaptive immune response. Although the thymus constantly undergoes acute stresses and regeneration cycles, it undergoes age-related involution over time, and is very sensitive to insults, e.g., infections, stress, and cytoreductive therapies. Thymus dysfunction resulting from any of these factors can lead to immunodeficiency and a general increase in mortality.

[0003] FOXN1 is a transcription factor that regulates thymic epithelial cell development and thymus organogenesis. FOXN1 deficiency is known to disrupt thymic architecture and thymic T cell development, while administration of recombinant FOXN1 protein to mice increases thymic epithelial cell development. Thus, compounds that promote FOXN1 expression, i.e., FOXN1 activators, may be useful in promoting thymus regeneration, immune reconstitution, skin wound healing, and / or augmenting hair growth.

[0004] Therefore, there is a need in the art for compounds that are FOXN1 activators. BRIEF SUMMARY

[0005] The present disclosure provides a compound having Formula (I):

[0006] or a salt or solvate thereof, wherein:- 2 -

[0007] Ring A is selected from optionally substituted C6-C10aryl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted 5- or 6-memberered heteroaryl;

[0008] each is a single or a double bond consistent with the valences of X7, X8, and X9;

[0009] X5is selected from a bond, -NR16- and -O-;

[0010] X7is selected from -N- and -NR19-;

[0011] X8is selected from -N-, -NR20-, and -CR8aR8b-;

[0012] X9is selected from -N-, -NR25, CR9aR9b, and -C(=O)-;

[0013] R8aand R9aare each independently selected from hydrogen, halo, cyano, optionally substituted C1-C6alkyl, optionally substituted C6-C10aryl, -C(=O)OR25, and - C(=O)NR26R27;

[0014] R8band R9bare each independently absent or are selected from hydrogen and optionally substituted C1-C6 alkyl;

[0015] R16is selected from hydrogen and optionally substituted C1-C6alkyl;

[0016] R19is selected from hydrogen, optionally substituted C1-C6 alkyl, -C(=O)R19a, -C(=O)OR19a, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C6-C10aryl, and optionally substituted 5- to 10-membered heteroaryl;

[0017] R19ais selected from hydrogen and C1-C6 alkyl;

[0018] R20is selected from hydrogen and C1-C6alkyl;

[0019] R21is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6alkyl, and C2-C6 alkenyl;

[0020] R22is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6alkyl, C2-C6alkenyl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted C6-C10 aryl;

[0021] R23is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, and C2-C6alkenyl;

[0022] R24is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted C6-C10aryl;

[0023] one of R21, R22, R23, and R24is absent;

[0024] R25is selected from hydrogen and C1-C6 alkyl; and

[0025] R26and R27are each independently selected from hydrogen and C1-C6alkyl.- 3 -

[0026] In some aspects, the compound of Formula (I) has Formula (I-A):

[0027] wherein:

[0028] X6is selected from -N- and -CH-;

[0029] R17is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy-C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6- membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl; and

[0030] R18is selected from hydrogen, halo, optionally substituted C1-C6 alkyl, and C2-C3 alkynyl.

[0031] In some aspects, the compound of Formula (I) or Formula (I-A) has Formula (I-B):

[0032] or a salt or solvate thereof, wherein:

[0033] each is a single or a double bond consistent with the valences of X7and X8;

[0034] X5is selected from -NR16- and -O-;

[0035] X7is selected from -N- and -NR19-;

[0036] X8is selected from -N-, -NR20-, and -CH-;

[0037] R16is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0038] R19is selected from hydrogen, optionally substituted C1-C6 alkyl, -C(=O)R19a, -C(=O)OR19a, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo;

[0039] R19ais selected from hydrogen and C1-C6 alkyl; and

[0040] R20is selected from hydrogen and C1-C6alkyl;

[0041] wherein when X5is -NH-, X6is -N-, R18is chloro, X7is -NR19-, and X8is -N-, R19is not 2-methoxyethyl.

[0042] In some aspects, the compound of Formula (I-B) has Formula (I-C):- 4 -

[0043] In some aspects, the compound of Formula (I-B) has Formula (I-D):

[0044] In some aspects, the compound of Formula (I-B) has Formula (I-E):

[0045] In some aspects, the compound of Formula (I-B) has Formula (I-F):

[0046] In some aspects, the compound of Formula (I-B) has Formula (I-G):

[0047] In some aspects, the compound of Formula (I-B) has Formula (I-H):.

[0048] In some aspects, the compound of Formula (I-B) has Formula (I-I):- 5 -(I-I).

[0049] In some aspects, the compound of Formula (I) has Formula (I-J):

[0050] wherein R22is selected from optionally substituted 5- or 6-membered heterocyclo and optionally substituted C6-C10 aryl.

[0051] In some aspects, X5is -NR16-.

[0052] In some aspects, R16is hydrogen, methyl, or cyclopropylmethyl.

[0053] In some aspects, R16is hydrogen.

[0054] In some aspects, X5is -O-.

[0055] In some aspects, X6is -N-.

[0056] In some aspects, R17is hydrogen or methyl.

[0057] In some aspects, R17is methyl.

[0058] In some aspects, R17is optionally substituted C1-C6alkyl.

[0059] In some aspects, R17is C1-C6alkyl substituted with amino, hydroxy, C1-C6alkoxy, -C(=O)R18a, -C(=O)OR18a, or C3-C7 cycloalkyl, wherein R18ais selected from hydrogen and C1-C6alkyl.

[0060] In some aspects, R17is:

[0061] In some aspects, R17is optionally substituted 5- or 6-membered heterocyclo or optionally substituted 5- or 6-membered heteroaryl.

[0062] In some aspects, R17is:.- 6 -

[0063] In some aspects, R18is hydrogen, methyl, or chloro.

[0064] In some aspects, R18is methyl.

[0065] In some aspects, R19is hydrogen or methyl.

[0066] In some aspects, R19is hydrogen.

[0067] In some aspects, R19is -C(=O)CH3 or -C(=O)OC(CH3)3.

[0068] In some aspects, R19is optionally substituted C1-C6 alkyl.

[0069] In some aspects, R19is C1-C6alkyl substituted with amino, hydroxy, C1-C6alkoxy, C3-C7cycloalkyl, optionally substituted 5- or 6 membered heterocyclo, -OC(=O)R19b, or -C(=O)NR19bR19c, wherein R19band R19care each independently selected from hydrogen and C1-C6alkyl.

[0070] In some aspects, R19is:.

[0071] In some aspects, R19is:.

[0072] In some aspects, R19is optionally substituted 5- or 6 membered heterocyclo.

[0073] In some aspects, R19is:- 7 -

[0074] In some aspects, R19is:.

[0075] In some aspects, R20is hydrogen or methyl.

[0076] In some aspects, R21is hydrogen.

[0077] In some aspects, R22is hydrogen or halo.

[0078] In some aspects, R22is chloro.

[0079] In some aspects, R23is hydrogen or halo.

[0080] In some aspects, R23is chloro.

[0081] In some aspects, R24is hydrogen, halo, or optionally substituted phenyl.

[0082] In some aspects, R24is chloro.

[0083] In some aspects, R24is 3-hydroxyphenyl.

[0084] In some aspects, the compound is selected from the group consisting of the compounds listed in Table 1.

[0085] The present disclosure also provides a compound having Formula (II):

[0086] or a salt or solvate thereof, wherein:

[0087] X1is absent or is selected from -NR1a-, -^(CH2)n-NR1a-, and -^NR1a-(CH2)n-, wherein the bond marked with a “^” is attached to R1;

[0088] n is selected from 1, 2, 3, and 4;

[0089] R1ais selected from hydrogen and optionally substituted C1-C6alkyl;

[0090] R1is selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy-C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6- membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl;- 8 -

[0091] R2is selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0092] R3is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C3-C7 cycloalkyl;

[0093] X10is selected from -NR6- and -O-;

[0094] R6is selected from hydrogen, optionally substituted C1-C4alkyl, and optionally substituted 5- to 10-membered heteroaryl;

[0095] X11is selected from -N- and -CR11x;

[0096] X12is selected from -N- and -CR12x;

[0097] X13is selected from -N- and -CR13x;

[0098] X14is selected from -N- and -CR14x;

[0099] with the proviso that no more than two of X11, X12, X13, and X14are -N-; and

[0100] R11x, R12x, R13x, and R14xare each independently selected from hydrogen, halo, C1- C4 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0101] In some aspects, the compound of Formula (II) has Formula (II-A):

[0102] or a salt or solvate thereof, wherein:

[0103] R4is selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 cycloalkyl;

[0104] R5is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C3-C7cycloalkyl;

[0105] Y1is selected from -NR7- and -O-; and

[0106] R7is selected from hydrogen and C1-C4alkyl;

[0107] wherein when X1is absent, R2is methyl, R3is hydrogen, R4is methyl, R5is methyl, and Y1is -O-, R1is not:- 9 -

[0108] In some aspects, the compound of Formula (II) has Formula (II-B):

[0109] wherein:

[0110] R14xis selected from optionally substituted 5- or 6-membered aryl and optionally substituted 5- or 6-membered heteroaryl;

[0111] X15is selected from -N- and -CH-;

[0112] R28is selected from hydrogen, halo, optionally substituted C1-C6alkyl, and C2-C3alkynyl; and

[0113] R29is selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy-C1-C6alkyl-, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6- membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0114] In some aspects:

[0115] R1ais selected from hydrogen and C1-C6alkyl;

[0116] R1is selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0117] R2is selected from hydrogen, C1-C6alkyl, C3-C7cycloalkyl, 5- or 6-membered aryl, and 5- or 6-membered heteroaryl;

[0118] R3is selected from hydrogen, C1-C6alkyl, and C3-C7cycloalkyl;

[0119] R4is selected from hydrogen, C1-C6alkyl, and C3-C7cycloalkyl; and

[0120] R5is selected from hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl.- 10 -

[0121] In some aspects, X1is absent.

[0122] In some aspects, R1is selected from C1-C6 alkoxy-C1-C6 alkyl-, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0123] In some aspects, R1is selected from:

[0124] wherein R1bis selected from hydrogen, C1-C4alkyl, -C(=O)O(CH3)3, and - C(=O)CH3.

[0125] In some aspects, X1is -NR1a-.

[0126] In some aspects, R1ais selected from hydrogen and methyl.

[0127] In some aspects, R1is selected from:

[0128] In some aspects, X1is -^NR1a-(CH2)n-.

[0129] In some aspects, R1ais selected from hydrogen and methyl.

[0130] In some aspects, n is 1.

[0131] In some aspects, R1is:.

[0132] In some aspects, R2is C1-C6alkyl.

[0133] In some aspects, R2is methyl, ethyl, or isopropyl.

[0134] In some aspects, R2is phenyl.

[0135] In some aspects, R3is hydrogen.

[0136] In some aspects, R4is C1-C6alkyl.- 11 -

[0137] In some aspects, R4is methyl.

[0138] In some aspects, R5is C1-C6 alkyl.

[0139] In some aspects, R5is methyl.

[0140] In some aspects, Y1is -O-.

[0141] In some aspects, Y1is -NR7-.

[0142] In some aspects, R7is hydrogen or methyl.

[0143] In some aspects, R6is hydrogen or methyl.

[0144] In some aspects, the compound is selected from the group consisting of the compounds listed in Table 2.

[0145] The present disclosure also provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0146] The present disclosure also provides a method of promoting thymus regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0147] The present disclosure also provides a method of promoting immune reconstitution in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0148] The present disclosure also provides a method of activating FOXN1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0149] In some aspects, the subject is in need of FOXN1 activation due to hematopoietic stem cell transplantation, immune deficiency due to HIV, HIV therapy, autoimmune disease, inborn errors of thymic development, administration of a vaccine, age-related immune senescence, administration of exogenous glucocorticoids, bacterial or viral infections, radiation, immunotherapy, or cytoreductive treatments, zinc deficiency, thymus involution, diabetes-related ulcers, foot ulcers, chronic wounds, alopecia, or a combination thereof.

[0150] In some aspects, the subject is in need of FOXN1 activation to treat or prevent immune deficiency due to HIV, autoimmune disease, age-related immune senescence, bacterial or viral infections, zinc deficiency, thymus involution, diabetes-related ulcers, foot ulcers, chronic wounds, alopecia, or a combination thereof.- 12 -

[0151] The present disclosure also provides a method of promoting skin wound healing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0152] In some aspects, the subject has a diabetes-related ulcer, a foot ulcer, a chronic wound, or a combination thereof.

[0153] The present disclosure also provides a method of augmenting hair growth, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0154] In some aspects, the subject has alopecia.

[0155] The present disclosure also provides a method of enhancing immune function or promoting thymic regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject is in need of immune function enhancement or thymic regeneration due to administration of CAR-T cells or other adoptive T-cell therapies, recovery from sepsis or critical illness, idiopathic T-cell lymphopenia, immunosuppression following solid organ transplantation, or a combination thereof. In some aspects, the subject is at risk of or recovering from infection due to impaired T-cell function. In some aspects, the subject is an elderly individual, an immunocompromised patient, a recipient of immunosuppressive therapy, or a combination thereof.

[0156] The present disclosure also provides a method of promoting immune tolerance or reducing transplant-related complications in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject is receiving a hematopoietic stem cell transplant or solid organ transplant. In some aspects, the method reduces the risk of graft-versus-host disease (GVHD). In some aspects, the method enhances immune reconstitution.

[0157] The present disclosure also provides a method of treating or supporting recovery from a thymic epithelial tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject has a thymoma or thymic carcinoma.- 13 -

[0158] The present disclosure also provides a method of promoting immune surveillance or reducing cancer risk in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject has an age-related decline in immune function, a personal or familial history of cancer, or a genetic predisposition to immune dysfunction.

[0159] The present disclosure also provides a method of augmenting hair growth or restoring hair loss in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the hair loss is chemotherapy-induced, radiation- induced, or idiopathic in origin.

[0160] The present disclosure also provides a method of promoting skin repair or regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject has a radiation-induced skin injury, a surgical wound, or age-related skin atrophy.

[0161] The present disclosure also provides a method of promoting dermal regeneration or treating skin aging in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0162] The present disclosure also provides a method of preconditioning a non-human donor organism for xenotransplantation of a composite organ comprising thymic tissue, comprising administering to the donor a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the method improves thymic tissue function, promotes immune system development, or enhances compatibility of the graft with the recipient immune system.

[0163] Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.- 14 - DETAILED DESCRIPTION I. Definitions

[0164] As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

[0165] The term “disease” or “condition” denotes disturbances and / or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and / or malfunctions.

[0166] The term “therapeutically effective amount” or “effective dose” as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to a subject in need thereof.

[0167] The term “container” means any receptacle and closure therefore suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0168] The term “insert” means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the “label” for a pharmaceutical product.

[0169] The use of the terms “a,” “an,” “the,” and similar referents in the context of describing the disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein,- 15 - is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0170] The term “halo” as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I.

[0171] The term “hydroxy” as herein used by itself or as part of another group refers to -OH.

[0172] The term “alkyl” as used herein by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C1-C12alkyl, or the number of carbon atoms designated, e.g., a C1alkyl such as methyl, a C2alkyl such as ethyl, etc. In one aspect, the alkyl is a C1-C10alkyl. In another aspect, the alkyl is a C1-C6 alkyl. In another aspect, the alkyl is a C1-C4 alkyl. In another aspect, the alkyl is a C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C12alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0173] The term “optionally substituted alkyl” as used herein by itself or as part of another group refers to an alkyl group that is either unsubstituted or substituted with one, two, or three substituents.

[0174] The term “alkenyl” as used herein by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-to-carbon double bonds. In one aspect, the alkenyl group is a C2-C6alkenyl group. In another aspect, the alkenyl group is a C2-C4 alkenyl group. In another aspect, the alkenyl group has one carbon-to-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0175] The term “haloalkyl” as used herein by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and / or iodine atoms. In one aspect, the alkyl is substituted by one, two, or three fluorine and / or chlorine atoms. In another aspect, the alkyl is substituted by one, two, or three fluorine atoms. In another aspect, the alkyl is a C1-C6 alkyl. In another aspect, the alkyl is a C1-C4 alkyl. In another aspect, the alkyl group is a C1or C2alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.- 16 -

[0176] The term “alkoxy” as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one aspect, the alkyl is a C1-C6 alkyl and resulting alkoxy is thus referred to as a “C1-C6 alkoxy.” In another aspect, the alkyl is a C1-C4alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0177] The term “cycloalkyl” as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-12 cycloalkyl, or the number of carbons designated, e.g., a C3 cycloalkyl such a cyclopropyl, a C4cycloalkyl such as cyclobutyl, etc. In one aspect, the cycloalkyl is bicyclic, i.e., it has two rings. In another aspect, the cycloalkyl is monocyclic, i.e., it has one ring. In another aspect, the cycloalkyl is a C3-8 cycloalkyl. In another aspect, the cycloalkyl is a C3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another aspect, the cycloalkyl is a C5cycloalkyl, i.e., cyclopentyl or cyclopentenyl. In another aspect, the cycloalkyl is a C6 cycloalkyl, i.e., cyclohexyl or cyclohexenyl. Non- limiting exemplary C3-12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0178] The term “optionally substituted cycloalkyl” as used herein by itself or as part of another group refers to a cycloalkyl group that is either unsubstituted or substituted with one, two, or three substituents.

[0179] The term “heterocyclo” as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic groups containing three to eighteen ring members, i.e., a 3- to 18-membered heterocyclo, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom may independently be oxidized to give a sulfoxide, i.e., S(=O), or sulfone, i.e., S(=O)2. The term heterocyclo includes groups wherein one or more -CH2- groups is replaced with one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2-one. The term heterocyclo also includes groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as indoline,- 17 - indolin-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-1H- benzo[d]azepine, or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0180] The term “optionally substituted heterocyclo” as used herein by itself or part of another group refers to a heterocyclo group that is either unsubstituted or substituted with one to four substituents. Substitution may occur on any available carbon or nitrogen atom of the heterocyclo group.

[0181] The term “aryl” as used herein by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C14aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one aspect, the aryl group is phenyl or naphthyl. In another aspect, the aryl group is phenyl.

[0182] The term “optionally substituted aryl” as used herein by itself or as part of another group refers to aryl that is either unsubstituted or substituted with one to five substituents. In one aspect, the optionally substituted aryl is an optionally substituted phenyl. In another aspect, the optionally substituted phenyl has four substituents. In another aspect, the optionally substituted phenyl has three substituents. In another aspect, the optionally substituted phenyl has two substituents. In another aspect, the optionally substituted phenyl has one substituent.

[0183] The term “heteroaryl” as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to 14 fourteen ring members, i.e., a 5- to 14-membered heteroaryl, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one aspect, the heteroaryl has three heteroatoms. In another aspect, the heteroaryl has two heteroatoms. In another aspect, the heteroaryl has one heteroatom. In another aspect, the heteroaryl is a 5- to 10-membered heteroaryl. In another aspect, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another aspect, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,- 18 - pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one aspect, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H- pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin- 4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4- yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0184] The term “optionally substituted heteroaryl” as used herein by itself or as part of another group refers to a heteroaryl that is either unsubstituted or substituted with one to four substituents. In one aspect, the optionally substituted heteroaryl has two substituents. In another aspect, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.

[0185] The term “amino” as used by itself or as part of another group refers to a radical of the formula -NR21aR21b, wherein R21aand R21bare independently hydrogen, alkyl, haloalkyl, (hydroxy)alkyl-, (alkoxy)alkyl-, (amino)alkyl-, heteroalkyl-, cycloalkyl, heterocyclo, aryl, heteroaryl, (aryl)alkyl-, (cycloalkyl)alkyl-, (heterocyclo)alkyl-, or (heteroaryl)alkyl-.

[0186] In one aspect, the amino is -NH2.

[0187] In another aspect, the amino is an “alkylamino,” i.e., an amino group wherein R21ais C1-6alkyl and R21bis hydrogen. In one aspect, R21ais C1-C4alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0188] In another aspect, the amino is a “dialkylamino,” i.e., an amino group wherein R21aand R21bare each independently C1-6alkyl. In one aspect, R21aand R21bare each independently C1-C4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0189] The term “optionally substituted amino” as used herein by itself or as part of another group refers to an amino, e.g., a radical of the formula -NR21aR21b, as defined above, wherein R21aand R21bare either unsubstituted or are further substituted with one to four substituents.- 19 -

[0190] The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H (or deuterium (D)),3H,11C,13C, 14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively, e.g.,3H,11C, and14C. In one aspect, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another aspect, provided is a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number." Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.

[0191] As noted above, Compounds of the Disclosure contain one or more asymmetric carbon atoms and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure. All conformational isomers, i.e., stereoisomers produced by rotation about a σ bond, are also encompassed by the present disclosure.

[0192] As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0193] The term “chiral center” or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.

[0194] The terms “enantiomer” and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.- 20 -

[0195] The term “racemic” refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one aspect, Compounds of the Disclosure are racemic.

[0196] The term “absolute configuration” refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0197] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0198] The term “enantiomeric excess” or “ee” refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R - S│*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α]obs / [α]max)*100, where [α]obsis the optical rotation of the mixture of enantiomers and [α]maxis the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

[0199] The term “about,” as used herein, includes the recited number ± 10%. Thus, “about 10” means 9 to 11. II. Compounds of the Disclosure

[0200] The present disclosure provides compounds represented by any one of Formulae (I)-(IV), and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof. These compounds, and the salts and solvates thereof, are collectively referred to herein as “Compounds of the Disclosure” or individually as a “Compound of the Disclosure.” Compounds of the Disclosure are FOXN1 activators. FOXN1 activators are useful in promoting thymus regeneration and / or immune reconstitution in a subject in need thereof, and / or in treating diseases or conditions wherein activation of FOXN1 provides a therapeutic benefit to a subject.

[0201] In some aspects, Compounds of the Disclosure are compounds having Formula (I):(I),- 21 -

[0202] or a salt or solvate thereof, wherein:

[0203] Ring A is selected from optionally substituted C6-C10 aryl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted 5- or 6-memberered heteroaryl;

[0204] each is a single or a double bond consistent with the valences of X7, X8, and X9;

[0205] X5is selected from a bond, -NR16- and -O-;

[0206] X7is selected from -N- and -NR19-;

[0207] X8is selected from -N-, -NR20-, and -CR8aR8b-;

[0208] X9is selected from -N-, -NR25, CR9aR9b, and -C(=O)-;

[0209] R8aand R9aare each independently selected from hydrogen, halo, cyano, optionally substituted C1-C6alkyl, optionally substituted C6-C10aryl, -C(=O)OR25, and - C(=O)NR26R27;

[0210] R8band R9bare each independently absent or are selected from hydrogen and optionally substituted C1-C6alkyl;

[0211] R16is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0212] R19is selected from hydrogen, optionally substituted C1-C6 alkyl, -C(=O)R19a, -C(=O)OR19a, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C6-C10aryl, and optionally substituted 5- to 10-membered heteroaryl;

[0213] R19ais selected from hydrogen and C1-C6alkyl;

[0214] R20is selected from hydrogen and C1-C6alkyl;

[0215] R21is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, and C2-C6alkenyl;

[0216] R22is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6alkyl, C2-C6 alkenyl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted C6-C10 aryl;

[0217] R23is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6alkyl, and C2-C6 alkenyl;

[0218] R24is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, C2-C6alkenyl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted C6-C10aryl;

[0219] one of R21, R22, R23, and R24is absent;

[0220] R25is selected from hydrogen and C1-C6alkyl; and- 22 -

[0221] R26and R27are each independently selected from hydrogen and C1-C6alkyl.

[0222] In some aspects, Compounds of the Disclosure are compounds having Formula (I-A):

[0223] wherein:

[0224] X6is selected from -N- and -CH-;

[0225] R17is selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy-C1-C6alkyl-, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6- membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl; and

[0226] R18is selected from hydrogen, halo, optionally substituted C1-C6alkyl, and C2-C3alkynyl.

[0227] In some aspects, Compounds of the Disclosure are compounds having Formula (I-B):

[0228] or a salt or solvate thereof, wherein:

[0229] each is a single or a double bond consistent with the valences of X7and X8;

[0230] X5is selected from -NR16- and -O-;

[0231] X7is selected from -N- and -NR19-;

[0232] X8is selected from -N-, -NR20-, and -CH-;

[0233] R16is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0234] R19is selected from hydrogen, optionally substituted C1-C6 alkyl, -C(=O)R19a, -C(=O)OR19a, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo;

[0235] R19ais selected from hydrogen and C1-C6 alkyl; and

[0236] R20is selected from hydrogen and C1-C6alkyl;- 23 -

[0237] wherein when X5is -NH-, X6is -N-, R18is chloro, X7is -NR19-, and X8is -N-, R19is not 2-methoxyethyl.

[0238] In some aspects, Compounds of the Disclosure are compounds having Formula (I-C):

[0239] In some aspects, Compounds of the Disclosure are compounds having Formula (I-D):

[0240] In some aspects, Compounds of the Disclosure are compounds having Formula (I-E):

[0241] In some aspects, Compounds of the Disclosure are compounds having Formula (I-F):

[0242] In some aspects, Compounds of the Disclosure are compounds having Formula (I-G):- 24 -

[0243] In some aspects, Compounds of the Disclosure are compounds having Formula (I-H):

[0244] In some aspects, Compounds of the Disclosure are compounds having Formula (I-I):

[0245] In some aspects, Compounds of the Disclosure are compounds having Formula (I-J):(I-J),

[0246] wherein R22is selected from optionally substituted 5- or 6-membered heterocyclo and optionally substituted C6-C10 aryl.

[0247] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I)-(I-J), wherein X5is -NR16-.

[0248] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I)-(I-J), wherein R16is hydrogen, methyl, or cyclopropylmethyl.

[0249] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I)-(I-J), wherein R16is hydrogen.

[0250] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I)-(I-J), wherein X5is -O-.

[0251] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein X6is -N-.- 25 -

[0252] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R17is hydrogen or methyl.

[0253] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R17is methyl.

[0254] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-I), wherein R17is optionally substituted C1-C6 alkyl.

[0255] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-I), wherein R17is C1-C6alkyl substituted with amino, hydroxy, C1-C6alkoxy, -C(=O)R18a, -C(=O)OR18a, or C3-C7 cycloalkyl, wherein R18ais selected from hydrogen and C1-C6alkyl.

[0256] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-I), wherein R17is:

[0257] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-I), wherein R17is optionally substituted 5- or 6-membered heterocyclo or optionally substituted 5- or 6-membered heteroaryl.

[0258] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-I), wherein R17is:.

[0259] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-I), wherein R18is hydrogen, methyl, or chloro.

[0260] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-I), wherein R18is methyl.

[0261] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is hydrogen or methyl.

[0262] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is hydrogen.

[0263] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is -C(=O)CH3or -C(=O)OC(CH3)3.- 26 -

[0264] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is optionally substituted C1-C6 alkyl.

[0265] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is C1-C6alkyl substituted with amino, hydroxy, C1-C6alkoxy, C3-C7 cycloalkyl, optionally substituted 5- or 6 membered heterocyclo, -OC(=O)R19b, or -C(=O)NR19bR19c, wherein R19band R19care each independently selected from hydrogen and C1-C6alkyl.

[0266] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is:.

[0267] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is:.

[0268] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is optionally substituted 5- or 6 membered heterocyclo.

[0269] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is:- 27 -

[0270] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R19is:.

[0271] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R20is hydrogen or methyl.

[0272] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R21is hydrogen.

[0273] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R22is hydrogen or halo.

[0274] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R22is chloro.

[0275] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R23is hydrogen or halo.

[0276] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R23is chloro.

[0277] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R24is hydrogen, halo, or optionally substituted phenyl.

[0278] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R24is chloro.

[0279] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I-A)-(I-J), wherein R24is 3-hydroxyphenyl.

[0280] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (I)-(I-J), wherein the compound is selected from the group consisting of the compounds listed in Table 1. Table 1- 28 -- 29 -- 30 -- 31 -- 32 -- 33 -- 34 -- 35 -- 36 -- 37 -- 38 -- 39 -- 40 -- 41 -- 42 -- 43 -- 44 -- 45 -- 46 -- 47 -- 48 -- 49 -- 50 -- 51 -- 52 -- 53 -- 54 -- 55 -- 56 -- 57 -- 58 -- 59 -- 60 -- 61 -- 62 -- 63 -- 64 -- 65 -- 66 -- 67 -- 68 -

[0281] The present disclosure also provides a compound having Formula (II):

[0282] or a salt or solvate thereof, wherein:

[0283] X1is absent or is selected from -NR1a-, -^(CH2)n-NR1a-, and -^NR1a-(CH2)n-, wherein the bond marked with a “^” is attached to R1;

[0284] n is selected from 1, 2, 3, and 4;

[0285] R1ais selected from hydrogen and optionally substituted C1-C6 alkyl;

[0286] R1is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy-C1-C6alkyl-, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6- membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0287] R2is selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0288] R3is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C3-C7cycloalkyl;

[0289] X10is selected from -NR6- and -O-;

[0290] R6is selected from hydrogen, optionally substituted C1-C4alkyl, and optionally substituted 5- to 10-membered heteroaryl;

[0291] X11is selected from -N- and -CR11x;

[0292] X12is selected from -N- and -CR12x;

[0293] X13is selected from -N- and -CR13x;

[0294] X14is selected from -N- and -CR14x;

[0295] with the proviso that no more than two of X11, X12, X13, and X14are -N-; and- 69 -

[0296] R11x, R12x, R13x, and R14xare each independently selected from hydrogen, halo, C1- C4 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0297] In some aspects, Compounds of the Disclosure are compounds having Formula (II-(II-A),

[0298] or a salt or solvate thereof, wherein:

[0299] R4is selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7cycloalkyl;

[0300] R5is selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 cycloalkyl;

[0301] Y1is selected from -NR7- and -O-; and

[0302] R7is selected from hydrogen and C1-C4alkyl;

[0303] wherein when X1is absent, R2is methyl, R3is hydrogen, R4is methyl, R5is methyl, and Y1is -O-, R1is not: ,

[0304] In some aspects, Compounds of the Disclosure are compounds having Formula (II- B):(II-B),- 70 -

[0305] wherein:

[0306] R14xis selected from optionally substituted 5- or 6-membered aryl and optionally substituted 5- or 6-membered heteroaryl;

[0307] X15is selected from -N- and -CH-;

[0308] R28is selected from hydrogen, halo, optionally substituted C1-C6 alkyl, and C2-C3 alkynyl; and

[0309] R29is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy-C1-C6alkyl-, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6- membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0310] In some aspects, Compounds of the Disclosure are compound having Formula (II), wherein:

[0311] R1ais selected from hydrogen and C1-C6 alkyl;

[0312] R1is selected from C1-C6alkyl, C1-C6alkoxy-C1-C6alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0313] R2is selected from hydrogen, C1-C6alkyl, C3-C7cycloalkyl, 5- or 6-membered aryl, and 5- or 6-membered heteroaryl;

[0314] R3is selected from hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl;

[0315] R4is selected from hydrogen, C1-C6alkyl, and C3-C7cycloalkyl; and

[0316] R5is selected from hydrogen, C1-C6alkyl, and C3-C7cycloalkyl.

[0317] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein X1is absent.

[0318] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein R1is selected from C1-C6 alkoxy-C1-C6 alkyl-, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0319] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein R1is selected from:- 71 -

[0320] wherein R1bis selected from hydrogen, C1-C4 alkyl, -C(=O)O(CH3)3, and - C(=O)CH3.

[0321] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein X1is -NR1a-.

[0322] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein R1ais selected from hydrogen and methyl.

[0323] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein R1is selected from:

[0324] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein X1is -^NR1a-(CH2)n-.

[0325] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein R1ais selected from hydrogen and methyl.

[0326] In some aspects, Compounds of the Disclosure are compound having Formula (II) or (II-A), wherein n is 1.

[0327] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R1is:.

[0328] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R2is C1-C6alkyl.- 72 -

[0329] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R2is methyl, ethyl, or isopropyl.

[0330] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R2is phenyl.

[0331] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R3is hydrogen.

[0332] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R4is C1-C6alkyl.

[0333] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R4is methyl.

[0334] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R5is C1-C6 alkyl.

[0335] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R5is methyl.

[0336] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein Y1is -O-.

[0337] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein Y1is -NR7-.

[0338] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R7is hydrogen or methyl.

[0339] In some aspects, Compounds of the Disclosure are compound having any one of Formulae (II)-(II-B), wherein R6is hydrogen or methyl.

[0340] In some aspects, Compounds of the Disclosure are compounds having Formula (I), wherein the compound is selected from the group consisting of the compounds listed in Table 2.- 73 - Table 2- 74 -- 75 -- 76 -- 77 -- 78 -- 79 -- 80 -- 81 -- 82 -- 83 -

[0341] In some aspects, Compounds of the Disclosure are compounds having Formula (III):- 84 -

[0342] or a salt or solvate thereof, wherein:

[0343] X2, X3, and X4are each independently selected from -CH- and -N-, wherein no more than one of X2, X3, and X4is -N-;

[0344] R9is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C5-C6 aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0345] Y2is selected from -^C(=O)N(R10)-, -^C(=O)N(R10)CH2-, -^N(R10)C(=O)-, and -^CH2C(=O)N(R10)-, wherein the bond marked with a “^” is attached to the phenyl;

[0346] R10is selected from hydrogen and optionally substituted C1-C4alkyl;

[0347] R11is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6alkoxy-C1-C6alkyl-, optionally substituted amino-C1-C6alkyl- , -C(=O)R11a, -CH2C(=O)NR11bR11c, C3-C7cycloalkyl-C1-C6alkyl-, 5- or 6-membered heterocyclo-C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C5-C6 aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0348] R11ais selected from optionally substituted C1-C4 alkyl; and

[0349] R11band R11care each independently selected from hydrogen and optionally substituted C1-C4alkyl;

[0350] wherein,

[0351] when X2is -N-, X3is -CH-, X4is -CH-, and Y2is -^C(=O)N(H)-, R11is not:

[0352] whennot: or .- 85 -

[0353] In some aspects, Compounds of the Disclosure are compounds having Formula (II), wherein:

[0354] R11is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, amino-C1- C6alkyl-, -C(=O)R11a, -CH2C(=O)NR11bR11c, C3-C7cycloalkyl-C1-C6alkyl-, 5- or 6- membered heterocyclo-C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C5-C6 aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0355] R11ais selected from C1-C4alkyl; and

[0356] R11band R11care each independently selected from hydrogen and C1-C4 alkyl.

[0357] In some aspects, Compounds of the Disclosure are compounds having Formula (III- A):

[0358] In some aspects, Compounds of the Disclosure are compounds having Formula (III- B):

[0359] In some aspects, Compounds of the Disclosure are compounds having Formula (III- C):

[0360] In some aspects, Compounds of the Disclosure are compounds having Formula (III- D):- 86 -

[0361] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein X2is -N-, X3is -CH-, and X4is -CH- .

[0362] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein X2is -CH-, X3is -CH-, and X4is - CH-.

[0363] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein X2is -CH-, X3is -N-, and X4is -CH- .

[0364] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein X2is -CH-, X3is -CH-, and X4is -N- .

[0365] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R9is C1-C6 alkyl.

[0366] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R9is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

[0367] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R9is methyl.

[0368] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R9is selected from optionally substituted C1-C6alkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C5-C6aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0369] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R9is selected from -C(=O)CH3, C1- C6 alkyl, C1-C4 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl-C1-C6 alkyl-, optionally substituted- 87 - amino-C1-C6alkyl, C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C5-C6 aryl, and optionally substituted 5- or 6-membered heteroaryl.

[0370] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R9is selected from:

[0371] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R10is hydrogen or methyl.

[0372] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R11is selected from 5- or 6-membered heteroaryl-C1-C6alkyl-, C1-C6alkoxy-C1-C6alkyl-, 5- or 6-membered heterocyclo-C1-C6alkyl-, C3-C7 cycloalkyl, 5- or 6-membered heterocyclo, C5-C6 aryl, and 5- or 6-membered heteroaryl.

[0373] In some aspects, Compounds of the Disclosure are compounds having any one of Formulae (III-A), (III-B), (III-C), or (III-D), wherein R11is selected from: ,.

[0374] In some aspects, Compounds of the Disclosure are compounds having Formula (III), wherein the compound is selected from the group consisting of any one of the compounds listed in Table 3.- 88 - Table 3- 89 -- 90 -- 91 -- 92 -- 93 -- 94 -

[0375] In some aspects, Compounds of the Disclosure are compounds having Formula (IV):- 95 -

[0376] or a salt or solvate thereof, wherein:

[0377] R13is selected from optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl;

[0378] R14is selected from optionally substituted C1-C6alkyl, optionally substituted C3-C7cycloalkyl-C1-C6alkyl-, optionally substituted 5- or 6-membered aryl-C1-C6alkyl-, and optionally substituted 5- or 6-membered heteroaryl-C1-C6 alkyl-; and

[0379] R15is selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3-C7cycloalkyl-C1-C6alkyl-, optionally substituted 5- or 6-membered aryl- C1-C6 alkyl-, and optionally substituted 5- or 6-membered heteroaryl-C1-C6 alkyl-; or

[0380] R14and R15together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclo;

[0381] wherein:

[0382] when R13is methyl, R14and R15together with the nitrogen atom to which they are attached do not form a 4-methyl-piperidyl group;

[0383] when R13is ethyl and R14is hydrogen, R15is not 4-chlorobenzyl;

[0384] when R13is ethyl and R14is methyl, R15is not benzyl;

[0385] when R13is trifluoromethyl and R14is hydrogen, R15is not 2-(thiophen-2-yl)ethyl; and

[0386] when R13is trifluoromethyl, R14and R15together with the nitrogen atom to which they are attached do not form an azepanyl group.

[0387] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is selected from C1-C6 alkyl, C1-C6 haloalkyl, and phenyl.

[0388] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is methyl, ethyl, or isopropyl.

[0389] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is methyl.

[0390] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is ethyl.- 96 -

[0391] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is isopropyl.

[0392] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is difluoromethyl or trifluoromethyl.

[0393] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is difluoromethyl.

[0394] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is trifluoromethyl.

[0395] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is optionally substituted phenyl.

[0396] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R13is phenyl.

[0397] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14is optionally substituted 5- or 6-membered aryl-C1-C6alkyl- or optionally substituted 5- or 6-membered heteroaryl-C1-C6 alkyl-.

[0398] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14is phenyl-C1-C6alkyl-, halo-phenyl-C1-C6alkyl-, or 5- or 6-membered heteroaryl-C1-C6alkyl-.

[0399] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14is selected from:

[0400] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R15is hydrogen or methyl.

[0401] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14and R15together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclo.

[0402] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14and R15together with the nitrogen atom to which they are attached form an optionally substituted 5-membered heterocyclo.

[0403] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14and R15together with the nitrogen atom to which they are attached form an optionally substituted 6-membered heterocyclo.- 97 -

[0404] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14and R15together with the nitrogen atom to which they are attached form an optionally substituted 7-membered heterocyclo.

[0405] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein R14and R15together with the nitrogen atom to which they are attached form:.

[0406] In some aspects, Compounds of the Disclosure are compounds having Formula (IV), wherein the compound is selected from the group consisting of any one of the compounds listed in Table 4. Table 4- 98 -

[0407] The present disclosure also provides the compound listed in Table 5. Table 5

[0408] In some aspects, the disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable carrier or excipient.

[0409] Compounds of the Disclosure may contain an asymmetric carbon atom. In some aspects, Compounds of the Disclosure are racemic compounds. In other aspects, Compounds of the Disclosure are enantiomerically enriched, e.g., the enantiomeric excess or “ee” of the compound is about 5% or more as measured by chiral HPLC. In another aspect, the ee is about 10%. In another aspect, the ee is about 20%. In another aspect, the ee is about 30%. In another aspect, the ee is about 40%. In another aspect, the ee is about 50%. In another aspect, the ee is about 60%. In another aspect, the ee is about 70%. In another aspect, the ee is about 80%. In another aspect, the ee is about 85%. In another aspect, the ee is about 90%. In another aspect, the ee is about 91%. In another aspect, the ee is about 92%. In another aspect, the ee is about 93%. In another aspect, the ee is about- 99 - 94%. In another aspect, the ee is about 95%. In another aspect, the ee is about 96%. In another aspect, the ee is about 97%. In another aspect, the ee is about 98%. In another aspect, the ee is about 99%.

[0410] The present disclosure encompasses all possible stereoisomeric, e.g., diastereomeric, forms of Compounds of the Disclosure. When a Compound of the Disclosure is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883-888 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of the Compounds of the Disclosure are possible, the present disclosure is intended to include all tautomeric forms of the compounds.

[0411] The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure, including pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” refers to non-toxic salt forms of Compounds of the Disclosure. See e.g., Gupta et al., Molecules 23:1719 (2018). Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation. The pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present- 100 - in the Compounds of the Disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference to Compounds of the Disclosure appearing herein is intended to include the actual compound as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0412] The present disclosure also encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term “solvate” as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A.L. Bingham et al., Chem. Commun.603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.- 101 -

[0413] Compounds of the Disclosure can be prepared, e.g., using the synthetic methods shown in Schemes 1-5, or derivatives thereof.

[0414] The synthetic scheme depicted by Scheme 1, or a derivative thereof, can be used to synthesize compounds of Formula (I). Scheme 1

[0415] The synthetic scheme depicted by Scheme 2, or a derivative thereof, can be used to synthesize compounds of Formula (II). Scheme 2

[0416] The synthetic scheme depicted by Scheme 3, or a derivative thereof, can be used to synthesize compounds of Formula (III). Scheme 3- 102 -

[0417] The synthetic scheme depicted by Scheme 4, or a derivative thereof, can be used to synthesize compounds of Formula (IV). Scheme 4

[0418] The synthetic scheme depicted by Scheme 5, or a derivative thereof, can be used to synthesize compounds of Table 5. Scheme 5III. Therapeutic Methods of the Disclosure

[0419] The present disclosure provides a method of promoting thymus regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure or a pharmaceutical composition thereof.

[0420] In some aspects, the subject is in need of thymus regeneration due to hematopoietic stem cell transplantation, immune deficiency due to HIV, HIV therapy, autoimmune disease, inborn errors of thymic development, administration of a vaccine, age-related immune senescence, administration of exogenous glucocorticoids, bacterial or viral infections, radiation, immunotherapy, or cytoreductive treatments, zinc deficiency, thymus involution, or a combination thereof.

[0421] The present disclosure also provides a method of promoting immune reconstitution in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure or a pharmaceutical composition thereof.

[0422] In some aspects, the subject is in need of immune reconstitution due to hematopoietic stem cell transplantation, immune deficiency due to HIV, HIV therapy, autoimmune disease, inborn errors of thymic development, administration of a vaccine,- 103 - age-related immune senescence, administration of exogenous glucocorticoids, bacterial or viral infections, radiation, immunotherapy, or cytoreductive treatments, zinc deficiency, thymus involution, or a combination thereof.

[0423] The present disclosure provides a method of activating FOXN1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure or a pharmaceutical composition thereof.

[0424] In some aspects, the subject is in need of FOXN1 activation due to hematopoietic stem cell transplantation, immune deficiency due to HIV, HIV therapy, autoimmune disease, inborn errors of thymic development, administration of a vaccine, age-related immune senescence, administration of exogenous glucocorticoids, bacterial or viral infections, radiation, immunotherapy, or cytoreductive treatments, zinc deficiency, thymus involution, diabetes-related ulcers, foot ulcers, chronic wounds, alopecia, or a combination thereof.

[0425] In some aspects, the subject is in need of FOXN1 activation to treat or prevent immune deficiency due to HIV, autoimmune disease, age-related immune senescence, bacterial or viral infections, zinc deficiency, thymus involution, diabetes-related ulcers, foot ulcers, chronic wounds, alopecia, or a combination thereof.

[0426] The present disclosure also provides a method of promoting skin wound healing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.

[0427] In some aspects, the subject has a diabetes-related ulcer, a foot ulcer, a chronic wound, or a combination thereof.

[0428] The present disclosure also provides a method of augmenting hair growth, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.

[0429] In some aspects, the subject has alopecia.

[0430] The present disclosure also provides a method of enhancing immune function or promoting thymic regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject is in need of immune function enhancement or thymic regeneration due to administration of CAR-T cells or other adoptive T-cell therapies, recovery from sepsis or critical illness, idiopathic T-cell- 104 - lymphopenia, immunosuppression following solid organ transplantation, or a combination thereof.

[0431] In some aspects, the subject is at risk of or recovering from infection due to impaired T-cell function.

[0432] In some aspects, the subject is an elderly individual, an immunocompromised patient, a recipient of immunosuppressive therapy, or a combination thereof.

[0433] The present disclosure also provides a method of promoting immune tolerance or reducing transplant-related complications, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject is receiving a hematopoietic stem cell transplant or solid organ transplant.

[0434] In some aspects, the method reduces the risk of graft-versus-host disease (GVHD).

[0435] In some aspects, the method enhances immune reconstitution.

[0436] The present disclosure also provides a method of treating or supporting recovery from a thymic epithelial tumor, comprising administering to a subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject has a thymoma or thymic carcinoma.

[0437] The present disclosure also provides a method of promoting immune surveillance or reducing cancer risk in a high-risk subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject has an age-related decline in immune function, a personal or familial history of cancer, or a genetic predisposition to immune dysfunction.

[0438] The present disclosure also provides a method of augmenting hair growth or restoring hair loss in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the hair loss is chemotherapy-induced, radiation- induced, or idiopathic in origin.

[0439] The present disclosure also provides a method of promoting skin repair or regeneration, comprising administering to a subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the subject has a radiation-induced skin injury, a surgical wound, or age-related skin atrophy.- 105 -

[0440] The present disclosure also provides a method of promoting dermal regeneration or treating skin aging in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0441] The present disclosure also provides a method of preconditioning a non-human donor organism for xenotransplantation of a composite organ comprising thymic tissue, comprising administering to the donor a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the method improves thymic tissue function, promotes immune system development, or enhances compatibility of the graft with the recipient immune system.

[0442] The present disclosure provides compounds that are FOXN1 activators for promoting thymus regeneration and / or immune reconstitution, and / or for the treatment of diseases and conditions wherein activation of FOXN1 has a beneficial effect. These compounds typically have EC50(the drug concentration that results in 50% FOXN1 activation) values of less than 100 μM, e.g., less than 50 μM, less than 25 μM, and less than 5 μM, or less than about 1 µM.

[0443] In some aspects, Compounds of the Disclosure are administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of Compounds of the Disclosure.

[0444] Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed.1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.

[0445] Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example,- 106 - tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Buffers and pH modifiers can also be added to stabilize the pharmaceutical composition.

[0446] Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0447] Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0448] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly- 107 - concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0449] In particular, the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood. IV. Kits of the Disclosure

[0450] In another aspect, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates its use to practice methods of the present disclosure. In one aspect, the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice a method disclosed herein. In one aspect, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration.- 108 - EXAMPLES EXAMPLE 1 Synthesis of 2-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (Representative Procedure for Synthesis of Compounds of Formula (II))

[0451] Step 1: To a suspension of 2,6-dichloropyridin-4-amine (20.0 g, 1 Eq, 123 mmol) and potassium acetate (48.2 g, 4 Eq, 491 mmol) in acetic acid (100 mL), ICl (19.9 g, 6.15 mL, 1 Eq, 123 mmol) in acetic acid (100 mL) was added dropwise over 30 minutes. The mixture was warmed to 40 °C and stirred for 24 hours. The mixture was cooled to rt and water (200 ml) was added. The precipitate formed was collected by filtration, washed with water (50 ml) and dried in vacuo to afford 2,6-dichloro-3-iodopyridin-4-amine (36.2 g, 0.12 mol, 96 %, 94% Purity) as a pale orange solid.

[0452] 1H NMR in DMSO-d6was consistent with product structure at >95% purity. 1H NMR (400 MHz, DMSO) δ 6.87 (s, 2H), 6.56 (s, 1H).

[0453] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 288.8 / 290.8 (M+H)+(ES+) at 1.24 min, 93.8% purity 254 nm.

[0454] Step 2: To a solution of 2,6-dichloro-3-iodopyridin-4-amine (4 x 1g, 1 eq, 3.46 mmol) in DMF (10.0 mL) in four microwave vials, prop-1-yne (693 mg, 17.3 mL, 1.00 molar, 5 eq, 17.3 mmol), CuI (65.9 mg, 0.1 eq, 0.35 mmol) and Bis-(triphenylphosphino)- palladous chloride (243 mg, 0.1 eq, 0.35 mmol) were added. The mixture was degassed with N2 (bubbling) for 5 minutes and was stirred at 60 °C for 2 days. The mixture was cooled to rt, diluted with EtOAc (100 ml) and washed with sat. aq. NH4Cl (50 ml). The- 109 - organic layer was further washed with water (100 ml) and brine (2 x 100 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

[0455] The crude product was purified by chromatography on silica gel (80 g cartridge, 0- 50% EtOAc / isohexane) to afford 2,6-dichloro-3-(prop-1-yn-1-yl)pyridin-4-amine (2.47 g, 8.6 mmol, 62 %, 70% Purity) as a tan solid.

[0456] 1H NMR in DMSO-d6 was consistent with product structure at 70% purity.1H NMR (400 MHz, DMSO) δ 6.89 (s, 2H), 6.61 (s, 1H), 2.13 (s, 3H).

[0457] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 201.0 / 203.0 (M+H)+(ES+) at 1.26 min, 70.9% purity 260nm + / - 90nm.

[0458] Step 3: To a solution of 2,6-dichloro-3-(prop-1-yn-1-yl)pyridin-4-amine (2.47 g, 70% Wt, 1 Eq, 8.60 mmol) in DMF (40.0 mL), potassium tert-butoxide (1.93 g, 2 Eq, 17.2 mmol) was added. The mixture was stirred at 80 °C for 2 hours. The mixture was cooled to rt and water (100 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford 4,6-dichloro-2-methyl- 1H-pyrrolo[3,2-c]pyridine (1.45 g, 6.9 mmol, 80 %, 95% Purity) as a tan solid.

[0459] 1H NMR in DMSO-d6was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 7.39 (d, J = 0.9 Hz, 1H), 6.32 – 6.26 (m, 1H), 2.41 (d, J = 1.0 Hz, 3H).

[0460] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 201.0 / 203.0 (M+H)+(ES+) at 1.32 min, 96.0% purity 260nm + / - 90nm.

[0461] Step 4: To a solution of 4,6-dichloro-1,2-dimethyl-1H-pyrrolo[3,2-c]pyridine (85.0 mg, 1 Eq, 395 μmol) in 2-Methyltetrahydrofuran (1.20 mL), potassium carbonate (164 mg, 296 μL, 4.00 molar, 3 Eq, 1.19 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenol (87.0 mg, 82.8 μL, 1 Eq, 395 μmol) were added. The mixture was degassed (N2bubbling) for 5 minutes and Pd(dppf)Cl2 (28.9 mg, 0.1 Eq, 39.5 μmol) was added. The mixture was further degassed (N2 bubbling) for 5 minutes and was stirred at 80 °C for 3 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 2-(6-chloro-1,2-dimethyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (75.0 mg, 0.26 mmol, 66 %, 95% Purity) as a pale yellow solid.- 110 -

[0462] 1H NMR in DMSO-d6was consistent with product structure at >95% purity.1H NMR (500 MHz, DMSO) δ 12.60 (s, 1H), 7.99 (dd, J = 7.8, 1.6 Hz, 1H), 7.72 (d, J = 0.9 Hz, 1H), 7.33 (td, J = 7.6, 1.6 Hz, 1H), 7.02 – 6.95 (m, 2H), 6.80 (s, 1H), 3.75 (s, 3H), 2.48 (d, J = 1.0 Hz, 3H).

[0463] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 273.0 / 275.0 (M+H)+(ES+) at 1.84 min, 98.7% purity 254 nm.

[0464] Step 5: To a solution of 2-(6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (70.0 mg, 1 Eq, 271 μmol) in 1,4-Dioxane (2.00 mL), 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (90.5 mg, 1.5 Eq, 406 μmol) and potassium carbonate (112 mg, 541 μL, 1.50 molar, 3 Eq, 812 μmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd-118 (17.6 mg, 0.1 Eq, 27.1 μmol) was added. The mixture was further degassed (N2 bubbling) for 5 minutes and was stirred at 90 °C for 30 minutes. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford the desired product with low purity. The product was further purified by preparative HPLC: the residue was dissolved in 1.8 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X- Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min- 1 eluting with a 0.1% Formic acid in water-MeCN gradient over 8.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 ACN over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 17.5% MeCN; 0.5-5.5 min, ramped from 17.5% MeCN to 47.5% MeCN; 5.5-5.6 min, ramped from 47.5% MeCN to 100% MeCN; 5.6-8.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 2-(6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (21.0 mg, 62 μmol, 23 %, 95% Purity) as a pale yellow solid.

[0465] 1H NMR in DMSO-d6was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 14.81 (s, 1H), 11.94 (s, 1H), 8.23 – 8.16 (m, 1H), 7.46 (s, 1H), 7.35 – 7.26 (m, 1H), 7.03 – 6.92 (m, 2H), 6.86 (s, 1H), 2.53 (s, 3H), 2.35 (s, 3H). (3H, s under the DMSO peak, see HSQC).- 111 -

[0466] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 320.2 (M+H)+(ES+) at 0.90 min, 99.6% purity 254 nm. EXAMPLE 2 Synthesis of N-((1-isobutyl-1H-imidazol-5-yl)methyl)-3-(1-methyl-6-oxo-1,6-dihydropyridazin- 3-yl)benzamide (Representative Procedure for Synthesis of Compounds of Formula (III))

[0467] Step 1: To a solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate (1.0 g, 1.5 Eq, 4.0 mmol) in ACN (8.00 mL), 6-bromo-2-methylpyridazin- 3(2H)-one (0.50 g, 1 Eq, 2.6 mmol), K2CO3(1.1 g, 2.0 mL, 4.00 molar, 3 Eq, 7.9 mmol) and Pd(dppf)Cl2 (0.19 g, 0.1 Eq, 0.26 mmol) were added. The mixture was degassed (Vacuum / N2), warmed to 80 °C and stirred for 1 hour. The mixture was cooled to rt and water (10 ml) was added. The solid was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to afford methyl 4-(1-methyl-6-oxo-1,6- dihydropyridazin-3-yl)benzoate (0.61 g, 2.4 mmol, 90 %, 95% Purity) as a white solid.

[0468] 1H NMR in DMSO-d6was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.13 (d, J = 9.8 Hz, 1H), 8.10 – 8.00 (m, 4H), 7.09 (d, J = 9.7 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H).

[0469] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 245.0 (M+H)+(ES+) at 1.13 min, 100.0% purity 254 nm.

[0470] Step 2: To a solution of methyl 4-(1-methyl-6-oxo-1,6-dihydropyridazin-3- yl)benzoate (0.34 g, 1 Eq, 1.4 mmol) in THF (3.00 mL) / MeOH (1.00 mL) / H2O (1.00 mL), LiOH, H2O (64 mg, 1.1 Eq, 1.5 mmol) was added. The mixture was stirred at 45 °C for 1 hour. The mixture was concentrated in vacuo to afford 4-(1-methyl-6-oxo-1,6-- 112 - dihydropyridazin-3-yl)benzoic acid, Lithium (0.32 g, 1.3 mmol, 92 %, 95% Purity) as a white solid.

[0471] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.05 (d, J = 9.7 Hz, 1H), 7.97 – 7.89 (m, 2H), 7.81 – 7.74 (m, 2H), 7.02 (d, J = 9.7 Hz, 1H), 3.74 (s, 3H).

[0472] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 231.0 (M+H)+(ES+) at 0.85 min, 98.0% purity 260nm + / - 90nm.

[0473] Step 3: To a solution of 4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzoic acid, Lithium (100 mg, 1 Eq, 422 μmol) in DMF (2.00 mL), (1-isobutyl-1H-imidazol-5- yl)methanamine dihydrochloride (124 mg, 1.3 Eq, 548 μmol), DIPEA (272 mg, 367 μL, 5 Eq, 2.11 mmol) and HATU (240 mg, 1.5 Eq, 632 μmol) were successively added. The mixture was stirred at rt for 2 hours. The mixture was diluted with water (10 ml) and extracted with EtOAc (3 x 10 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to affordN-((1-isobutyl-1H-imidazol-5-yl)methyl)-4-(1-methyl-6-oxo-1,6-dihydropyridazin- 3-yl)benzamide (133 mg, 0.35 mmol, 82 %, 95% Purity) as a pale yellow solid.

[0474] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.96 (t, J = 5.6 Hz, 1H), 8.12 (d, J = 9.8 Hz, 1H), 7.98 (d, J = 1.0 Hz, 4H), 7.56 (d, J = 1.2 Hz, 1H), 7.07 (d, J = 9.7 Hz, 1H), 6.84 (d, J = 1.1 Hz, 1H), 4.49 (d, J = 5.5 Hz, 2H), 3.79 (d, J = 7.4 Hz, 2H), 3.76 (s, 3H), 1.95 (dq, J = 13.6, 6.8 Hz, 1H), 0.82 (d, J = 6.7 Hz, 6H).

[0475] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 366.2 (M+H)+(ES+) at 0.70 min, 100.0% purity 254 nm.- 113 - EXAMPLE 3 Synthesis of N-(4-chlorobenzyl)-3-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Representative Procedure for Synthesis of Compounds of Formula (IV))

[0476] Step 1: A suspension of (Z)-3-chloro-6-hydrazineylidene-1,6-dihydropyridazine (1.00 g, 1 Eq, 6.92 mmol) in propionic acid (10.2 g, 10.4 mL, 20 Eq, 138 mmol) was stirred at 100 °C for 2 hours. The mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in EtOAc (20 ml) and washed with Sat. aq. NaHCO3solution (50 ml). The aqueous layer was further extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo to afford 6-chloro-3-ethyl-[1,2,4]triazolo[4,3-b]pyridazine (0.74 g, 3.8 mmol, 56 %, 95% Purity) as a pale brown solid.

[0477] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.41 (d, J = 9.6 Hz, 1H), 7.46 (d, J = 9.6 Hz, 1H), 3.08 (q, J = 7.5 Hz, 2H), 1.37 (t, J = 7.5 Hz, 3H).

[0478] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 183.0 / 185.0 (M+H)+(ES+) at 0.81 min, 98.4% purity 260nm + / - 90nm.

[0479] Step 2: To a solution of 6-chloro-3-ethyl-[1,2,4]triazolo[4,3-b]pyridazine (50.0 mg, 1 Eq, 274 μmol) in Ethanol (2.00 mL), (4-chlorophenyl)methanamine (58.2 mg, 50.0 μL, 1.5 Eq, 411 μmol) was added and the mixture was stirred at 80 °C for 48 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-5% MeOH / DCM) to afford N-(4- chlorobenzyl)-3-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (40 mg, 0.13 mmol, 48 %, 95% Purity) as a pale yellow solid.

[0480] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 7.91 – 7.84 (m, 2H), 7.47 – 7.36 (m, 4H), 6.80 (d, J = 9.8 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 2.89 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).- 114 -

[0481] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 288.1 / 290.0 (M+H)+(ES+) at 1.32 min, 100.0% purity 254 nm. EXAMPLE 4 Synthesis of 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)- one (Representative Procedure for Synthesis of Compounds of Formula (I))

[0482] Step 1: To a solution of 1H-indol-5-amine (1.00 g, 1 Eq, 7.57 mmol) in dry DMF (30.0 mL) at 0 °C, NaH (363 mg, 60% Wt, 1.2 Eq, 9.08 mmol) was added. The mixture was stirred for 30 minutes at the same temperature and 2-Bromoethylmethyl ether (1.26 g, 860 μL, 1.2 Eq, 9.08 mmol) was added dropwise over 5 minutes. The mixture was warmed to rt and was stirred for 18 hours. Water (50 ml) was cautiously added and the mixture was extracted with EtOAc (3 x 50 ml). The organic layers were combined, washed with brine (2 x 100 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford 1-(2-methoxyethyl)-1H-indol-5-amine (1.03 g, 5.1 mmol, 68 %, 95% Purity) as a pale yellow solid.

[0483] 1H NMR in DMSO-d6was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 7.18 – 7.09 (m, 2H), 6.66 (d, J = 2.1 Hz, 1H), 6.51 (dd, J = 8.6, 2.1 Hz, 1H), 6.10 (dd, J = 3.0, 0.8 Hz, 1H), 4.45 (s, 2H), 4.18 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.4 Hz, 2H), 3.20 (s, 3H).

[0484] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 191.2 (M+H)+(ES+) at 0.14 min, 95.8% purity 254 nm.

[0485] Step 2: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) in DMSO (1.00 mL), DIPEA (144 mg, 195 μL, 2 Eq, 1.12 mmol) and 1-(2- methoxyethyl)-1H-indol-5-amine (128 mg, 1.2 Eq, 670 μmol) were added. The mixture- 115 - was stirred at 120 °C under microwave irradiation for 18 hours. The mixture was cooled to rt and EtOAc (10 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (10 ml). The aqueous layer was further extracted with EtOAc (10 ml) and the organic layers were combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford the desired product with low purity. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 10-60% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 4-chloro-5-((1-(2-methoxyethyl)- 1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (79.0 mg, 0.23 mmol, 40 %, 95% Purity) as a tan solid.

[0486] 1H NMR in DMSO-d6was consistent with product structure at >95% purity.1H NMR (500 MHz, DMSO) δ 8.62 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.46 – 7.37 (m, 3H), 7.02 (dd, J = 8.6, 2.1 Hz, 1H), 6.43 (dd, J = 3.1, 0.8 Hz, 1H), 4.34 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.59 (s, 3H), 3.23 (s, 3H).

[0487] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 333.0 / 335.0 (M+H)+(ES+) at 1.23 min, 98.8% purity 254 nm. EXAMPLE 5 Synthesis of 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)- one (Representative Procedure for Synthesis of Compounds of Formula (I))

[0488] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) in dry DMF (10.0 mL) at rt, K2CO3 (1.3 g, 3 Eq, 9.3 mmol) and 2-chloro-N,N-dimethylethan-1-amine, HCl (0.58 g, 1.3 Eq, 4.0 mmol) were added. The mixture was warmed to 80 °C and was stirred for 2 hours. Water (20 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc in isohexane) to afford N,N-- 116 - dimethyl-2-(5-nitro-1H-indol-1-yl)ethan-1-amine (0.547 g, 2.2 mmol, 72 %, 95% Purity) as a yellow solid.

[0489] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.56 (d, J = 2.3 Hz, 1H), 8.01 (dd, J = 9.1, 2.3 Hz, 1H), 7.71 (dt, J = 9.2, 0.7 Hz, 1H), 7.66 (d, J = 3.2 Hz, 1H), 6.73 (dd, J = 3.2, 0.8 Hz, 1H), 4.34 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.17 (s, 6H).

[0490] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water): m / z 234.3 (M+H)+(ES+) at 1.31 min, 100.0% purity 210-400nm.

[0491] Step 2: A solution of N,N-dimethyl-2-(5-nitro-1H-indol-1-yl)ethan-1-amine (0.10 g, 1 Eq, 0.43 mmol) in MeOH (5.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 1 pass). The residue was concentrated in vacuo to afford 1-(2-(dimethylamino)ethyl)- 1H-indol-5-amine (88.0 mg, 0.39 mmol, 92 %, 91% Purity) as a purple oil.

[0492] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water):3917-213-1- ms, m / z 204.0 (M+H)+(ES+) at 0.85 min, 91.4% purity 210-400nm.

[0493] 1H NMR in DMSO-d6was consistent with product structure at 95% purity.1H NMR (400 MHz, DMSO) δ 7.17 – 7.09 (m, 2H), 6.66 (dd, J = 2.1, 0.6 Hz, 1H), 6.51 (dd, J = 8.6, 2.1 Hz, 1H), 6.09 (dd, J = 3.0, 0.8 Hz, 1H), 4.47 (s, 2H), 4.11 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 6.8 Hz, 2H), 2.16 (s, 6H).

[0494] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (60.0 mg, 1 Eq, 335 μmol) in DMSO (1.00 mL), DIPEA (86.6 mg, 117 μL, 2 Eq, 670 μmol) and 1-(2- (dimethylamino)ethyl)-1H-indol-5-amine (81.8 mg, 1.2 Eq, 402 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and EtOAc (10 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (10 ml). The aqueous layer was further extracted with EtOAc (10 ml) and the organic layers were combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 10% (0.7 M Ammonia / MeOH) / DCM) to afford 4-chloro-5-((1-(2-(dimethylamino)ethyl)- 1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (24.0 mg, 66 μmol, 20 %, 95% Purity) as a yellow solid.

[0495] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.47 – 7.39 (m, 3H),- 117 - 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.42 (dd, J = 3.1, 0.8 Hz, 1H), 4.26 (t, J = 6.6 Hz, 2H), 3.59 (s, 3H), 2.61 (t, J = 6.6 Hz, 2H), 2.19 (s, 6H).

[0496] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water): m / z 346.3 / 348.3 (M+H)+(ES+) at 1.14 min, 97.2% purity 210-400nm. EXAMPLE 6 Synthesis of 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)- one (Representative Procedure for Synthesis of Compounds of Table 5)

[0497] Step 1: To a solution of benzo[cd]indol-2(1H)-one (2.00 g, 1 Eq, 11.8 mmol) in DMF (20.0 mL), K2CO3(3.27 g, 2 Eq, 23.6 mmol) and MeI (2.18 g, 961 μL, 1.3 Eq, 15.4 mmol) were added. The mixture was stirred at 45 °C for 18 hours. Partial conversion observed by LCMS. MeI (3.36 g, 1.48 mL, 2 Eq, 23.6 mmol) was added and stirring at 45 °C was continued for 24 hours. The mixture was cooled to rt and water (100 ml) was added. The mixture was extracted with EtOAc (3 x 50 ml). The organic layers were combined, washed with brine (2 x 100 ml), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / isohexane) to afford 1-methylbenzo[cd]indol-2(1H)-one (2.01 g, 10 mmol, 88 %, 95% Purity) as a pale yellow solid.

[0498] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.21 – 8.14 (m, 1H), 8.07 – 8.03 (m, 1H), 7.84 – 7.75 (m, 1H), 7.66 – 7.62 (m, 1H), 7.59 – 7.52 (m, 1H), 7.16 (d, J = 7.0 Hz, 1H), 3.38 (s, 3H).

[0499] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 184.2 (M+H)+(ES+) at 1.21 min, 80.3% purity 260nm + / - 90nm.

[0500] Step 2: To a solution of 1-methylbenzo[cd]indol-2(1H)-one (1.00 g, 1 Eq, 5.46 mmol) in Chloroform (30.0 mL), chlorosulfonic acid (1.91 g, 1.10 mL, 3 Eq, 16.4 mmol) was added dropwise over 5 minutes. The mixture was warmed to 50 °C for 3 hours. The mixture was cooled to rt and was poured onto ice-water (100 ml). The mixture was- 118 - extracted with DCM (2 x 50 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-methyl-2-oxo-1,2-dihydrobenzo[cd]indole- 6-sulfonyl chloride (0.494 g, 1.6 mmol, 29 %, 90% Purity) as a yellow solid.

[0501] 1H NMR in DMSO-d6was consistent with product structure at 90% purity.1H NMR (400 MHz, DMSO) δ 8.73 (dd, J = 8.4, 0.7 Hz, 1H), 8.01 (dd, J = 7.0, 0.7 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.78 (dd, J = 8.4, 7.0 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 3.36 (s, 3H).

[0502] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 282.0 / 284.0 (M+H)+(ES+) at 1.49 min, 67.1% purity 254 nm.

[0503] Step 3: To a solution of 1-methyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonyl chloride (0.10 g, 90% Wt, 1 Eq, 0.32 mmol) in dry DCM (2.00 mL), N-ethyl-N- isopropylpropan-2-amine (0.12 g, 3 Eq, 0.96 mmol), piperidine (41 mg, 47 μL, 1.5 Eq, 0.48 mmol) and N,N-dimethylpyridin-4-amine (3.9 mg, 0.1 Eq, 32 μmol) were added successively. The mixture was stirred at rt for 18 hours. Sat. aq. NH4Cl (5 ml) was added and the layer were separated. The aqueous layer was extracted with DCM (2 x 10 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 1-methyl-6-(piperidin-1-ylsulfonyl)benzo[cd]indol-2(1H)-one (90.0 mg, 0.26 mmol, 81 %, 95% Purity) as a pale yellow solid.

[0504] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.1H NMR (400 MHz, DMSO) δ 8.66 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 6.9 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.96 (dd, J = 8.5, 7.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 3.40 (s, 3H), 3.02 – 2.94 (m, 4H), 1.55 – 1.45 (m, 4H), 1.37 – 1.27 (m, 2H).

[0505] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 331.0 (M+H)+(ES+) at 1.45 min, 97.4% purity 254 nm.- 119 - EXAMPLE 7 Preparation of Intermediates 4,5-dibromo-2-methylpyridazin-3(2H)-one

[0506] Step 1: To a solution of 4,5-dibromopyridazin-3(2H)-one (14.00 g, 1 Eq, 55.14 mmol) in DMF (100.0 mL), potassium carbonate (11.43 g, 1.5 Eq, 82.72 mmol) and iodomethane (11.74 g, 5.172 mL, 1.5 Eq, 82.72 mmol) were added. The mixture was warmed to 50 °C and stirred for 6 hours. The mixture was cooled to rt and water (300 ml) was added. The precipitate formed was collected by filtration, washed with water (50 ml) and dried in vacuo to afford 4,5-dibromo-2-methylpyridazin-3(2H)-one (9.70 g, 34 mmol, 62 %, 95% Purity) as a beige solid.

[0507] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0508] 1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 3.67 (s, 3H).

[0509] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-293-1-ms, m / z 266.8 / 268.8 / 270.8 (M+H)+ (ES+) at 0.84 min, 100.0% purity 260nm + / - 90nm.

[0510] Step 2: To a solution of 4,5-dibromo-2-methylpyridazin-3(2H)-one (13.00 g, 1 Eq, 48.52 mmol) in NMP (100.0 mL), lithium chloride (2.468 g, 1.2 Eq, 58.23 mmol) was added. The mixture was warmed to 100 °C and stirred for 18 hours. The mixture was cooled to rt and water (300 ml) was added. The mixture was extracted with EtOAc (3 x 100 ml). The organic layers were combined, washed with water (200 ml) and brine (2 x 200 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford 4-bromo-5-chloro-2- methylpyridazin-3(2H)-one (11.9 g, 44 mmol, 91 %, 83% Purity) as a pale yellow solid.

[0511] 1H NMR in DMSO-d6 was consistent with product structure at 85% purity.

[0512] 1H NMR (500 MHz, DMSO) δ 8.10 (s, 1H), 3.69 (s, 3H).

[0513] The product was analysed by LCMS (Waters Cortecs C18, 30 x 2.1 mm, 2.7μm, at 40 °C, 3 min method, 0.1% Formic acid, 5-100% MeCN / water):3917-294-1-ms, m / z 223.0 / 225.0 (M+H)+ (ES+) at 0.82 min, 82.7% purity 210-400nm.- 120 -

[0514] Step 3: To a solution of 4-bromo-5-chloro-2-methylpyridazin-3(2H)-one (10.0 g, 1 Eq, 44.8 mmol) in 1,4-Dioxane (50.00 mL) and Water (10.00 mL), caesium carbonate (29.2 g, 2 Eq, 89.5 mmol), methylboronic acid (2.95 g, 1.1 Eq, 49.2 mmol) and 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.64 g, 0.05 Eq, 2.24 mmol) were added. The mixture was degassed (N2 bubbling), warmed to 80 °C and stirred for 18 hours.

[0515] The mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by chromatography (solid load) on silica gel (220 g cartridge, 0-20% EtOAc / EtOH 3 / 1 in isohexane) to afford 5-chloro-2,4-dimethylpyridazin-3(2H)-one (6.00 g, 31 mmol, 70 %, 83% Purity) as a white solid.

[0516] 1H NMR in DMSO-d6 was consistent with product structure at 85% purity.

[0517] 1H NMR (500 MHz, DMSO) δ 7.99 (s, 1H), 3.64 (s, 3H), 2.15 (s, 3H).

[0518] The product was analysed by LCMS (Cortecs C18+, 90Å, 2.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): 3917-299-1-ms, m / z 159.0 / 161.0 (M+H)+ (ES+), at 0.81 min, 83% purity 210-400nm. 5-amino-2,4-dimethylpyridazin-3(2H)-one

[0519] Step 1: To a solution of 5-amino-4-chloropyridazin-3(2H)-one (10.00 g, 1 Eq, 68.70 mmol) in DMF (100.00 mL), potassium carbonate (18.99 g, 2 Eq, 137.4 mmol) and iodomethane (10.73 g, 4.726 mL, 1.1 Eq, 75.58 mmol) were added. The mixture was stirred at rt for 18 hours. Water (200 ml) was added, and the mixture was extracted with 10% IPA in DCM (5 x 100 ml). The organic layers were combined, washed with brine (1 x 200 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-50% 3 / 1 EtOAc / MeOH in isohexane) to afford 5-amino-4-chloro-2-methylpyridazin-3(2H)-one (9.00 g, 54 mmol, 78 %, 95% Purity) as a yellow solid.

[0520] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0521] 1H NMR (500 MHz, DMSO) δ 7.54 (s, 1H), 6.71 (s, 2H), 3.54 (s, 3H).- 121 -

[0522] The product was analysed by UPLC (ACQUITY UPLC BEH C18 Column, 130Å, 1.7 µm, 2.1 x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2- 100% MeCN / water):^3917-607-1-ms, m / z^160.2 / 162.2^(M+H)+ (ES+), at^0.40^min,^96%% purity 210-400nm.

[0523] Step 2: To a solution of 5-amino-4-chloro-2-methylpyridazin-3(2H)-one (9.00 g, 1 Eq, 56.4 mmol) in 1,4-Dioxane (100.00 mL) and Water (20.000 mL), caesium carbonate (36.8 g, 2 Eq, 113 mmol), methylboronic acid (16.9 g, 5 Eq, 282 mmol) and Pd 118 (1.84 g, 0.05 Eq, 2.82 mmol) were added. The mixture was degassed (vacuum / N2), warmed to 80 °C and stirred for 7 hours. The mixture was cooled to rt and supported on silica. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-60% 3 / 1 EtOAc / EtOH in isohexane) to afford 5-amino-2,4-dimethylpyridazin-3(2H)-one (7.00 g, 48 mmol, 85 %, 95% Purity) as a yellow solid.

[0524] 1H NMR in DMSO-d6 was consistent with product structure at 95% purity.

[0525] 1H NMR (400 MHz, DMSO) δ 7.41 (s, 1H), 6.01 (s, 2H), 3.48 (s, 3H), 1.79 (s, 3H).

[0526] NMR used to assess the purity.

[0527] The product was analysed by UPLC (ACQUITY UPLC BEH C18 Column, 130Å, 1.7 µm, 2.1 x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2- 100% MeCN / water):^3917-609-1-ms, m / z^140.2 (M+H)+ (ES+), at^0.37^min,^87% purity 254 nm. EXAMPLE 8 3,5-dimethyl-4-[2-methyl-4-(o-tolyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]isoxazole (Compound 4)

[0528] Step 1: To a solution of 4,6-dichloro-2-methyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 1 Eq, 995 μmol) in 2-Methyltetrahydrofuran (3.20 mL), potassium carbonate (412 mg, 746 μL, 4.00 molar, 3 Eq, 2.98 mmol) and 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxaborolane (239 mg, 1.1 Eq, 1.09 mmol) were added. The mixture was degassed (N2 bubbling) for 5- 122 - minutes and Pd(dppf)Cl2(72.8 mg, 0.1 Eq, 99.5 μmol) was added. The mixture was further degassed (N2 bubbling) for 5 minutes and was stirred at 70 °C for 18 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford 6-chloro-2- methyl-4-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine (114 mg, 0.42 mmol, 42 %, 95% Purity) as a pale yellow solid.

[0529] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0530] 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 7.41 – 7.25 (m, 5H), 5.99 – 5.94 (m, 1H), 2.37 (d, J = 1.0 Hz, 3H), 2.20 (s, 3H).

[0531] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-106-1-ms, m / z 257.0 / 259.0 (M+H)+ (ES+) at 1.37 min, 98.3% purity 254 nm.

[0532] Step 2: To a solution of 6-chloro-2-methyl-4-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine (110 mg, 1 Eq, 428 μmol) in DMF (1.50 mL), DBU (130 mg, 129 μL, 2 Eq, 857 μmol) was added. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (478 mg, 5 Eq, 2.14 mmol) and Pd-172 (26.0 mg, 0.1 Eq, 42.8 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 125 °C for 18 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 3% MeOH / DCM) to afford the desired product (48 mg) with low purity.

[0533] The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 5- 50% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 3,5-dimethyl- 4-(2-methyl-4-(o-tolyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isoxazole (16.0 mg, 48 μmol, 11 %, 95% Purity) as a pale yellow solid.

[0534] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0535] 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 7.42 – 7.24 (m, 5H), 5.94 (dt, J = 2.1, 1.0 Hz, 1H), 2.56 (s, 3H), 2.41 – 2.34 (m, 6H), 2.23 (s, 3H).

[0536] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-112-2-ms, m / z 318.2 (M+H)+ (ES+) at 0.88 min, 100.0% purity 254 nm.- 123 - EXAMPLE 9 3,5-dimethyl-4-[2-methyl-4-(o-tolyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]isoxazole (Compound 19)

[0537] Step 1: To a solution of 4,6-dichloro-2-methyl-1H-pyrrolo[3,2-c]pyridine (0.20 g, 1 Eq, 0.99 mmol) in THF (2.00 mL), DIPEA (0.26 g, 0.35 mL, 2 Eq, 2.0 mmol), boc2o (0.33 g, 0.34 mL, 1.5 Eq, 1.5 mmol) and DMAP (12 mg, 0.1 Eq, 99 μmol) were added. The mixture was stirred at rt for 2 hours. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford tert-butyl 4,6-dichloro-2-methyl-1H- pyrrolo[3,2-c]pyridine-1-carboxylate (0.22 g, 0.66 mmol, 66 %, 90% Purity) as a pale yellow solid.

[0538] 1H NMR in DMSO-d6 was consistent with product structure at 90% purity.

[0539] 1H NMR (400 MHz, DMSO) δ 7.94 (d, J = 0.8 Hz, 1H), 6.64 (t, J = 1.1 Hz, 1H), 2.59 (d, J = 1.3 Hz, 3H), 1.64 (s, 9H).

[0540] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-113-1-ms, m / z 301.0 / 303.0 (M+H)+ (ES+) at 2.06 min, 100.0% purity 254 nm.

[0541] Step 2: To a solution of tert-butyl 4,6-dichloro-2-methyl-1H-pyrrolo[3,2- c]pyridine-1-carboxylate (150 mg, 95% Wt, 1 Eq, 473 μmol) in 1,4-Dioxane (1.80 mL), potassium carbonate (196 mg, 355 μL, 4.00 molar, 3 Eq, 1.42 mmol) and 1-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (98.4 mg, 1 Eq, 473 μmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd(dppf)Cl2 (34.6 mg, 0.1 Eq, 47.3 μmol) was added. The mixture was further degassed (N2 bubbling) for 5 minutes and was stirred at 80 °C for 3 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford tert-butyl 6-chloro-2-methyl-4-(1-methyl-- 124 - 1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (115 mg, 0.32 mmol, 67 %, 95% Purity) as a pale yellow solid.

[0542] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0543] 1H NMR (400 MHz, DMSO) δ 7.86 (d, J = 0.8 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.30 – 7.25 (m, 1H), 6.87 (d, J = 2.3 Hz, 1H), 3.98 (s, 3H), 2.61 (d, J = 1.2 Hz, 3H), 1.65 (s, 9H).

[0544] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-119-1-ms, m / z 347.0 / 349.0 (M+H)+ (ES+) at 1.96 min, 97.8% purity 254 nm.

[0545] Step 3: To a solution of tert-butyl 6-chloro-2-methyl-4-(1-methyl-1H-pyrazol-3- yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (50.0 mg, 1 Eq, 144 μmol) in DMF (0.60 mL), DBU (43.9 mg, 43.5 μL, 2 Eq, 288 μmol) was added. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (161 mg, 5 Eq, 721 μmol) and Pd-172 (8.76 mg, 0.1 Eq, 14.4 μmol) were added. The mixture was further degassed (Vacuum / N2). The mixture was warmed to 125 °C and stirred for 20 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford the desired product with low purity. The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 5-50% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 3,5-dimethyl-4-(2-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H- pyrrolo[3,2-c]pyridin-6-yl)isoxazole (10.0 mg, 31 μmol, 36 %, 95% Purity) as a pale yellow solid.

[0546] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0547] 1H NMR (400 MHz, DMSO) δ 11.41 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 0.9 Hz, 1H), 6.96 (dt, J = 2.0, 1.0 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 3.97 (s, 3H), 2.62 (s, 3H), 2.45 (d, J = 1.5 Hz, 6H).

[0548] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-123-1-ms, m / z 308.2 (M+H)+ (ES+) at 0.73 min, 98.9% purity 254 nm.- 125 - EXAMPLE 10 3,5-dimethyl-4-[2-methyl-4-(3-pyridyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]isoxazole (Compound 21)

[0549] Step 1: To a solution of 4,6-dichloro-2-methyl-1H-pyrrolo[3,2-c]pyridine (100 mg, 1 Eq, 497 μmol) in 2-Methyltetrahydrofuran (1.50 mL), potassium carbonate (206 mg, 373 μL, 4.00 molar, 3 Eq, 1.49 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (112 mg, 1.1 Eq, 547 μmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd(dppf)Cl2(36.4 mg, 0.1 Eq, 49.7 μmol) was added. The mixture was further degassed (N2bubbling) for 5 minutes and was stirred at 60 °C for 2 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford 6- chloro-2-methyl-4-(pyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine (74.0 mg, 0.29 mmol, 57 %, 94% Purity) as a pale yellow solid.

[0550] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0551] 1H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.13 (dd, J = 2.3, 0.9 Hz, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.32 (dt, J = 8.0, 2.0 Hz, 1H), 7.60 – 7.52 (m, 1H), 7.37 (d, J = 0.9 Hz, 1H), 6.59 (s, 1H), 2.44 (d, J = 1.0 Hz, 3H).

[0552] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-81-1-ms, m / z 244.0 / 246.0 (M+H)+ (ES+) at 0.84 min, 100.0% purity 254 nm.

[0553] Step 2: To a solution of 6-chloro-2-methyl-4-(pyridin-3-yl)-1H-pyrrolo[3,2- c]pyridine (80 mg, 94% Wt, 1 Eq, 0.31 mmol) in DMF (1.00 mL), DBU (94 mg, 93 μL, 2 Eq, 0.62 mmol) was added. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.34 g, 5 Eq, 1.5 mmol) and Pd- 172 (19 mg, 0.1 Eq, 31 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 125 °C for 18 hours. The mixture was cooled to rt and concentrated in- 126 - vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 3% MeOH / DCM) to afford the desired product with low purity.

[0554] The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 5- 40% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 3,5-dimethyl- 4-(2-methyl-4-(pyridin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isoxazole (21.0 mg, 66 μmol, 21 %, 95% Purity) as a pale yellow solid.

[0555] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0556] 1H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 9.21 (d, J = 2.3 Hz, 1H), 8.64 (dd, J = 4.8, 1.7 Hz, 1H), 8.39 (dt, J = 7.9, 1.9 Hz, 1H), 7.61 – 7.53 (m, 1H), 7.43 (d, J = 0.9 Hz, 1H), 6.63 – 6.55 (m, 1H), 2.62 (s, 3H), 2.46 (d, J = 1.0 Hz, 3H), 2.45 (s, 3H).

[0557] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-98-2-ms, m / z 305.2 (M+H)+ (ES+) at 0.69 min, 100.0% purity 254 nm. EXAMPLE 11 3,5-dimethyl-4-[2-methyl-4-(p-tolyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]isoxazole (Compound 26)

[0558] Step 1: To a solution of 4,6-dichloro-2-methyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 1 Eq, 995 μmol) in 2-Methyltetrahydrofuran (3.20 mL), potassium carbonate (412 mg, 746 μL, 4.00 molar, 3 Eq, 2.98 mmol) and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane (239 mg, 1.1 Eq, 1.09 mmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd(dppf)Cl2 (72.8 mg, 0.1 Eq, 99.5 μmol) was added. The mixture was further degassed (N2bubbling) for 5 minutes and was stirred at 70 °C for 18 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford 6-chloro-2- methyl-4-(p-tolyl)-1H-pyrrolo[3,2-c]pyridine (153 mg, 0.55 mmol, 56 %, 93% Purity) as a pale yellow solid.- 127 -

[0559] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0560] 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 7.90 – 7.83 (m, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 0.9 Hz, 1H), 6.53 (t, J = 1.0 Hz, 1H), 2.42 (d, J = 1.0 Hz, 3H), 2.39 (s, 3H).

[0561] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-103-1-ms, m / z 257.0 / 259.0 (M+H)+ (ES+) at 1.54 min, 92.6% purity 254 nm.

[0562] Step 2: To a solution of 6-chloro-2-methyl-4-(p-tolyl)-1H-pyrrolo[3,2-c]pyridine (150 mg, 1 Eq, 584 μmol) in DMF (2.00 mL), DBU (178 mg, 176 μL, 2 Eq, 1.17 mmol) was added. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (652 mg, 5 Eq, 2.92 mmol) and Pd-172 (35.5 mg, 0.1 Eq, 58.4 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 125 °C for 18 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 3% MeOH / DCM) to afford the desired product (100 mg) with low purity.

[0563] The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 5- 50% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 3,5-dimethyl- 4-(2-methyl-4-(p-tolyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isoxazole (21.0 mg, 63 μmol, 11 %, 95% Purity) as a pale yellow solid.

[0564] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0565] 1H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 7.97 – 7.89 (m, 2H), 7.34 (dd, J = 4.4, 3.5 Hz, 3H), 6.52 (dt, J = 2.0, 1.1 Hz, 1H), 2.61 (s, 3H), 2.44 (d, J = 2.5 Hz, 6H), 2.39 (s, 3H).

[0566] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-109-2-ms, m / z 318.2 (M+H)+ (ES+) at 0.92 min, 97.8% purity 254 nm.- 128 - EXAMPLE 12 4-[6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl]phenol (Compound 28)

[0567] Step 1: To a solution of 4,6-dichloro-2-methyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 1 Eq, 995 μmol) in 2-Methyltetrahydrofuran (3.20 mL), potassium carbonate (412 mg, 746 μL, 4.00 molar, 3 Eq, 2.98 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenol (241 mg, 1.1 Eq, 1.09 mmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd(dppf)Cl2(72.8 mg, 0.1 Eq, 99.5 μmol) was added. The mixture was further degassed (N2bubbling) for 5 minutes and was stirred at 70 °C for 18 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford 4- (6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (251 mg, 0.87 mmol, 88 %, 90% Purity) as a pale yellow solid.

[0568] 1H NMR in DMSO-d6 was consistent with product structure at 90% purity.

[0569] 1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 9.73 (s, 1H), 7.86 – 7.78 (m, 2H), 7.20 (d, J = 0.9 Hz, 1H), 6.94 – 6.86 (m, 2H), 6.52 (dd, J = 2.2, 1.1 Hz, 1H), 2.41 (d, J = 1.0 Hz, 3H).

[0570] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-105-1-ms, m / z 259.0 / 261.0 (M+H)+ (ES+) at 0.94 min, 98.7% purity 260nm + / - 90nm.

[0571] Step 2: To a solution of 4-(6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (100 mg, 1 Eq, 387 μmol) in DMF (1.50 mL), DBU (118 mg, 117 μL, 2 Eq, 773 μmol) was added. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (431 mg, 5 Eq, 1.93 mmol) and Pd-172 (23.5 mg, 0.1 Eq, 38.7 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 125 °C for 18 hours. The mixture was cooled to rt and concentrated in- 129 - vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 3% MeOH / DCM) to afford the desired product with low purity.

[0572] The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 5- 45% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 4-(6-(3,5- dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (18.0 mg, 54 μmol, 14 %, 95% Purity) as a pale yellow solid.

[0573] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0574] 1H NMR (400 MHz, DMSO) δ 11.50 (s, 1H), 9.65 (s, 1H), 7.92 – 7.85 (m, 2H), 7.28 (d, J = 0.9 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.52 – 6.48 (m, 1H), 2.60 (s, 3H), 2.44 (d, J = 1.4 Hz, 6H).

[0575] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-111-2-ms, m / z 320.0 (M+H)+ (ES+) at 0.75 min, 100.0% purity 254 nm. EXAMPLE 13 2-(6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (Compound 32)

[0576] Step 1: To a solution of 2-(6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (40.0 mg, 1 Eq, 155 μmol) in 1,4-Dioxane (1.00 mL), 1,3-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (51.5 mg, 1.5 Eq, 232 μmol) and potassium carbonate (64.1 mg, 309 μL, 1.50 molar, 3 Eq, 464 μmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd-172 (9.39 mg, 0.1 Eq, 15.5 μmol) was added. The mixture was further degassed (N2 bubbling) for 5 minutes and was stirred at 80 °C for 4 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 2-(6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methyl-1H-- 130 - pyrrolo[3,2-c]pyridin-4-yl)phenol (31.0 mg, 92 μmol, 60 %, 95% Purity) as a pale yellow solid.

[0577] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0578] 1H NMR (400 MHz, DMSO) δ 15.53 (s, 1H), 11.76 (s, 1H), 8.18 (dd, J = 8.0, 1.7 Hz, 1H), 8.03 (s, 1H), 7.41 (d, J = 0.9 Hz, 1H), 7.34 – 7.25 (m, 1H), 7.00 – 6.90 (m, 2H), 6.80 (s, 1H), 3.85 (s, 3H), 2.48 (d, J = 0.9 Hz, 3H), 2.42 (s, 3H).

[0579] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-42-1-ms, m / z 319.2 (M+H)+ (ES+) at 0.78 min, 98.0% purity 254 nm. EXAMPLE 14 6-(1,3-dimethylpyrazol-4-yl)-1-methyl-2-phenyl-N-pyrimidin-4-yl-pyrrolo[3,2-c]pyridin-4- amine (Compound 33)

[0580] Step 1: To a solution of 6-chloro-1-methyl-2-phenyl-N-(pyrimidin-4-yl)-1H- pyrrolo[3,2-c]pyridin-4-amine (50.0 mg, 1 Eq, 149 μmol) in DMF (0.40 mL), 1,3- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (132 mg, 4 Eq, 596 μmol) and potassium carbonate (61.7 mg, 112 μL, 4.00 molar, 3 Eq, 447 μmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and 1,3-bis(2,6-Diisopropylphenyl)- 2H-imidazole; 3-chloropyridine; dichloropalladium (10.1 mg, 0.1 Eq, 14.9 μmol) was added. The mixture was further degassed (N2bubbling) for 5 minutes and was stirred at 80 °C for 18 hours.

[0581] The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford 6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-phenyl-N-(pyrimidin- 4-yl)-1H-pyrrolo[3,2-c]pyridin-4-amine with 90% purity as a pale yellow solid.- 131 -

[0582] This solid was dissolved in DMSO (1 ml) and was purified by chromatography on RP Flash C18 (12 g cartridge, 10-50% MeCN / (0.1% Formic Acid in Water)) to afford 6- (1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-phenyl-N-(pyrimidin-4-yl)-1H-pyrrolo[3,2- c]pyridin-4-amine (14.0 mg, 34 μmol, 21 %, 95% Purity) as a pale yellow solid.

[0583] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0584] 1H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 8.74 (s, 1H), 8.54 – 8.43 (m, 2H), 8.10 (s, 1H), 7.66 – 7.57 (m, 2H), 7.58 – 7.51 (m, 2H), 7.51 – 7.42 (m, 1H), 7.31 (d, J = 0.9 Hz, 1H), 7.16 (d, J = 0.9 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.48 (s, 3H).

[0585] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-66-1-ms, m / z 396.2 (M+H)+ (ES+) at 0.98 min, 100.0% purity 254 nm. EXAMPLE 15 6-(1,3-dimethylpyrazol-4-yl)-1-methyl-2-phenyl-N-pyrimidin-4-yl-pyrrolo[3,2-c]pyridin-4- amine (Compound 34)

[0586] Step 1: To a solution of 2-(6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (50.0 mg, 1 Eq, 193 μmol) in 1,4-Dioxane (0.60 mL), 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (129 mg, 3 Eq, 580 μmol) and potassium carbonate (80.1 mg, 145 μL, 4.00 molar, 3 Eq, 580 μmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and pd-172 (11.7 mg, 0.1 Eq, 19.3 μmol) was added. The mixture was further degassed (N2bubbling) for 5 minutes and was stirred at 80 °C for 18 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH / DCM) to afford 2-(6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methyl-1H-pyrrolo[3,2- c]pyridin-4-yl)phenol (36.0 mg, 0.11 mmol, 56 %, 95% Purity) as a pale yellow solid.

[0587] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.- 132 -

[0588] 1H NMR (400 MHz, DMSO) δ 15.70 (s, 1H), 12.41 (s, 1H), 11.76 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.34 – 7.23 (m, 2H), 7.00 – 6.88 (m, 2H), 6.83 (s, 1H), 2.32 (s, 6H). (3H under the DMSO peak as shown by HSQC).

[0589] 1H NMR in CD3OD was consistent with product structure at >95% purity.

[0590] 1H NMR (400 MHz, MeOD) δ 8.23 (dd, J = 7.9, 1.7 Hz, 1H), 7.31 – 7.22 (m, 2H), 7.00 – 6.89 (m, 2H), 6.85 – 6.80 (m, 1H), 2.54 (d, J = 1.0 Hz, 3H), 2.39 (s, 6H). (3 exchangeable Hs not shown).

[0591] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-59-1-ms, m / z 319.2 (M+H)+ (ES+) at 0.76 min, 99.0% purity 254 nm. EXAMPLE 16 2-[6-(3,5-dimethylisoxazol-4-yl)-2-phenyl-1H-pyrrolo[3,2-c]pyridin-4-yl]phenol (Compound 35)

[0592] Step 1: To a solution of 4,6-dichloro-2-phenyl-1H-pyrrolo[3,2-c]pyridine (180 mg, 95% Wt, 1 Eq, 650 μmol) in 2-Methyltetrahydrofuran (2.00 mL), potassium carbonate (269 mg, 487 μL, 4.00 molar, 3 Eq, 1.95 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenol (143 mg, 136 μL, 1 Eq, 650 μmol) were added. The mixture was degassed (N2bubbling) for 5 minutes and Pd(dppf)Cl2 (47.6 mg, 0.1 Eq, 65.0 μmol) was added. The mixture was further degassed (N2 bubbling) for 5 minutes and was stirred at 80 °C for 2 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, DCM) to afford 2-(6-chloro-2- phenyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (150 mg, 0.44 mmol, 68 %, 95% Purity) as a pale yellow solid.

[0593] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.- 133 -

[0594] 1H NMR (400 MHz, DMSO) δ 12.61 (s, 1H), 12.49 (s, 1H), 8.16 (dd, J = 7.9, 1.7 Hz, 1H), 8.04 – 7.96 (m, 2H), 7.57 – 7.50 (m, 2H), 7.50 – 7.46 (m, 2H), 7.45 – 7.32 (m, 2H), 7.08 – 6.97 (m, 2H).

[0595] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-75-1-ms, m / z 321.0 / 323.0 (M+H)+ (ES+) at 2.00 min, 100.0% purity 260nm + / - 90nm.

[0596] Step 2: To a solution of 2-(6-chloro-2-phenyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (50.0 mg, 1 Eq, 156 μmol) in 1,4-Dioxane (0.60 mL), potassium carbonate (64.6 mg, 117 μL, 4.00 molar, 3 Eq, 468 μmol) was added. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (104 mg, 3 Eq, 468 μmol) and Pd-172 (9.47 mg, 0.1 Eq, 15.6 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 80 °C for 4 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford the desired product with low purity. The residue (31 mg) was purified by chromatography on RP Flash C18 (12 g cartridge, 0-70% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 2-(6-(3,5-dimethylisoxazol-4-yl)-2-phenyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (14.0 mg, 35 μmol, 22 %, 95% Purity) as a pale yellow solid.

[0597] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0598] 1H NMR (500 MHz, DMSO) δ 14.67 (s, 1H), 12.54 (s, 1H), 8.38 (dd, J = 8.0, 1.6 Hz, 1H), 8.09 – 8.03 (m, 2H), 7.66 (s, 1H), 7.57 – 7.51 (m, 3H), 7.42 (t, J = 7.4 Hz, 1H), 7.39 – 7.32 (m, 1H), 7.08 – 7.02 (m, 1H), 6.98 (dd, J = 8.1, 1.3 Hz, 1H), 2.57 (s, 3H), 2.39 (s, 3H).

[0599] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-79-2-ms, m / z 382.2 (M+H)+ (ES+) at 1.33 min, 99.4% purity 254 nm.- 134 - EXAMPLE 17 2-[2-methyl-6-(1,3,5-trimethylpyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl]phenol (Compound 36)

[0600] Step 1: To a solution of 2-(6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (50.0 mg, 1 Eq, 193 μmol) in 1,4-Dioxane (0.60 mL), potassium carbonate (80.1 mg, 145 μL, 4.00 molar, 3 Eq, 580 μmol) was added. The mixture was degassed (Vacuum / N2) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (137 mg, 3 Eq, 580 μmol) and Pd-172 (11.7 mg, 0.1 Eq, 19.3 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 80 °C for 4 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-4% MeOH / DCM) to afford the desired product with low purity. The residue (42 mg) was purified by chromatography on RP Flash C18 (12 g cartridge, 5-45% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 2-(2-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (25.0 mg, 71 μmol, 37 %, 95% Purity) as a pale yellow solid. 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0601] 1H NMR (500 MHz, DMSO) δ 15.65 (s, 1H), 11.78 (s, 1H), 8.21 (dd, J = 7.9, 1.6 Hz, 1H), 7.31 – 7.24 (m, 2H), 6.95 (t, J = 7.8 Hz, 1H), 6.91 (dd, J = 8.2, 1.3 Hz, 1H), 6.84 (s, 1H), 3.75 (s, 3H), 2.49 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H).

[0602] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-88-2-ms, m / z 333.2 (M+H)+ (ES+) at 0.80 min, 100.0% purity 254 nm.- 135 - EXAMPLE 18 2-[6-(3,5-dimethylisoxazol-4-yl)-2-isopropyl-1H-pyrrolo[3,2-c]pyridin-4-yl]phenol (Compound 37)

[0603] Step 1: To a solution of 2,6-dichloro-3-iodopyridin-4-amine (2.00 g, 1 Eq, 6.92 mmol) in DMF (20.0 mL), 3-methylbut-1-yne (1.89 g, 2.83 mL, 4 Eq, 27.7 mmol), triethylamine (2.10 g, 2.89 mL, 3 Eq, 20.8 mmol), CuI (132 mg, 0.1 Eq, 692 μmol) and Bis-(triphenylphosphino)-palladous chloride (486 mg, 0.1 Eq, 692 μmol) were added. The mixture was degassed with N2 (bubbling) for 5 minutes and was stirred at 60 °C for 1 hour. The mixture was cooled to rt, diluted with EtOAc (50 ml) and washed with sat. aq. NH4Cl (50 ml). The organic layer was further washed with water (50 ml) and brine (2 x 50 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-1% MeOH / DCM) to afford 2,6-dichloro-3-(3-methylbut-1-yn-1-yl)pyridin-4-amine (1.44 g, 5.7 mmol, 82 %, 90% Purity) as a tan solid.

[0604] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0605] 1H NMR (400 MHz, DMSO) δ 6.74 (s, 2H), 6.63 (s, 1H), 2.88 (hept, J = 6.9 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H).

[0606] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-71-1-ms, m / z 229.0 / 231.0 (M+H)+ (ES+) at 1.62 min, 90% purity 260nm + / - 90nm.

[0607] Step 2: To a solution of 2,6-dichloro-3-(3-methylbut-1-yn-1-yl)pyridin-4-amine (1.40 g, 90% Wt, 1 Eq, 5.50 mmol) in DMF (20.0 mL), potassium tert-butoxide (1.23 g, 2 Eq, 11.0 mmol) was added. The mixture was stirred at 80 °C for 2 hours. Water (100 ml) was added and the precipitate formed was collected by filtration, washed with water (20- 136 - ml) and dried in vacuo to afford 4,6-dichloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (1.08 g, 4.5 mmol, 81 %, 95% Purity) as a tan solid.

[0608] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0609] 1H NMR (400 MHz, DMSO) δ 11.97 (s, 1H), 7.37 (d, J = 0.9 Hz, 1H), 6.28 (t, J = 0.9 Hz, 1H), 3.15 – 3.00 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H).

[0610] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-73-1-ms, m / z 229.0 / 231.0 (M+H)+ (ES+) at 1.62 min, 95.8% purity 254 nm.

[0611] Step 3: To a solution of 4,6-dichloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (500 mg, 1 Eq, 2.18 mmol) in 2-Methyltetrahydrofuran (6.00 mL), potassium carbonate (905 mg, 1.64 mL, 4.00 molar, 3 Eq, 6.55 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenol (480 mg, 457 μL, 1 Eq, 2.18 mmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd(dppf)Cl2 (160 mg, 0.1 Eq, 218 μmol) was added. The mixture was further degassed (N2bubbling) for 5 minutes and was stirred at 80 °C for 2 hours. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-1% MeOH / DCM) to afford 2- (6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (474 mg, 1.6 mmol, 72 %, 95% Purity) as a pale yellow solid.

[0612] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0613] 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 11.93 (s, 1H), 8.02 (dd, J = 7.9, 1.7 Hz, 1H), 7.40 (d, J = 0.9 Hz, 1H), 7.37 – 7.29 (m, 1H), 7.06 – 6.94 (m, 2H), 6.68 (d, J = 0.9 Hz, 1H), 3.19 – 3.03 (m, 1H), 1.34 (d, J = 6.9 Hz, 6H).

[0614] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-74-1-ms, m / z 287.0 / 289.0 (M+H)+ (ES+) at 1.90 min, 96.6% purity 260nm + / - 90nm.

[0615] Step 4: To a solution of 2-(6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (50.0 mg, 1 Eq, 174 μmol) in 1,4-Dioxane (0.60 mL), potassium carbonate (72.3 mg, 131 μL, 4.00 molar, 3 Eq, 523 μmol) was added in a microwave vial. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoxazole (194 mg, 5 Eq, 872 μmol) and Pd-172 (10.6 mg, 0.1 Eq, 17.4 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 130 °C for 2 hours under microwave irradiation. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3%- 137 - MeOH / DCM) to afford 2-(6-(3,5-dimethylisoxazol-4-yl)-2-isopropyl-1H-pyrrolo[3,2- c]pyridin-4-yl)phenol with 90% Purity as a pale yellow solid.

[0616] The solid was purified by chromatography on RP Flash C18 (12 g cartridge, 10- 60% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 2-(6-(3,5- dimethylisoxazol-4-yl)-2-isopropyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (23.0 mg, 0.065 mmol, 73 %, 95% Purity) as a pale yellow solid.

[0617] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0618] 1H NMR (500 MHz, DMSO) δ 14.78 (s, 1H), 11.96 (s, 1H), 8.22 (dd, J = 7.9, 1.7 Hz, 1H), 7.45 (s, 1H), 7.35 – 7.28 (m, 1H), 7.04 – 6.98 (m, 1H), 6.94 (dd, J = 8.2, 1.3 Hz, 1H), 6.83 (s, 1H), 3.22 – 3.13 (m, 1H), 2.53 (s, 3H), 2.35 (s, 3H), 1.37 (d, J = 6.9 Hz, 6H).

[0619] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-95-1-ms, m / z 348.2 (M+H)+ (ES+) at 1.11 min, 98.5% purity 260nm + / - 90nm. EXAMPLE 19 3,5-dimethyl-4-[2-methyl-4-(o-tolyl)-1H-pyrrolo[3,2-c]pyridin-6-yl]isoxazole (Compound 38)

[0620] Step 1: To a solution of 4,6-dichloro-2-methyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 1 Eq, 995 μmol) in 2-Methyltetrahydrofuran (3.20 mL), potassium carbonate (412 mg, 746 μL, 4.00 molar, 3 Eq, 2.98 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenol (241 mg, 1.1 Eq, 1.09 mmol) were added. The mixture was degassed (N2 bubbling) for 5 minutes and Pd(dppf)Cl2 (72.8 mg, 0.1 Eq, 99.5 μmol) was added. The mixture was further degassed (N2 bubbling) for 5 minutes and was stirred at 70 °C for 18 hours. The mixture was cooled to rt and concentrated in vacuo.The crude product was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford 3-- 138 - (6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (238 mg, 0.87 mmol, 88 %, 95% Purity) as a tan solid.

[0621] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0622] 1H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 9.55 (s, 1H), 7.43 – 7.35 (m, 2H), 7.34 – 7.27 (m, 2H), 6.84 (ddd, J = 7.9, 2.4, 1.2 Hz, 1H), 6.51 (s, 1H), 2.42 (d, J = 1.0 Hz, 3H).

[0623] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water): m / z 259.0 / 261.0 (M+H)+ (ES+) at 1.08 min, 100.0% purity 260nm + / - 90nm.

[0624] Step 2: To a solution of 3-(6-chloro-2-methyl-1H-pyrrolo[3,2-c]pyridin-4- yl)phenol (100 mg, 1 Eq, 387 μmol) in DMF (1.00 mL), DBU (118 mg, 117 μL, 2 Eq, 773 μmol) was added. The mixture was degassed (Vacuum / N2) and 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (431 mg, 5 Eq, 1.93 mmol) and Pd-172 (23.5 mg, 0.1 Eq, 38.7 μmol) were added. The mixture was further degassed (Vacuum / N2) and was stirred at 130 °C for 18 hours under microwave irradiation. The mixture was cooled to rt, water 10 ml was added and the solid formed was collected by filtration. The solid was purified by chromatography on silica gel (12 g cartridge, 0-3% MeOH / DCM) to afford the desired product with low purity.

[0625] The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 5- 45% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 3-(6-(3,5- dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)phenol (16.0 mg, 50 μmol, 50 %, 95% Purity) as a pale yellow solid.

[0626] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0627] 1H NMR (400 MHz, DMSO) δ 11.59 – 11.54 (m, 1H), 9.51 (s, 1H), 7.51 – 7.42 (m, 2H), 7.37 – 7.27 (m, 2H), 6.86 – 6.78 (m, 1H), 6.54 – 6.48 (m, 1H), 2.61 (s, 3H), 2.45 (d, J = 1.9 Hz, 6H).

[0628] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-116-1-ms, m / z 320.2 (M+H)+ (ES+) at 0.75 min, 100.0% purity 254 nm.- 139 - EXAMPLE 20 4-chloro-2-methyl-5-[(1-methylindol-5-yl)amino]pyridazin-3-one (Compound 93)

[0629] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) in DMSO (1.00 mL), DIPEA (144 mg, 195 μL, 2 Eq, 1.12 mmol) and 1-methyl- 1H-indol-5-amine (98.0 mg, 1.2 Eq, 670 μmol) were added. The mixture was stirred at 120 °C for 2 hours. The mixture was cooled to rt and EtOAc (25 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (25 ml). The aqueous layer was further extracted with EtOAc (25 ml) and the organic layers were combined, washed with brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-30% [3:1 EtOAc / EtOH]: isohexane to afford the desired product 4-chloro-2-methyl-5-((1-methyl-1H-indol-5- yl)amino)pyridazin-3(2H)-one (76.0 mg, 0.25 mmol, 45 %, 95% Purity) as a tan solid.

[0630] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity. 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.05 (dd, J = 8.6, 2.1 Hz, 1H), 6.43 (dd, J = 3.1, 0.8 Hz, 1H), 3.81 (s, 3H), 3.58 (s, 3H).

[0631] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-10-2-ms-1, m / z 289.3 / 291.2 (M+H)+ (ES+) at 1.15 min, 94.9% purity 210-400nm. EXAMPLE 21 5-chloro-2-methyl-4-[(1-methylindol-5-yl)amino]pyridazin-3-one (Compound 94)- 140 -

[0632] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) in DMSO (1.00 mL), DIPEA (144 mg, 195 μL, 2 Eq, 1.12 mmol) and 1-methyl- 1H-indol-5-amine (98.0 mg, 1.2 Eq, 670 μmol) were added. The mixture was stirred at 120 °C for 2 hours. The mixture was cooled to rt and EtOAc (25 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (25 ml). The aqueous layer was further extracted with EtOAc (25 ml) and the organic layers were combined, washed with brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-30% [3:1 EtOAc / EtOH]: isohexane to afford 5-chloro-2-methyl-4-((1-methyl-1H-indol-5-yl)amino)pyridazin-3(2H)-one (26.0 mg, 86 μmol, 15 %, 95% Purity) as a light tan solid.

[0633] 1H NMR in DMSO-d6 was consistent with product structure at >98% purity. 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.67 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 3.1 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 8.6, 2.1 Hz, 1H), 6.36 (dd, J = 3.0, 0.8 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 3H).

[0634] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-10-1-ms-2, m / z 289.6; 291.1 (M+H)+ (ES+) at 0.55 min, 95.6% purity 210-400nm. EXAMPLE 22 5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 95)

[0635] Step 1: To a solution of 1H-indol-5-amine (1.00 g, 1 Eq, 7.57 mmol) in dry DMF (30.0 mL) at 0 °C, NaH (363 mg, 60% Wt, 1.2 Eq, 9.08 mmol) was added. The mixture was stirred for 30 minutes at the same temperature and 2-Bromoethylmethyl ether (1.26 g, 860 μL, 1.2 Eq, 9.08 mmol) was added dropwise over 5 minutes. The mixture was warmed to rt and was stirred for 18 hours. Water (50 ml) was cautiously added and the mixture was- 141 - extracted with EtOAc (3 x 50 ml). The organic layers were combined, washed with brine (2 x 100 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford 1-(2-methoxyethyl)-1H-indol-5-amine (1.03 g, 5.1 mmol, 68 %, 95% Purity) as a pale yellow solid.

[0636] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0637] 1H NMR (400 MHz, DMSO) δ 7.18 – 7.09 (m, 2H), 6.66 (d, J = 2.1 Hz, 1H), 6.51 (dd, J = 8.6, 2.1 Hz, 1H), 6.10 (dd, J = 3.0, 0.8 Hz, 1H), 4.45 (s, 2H), 4.18 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.4 Hz, 2H), 3.20 (s, 3H).

[0638] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-129-1-ms, m / z 191.2 (M+H)+ (ES+) at 0.14 min, 95.8% purity 254 nm.

[0639] Step 2: To a solution of 5-chloro-2-methylpyridazin-3(2H)-one (80.0 mg, 1 Eq, 553 μmol) in DMSO (1.00 mL), DIPEA (143 mg, 193 μL, 2 Eq, 1.11 mmol) and 1-(2- methoxyethyl)-1H-indol-5-amine (126 mg, 1.2 Eq, 664 μmol) were added. The mixture was stirred at 120 °C under microwave irradiation for 1 hour. Analysis showed modest product formation. The mixture was stirred at 120 °C under conventional heating for 21 hours. The mixture was cooled to r.t. and EtOAc (25 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (25 ml). The aqueous layer was further extracted with EtOAc (25 ml) and the organic layers were combined, washed with brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% [3: 1 EtOAc:EtOH]: isohexanes) to afford 5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (61 mg, 0.20 mmol, 36 %, 98% Purity) as a tan solid.

[0640] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity. 1H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.61 (d, J = 2.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.41 – 7.33 (m, 2H), 6.98 (dd, J = 8.7, 2.1 Hz, 1H), 6.42 (dd, J = 3.1, 0.8 Hz, 1H), 5.79 (d, J = 2.7 Hz, 1H), 4.33 (t, J = 5.3 Hz, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.50 (s, 3H), 3.22 (s, 3H).

[0641] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 1 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-11-1-ms-152063, m / z 299.2 (M+H)+ (ES+) at 0.53 min, 97.9% purity 260nm + / - 90nm.- 142 - EXAMPLE 23 4-chloro-5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-tetrahydropyran-2-yl-pyridazin-3-one (Compound 96)

[0642] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (500 mg, 1 Eq, 3.03 mmol) in dry THF (3.00 mL) under a nitrogen atmosphere at r.t. was added PTSOH (115 mg, 0.2 Eq, 606 μmol) and 3,4-dihydro-2H-pyran (382 mg, 1.5 Eq, 4.55 mmol). The reaction mixture was stirred for 18 hours. The reaction was taken up in ethyl acetate (50 mL), and washed with a 2N aqueous sodium hydroxide solution (2×50 mL). The organics were then washed with a saturated aqueous sodium chloride solution (50 mL), dried over Na2SO4, filtered, rinsed, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% 20% EtOAc / isohexanes: isohexanes) to afford 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (382 mg, 1.4 mmol, 48 %, 94% Purity) as a white solid.

[0643] 1H NMR in d6-DMSO was consistent with the expected structure at 94% purity (5.5 w% EtOAc, impurities). 1H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 5.84 (dd, J = 10.5, 2.2 Hz, 1H), 3.99 – 3.92 (m, 1H), 3.66 – 3.55 (m, 1H), 2.10 – 2.00 (m, 1H), 1.97 – 1.89 (m, 1H), 1.73 – 1.62 (m, 2H), 1.57 – 1.44 (m, 2H).

[0644] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 1 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-8-1-ms-151764, m / z 271.0 (M+Na)+ (ES+) at 0.58 min, 98.9% purity 260nm + / - 90nm.

[0645] Step 2: To a solution of 1-(2-methoxyethyl)-1H-indol-5-amine (92.0 mg, 1.20 Eq, 484 μmol) in DMSO (750 μL), 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin- 3(2H)-one (100 mg, 1 Eq, 401 μmol) and DIPEA (104 mg, 140 μL, 2 Eq, 803 μmol) were added. The mixture was stirred at 90 °C under conventional heating for 1.5 hours. The mixture was cooled to rt and EtOAc (25 ml) was added. The mixture was washed with sat. aq. NaHCO3solution (25 ml). The aqueous layer was further extracted with EtOAc (25 ml)- 143 - and the organic layers were combined, washed with brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% [3: 1 EtOAc:EtOH]: isohexanes) eluting at 40% to afford the desired product 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2- (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (115 mg, 0.26 mmol, 64 %, 90% Purity) as a tan solid.

[0646] 1H NMR in DMSO-d6 was consistent with product structure at ~90% purity (3 w% EtOAc, minor impurities).1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 3.1 Hz, 1H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 5.83 (dd, J = 10.6, 2.2 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 3.92 (d, J = 11.4 Hz, 1H), 3.67 (t, J = 5.3 Hz, 2H), 3.63 – 3.51 (m, 1H), 3.23 (s, 3H), 2.06 – 1.95 (m, 1H), 1.95 – 1.85 (m, 1H), 1.73 – 1.62 (m, 1H), 1.62 – 1.52 (m, 1H), 1.52 – 1.37 (m, 2H).

[0647] The product was analysed by LCMS (Waters Cortecs C18, 30 x 2.1 mm, 2.7μm, at 40 °C, 3 min method, 0.1% Formic acid, 5-100% MeCN / water): 4036-13 TT1252114, m / z 403.2 / 405.0, at 0.644 min, 96.3% purity at 260nm + / - 90nm. EXAMPLE 24 4-chloro-5-(1H-indol-5-ylamino)-2-methyl-pyridazin-3-one (Compound 97)

[0648] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (500 mg, 1 Eq, 2.79 mmol) in DMSO (5.00 mL), DIPEA (742 mg, 1000 μL, 2.06 Eq, 5.74 mmol) and tert- butyl 5-amino-1H-indole-1-carboxylate (779 mg, 1.2 Eq, 3.35 mmol) were added. The mixture was stirred at 120 °C for 21 hours wherein over the course of the reaction the SNArs occurred followed by Boc deprotection of the products. The mixture was cooled to rt and EtOAc (50 ml) was added. The mixture was washed with sat. aq. NaHCO3solution (50 ml). The aqueous layer was further extracted with EtOAc (2x 50 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24- 144 - g cartridge, 0-60% [3:1 EtOAc / EtOH]: isohexane to afford the desired product with low purity. DCM (10 mL) was added to the dry product and slight sonication led to a dark solution and fine white precipitate which was allowed to settle. The brown liquid was removed and the solid further triturated a with DCM (2 x 10 mL). The solid was dried under reduced pressure to afford 4-((1H-indol-5-yl)amino)-5-chloro-2-methylpyridazin-3(2H)- one (240 mg, 0.85 mmol, 30 %, 97% Purity) as a light tan solid.

[0649] 1H NMR in DMSO-d6 was consistent with product structure at ~98% purity. 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.61 (s, 1H), 7.46 – 7.38 (m, 4H), 6.98 (dd, J = 8.4, 2.2 Hz, 1H), 6.46 – 6.39 (m, 1H), 3.58 (s, 3H).

[0650] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-16-2 trit 3, m / z 275.2 / 277.2 (M+H)+ (ES+) at 0.96 min, 97% purity 210-400nm. EXAMPLE 25 4-chloro-5-[[1-(cyclopropylmethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 98)

[0651] Step 1: To a solution of 5-((1H-indol-5-yl)amino)-4-chloro-2-methylpyridazin- 3(2H)-one (50.0 mg, 97% Wt, 1 Eq, 177 μmol) in dry DMF (0.90 mL) at 0 °C, sodium hydride (7.06 mg, 60% Wt, 1 Eq, 177 μmol) was added in portions. The mixture was stirred for 30 minutes at the same temperature and (bromomethyl)cyclopropane (25.0 mg, 1.05 Eq, 185 μmol) in DMF (0.10 mL) was added. The mixture was allowed to warm to rt and was stirred for 20 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with EtOAc (3 x 10 ml). The organic layers were combined, washed with 50 v% brine (2 x 20 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% [3:1 EtOAc / EtOH]: isohexane to afford 4-chloro-5-((1-(cyclopropylmethyl)-1H-indol-5-- 145 - yl)amino)-2-methylpyridazin-3(2H)-one (2.00 mg, 6.0 μmol, 3.4 %, 98% Purity) as a white lyophilised solid.

[0652] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H), 7.44 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 4.06 (d, J = 7.0 Hz, 2H), 3.59 (s, 3H), 1.30 – 1.24 (m, 1H), 0.56 – 0.47 (m, 2H), 0.46 – 0.34 (m, 2H).

[0653] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-18-2-MS-3, m / z 329.3 / 331.3 (M+H)+ (ES+) at 1.45 min, 94.4% purity 210-400nm EXAMPLE 26 4-chloro-5-[cyclopropylmethyl(1H-indol-5-yl)amino]-2-methyl-pyridazin-3-one (Compound 99)

[0654] Step 1: To a solution of 5-((1H-indol-5-yl)amino)-4-chloro-2-methylpyridazin- 3(2H)-one (50.0 mg, 97% Wt, 1 Eq, 177 μmol) in dry DMF (0.90 mL) at 0 °C, sodium hydride (7.06 mg, 60% Wt, 1 Eq, 177 μmol) was added in portions. The mixture was stirred for 30 minutes at the same temperature and (bromomethyl)cyclopropane (25.0 mg, 1.05 Eq, 185 μmol) in DMF (0.10 mL) was added. The mixture was allowed to warm to rt and was stirred for 20 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with EtOAc (3 x 10 ml). The organic layers were combined, washed with 50 v% brine (2 x 20 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% [3:1 EtOAc / EtOH]: isohexane to afford 4-chloro-5-((cyclopropylmethyl)(1H-indol-5- yl)amino)-2-methylpyridazin-3(2H)-one (19.0 mg, 57 μmol, 32 %, 98% Purity) was obtained as a yellow solid.- 146 -

[0655] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.68 (s, 1H), 7.40 – 7.30 (m, 3H), 6.91 (dd, J = 8.6, 2.2 Hz, 1H), 6.40 – 6.37 (m, 1H), 3.81 (d, J = 6.6 Hz, 2H), 3.61 (s, 3H), 1.19 – 1.06 (m, 1H), 0.46 – 0.34 (m, 2H), 0.18 – 0.03 (m, 2H).

[0656] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-18 2-F3 conc, m / z 329.2 / 331.0 (M+H)+ (ES+) at 1.41 min, 98.3% purity 260nm + / - 90nm. EXAMPLE 27 4-chloro-5-[[1-(cyclopropylmethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 100)

[0657] Step 1: To a solution of 5-((1H-indol-5-yl)amino)-4-chloro-2-methylpyridazin- 3(2H)-one (30.0 mg, 1 Eq, 109 μmol) in dry DMF (1.00 mL) at 0 °C, NaH (5.24 mg, 60% Wt, 1.2 Eq, 131 μmol) was added. The mixture was stirred for 30 minutes at the same temperature and 2-bromo-N,N-dimethylacetamide (21.8 mg, 15.6 μL, 1.2 Eq, 131 μmol) was added. The mixture was warmed to rt and was stirred for 2 hours. Water (10 ml) and Sat. Aq. NH4Cl (10 ml) were cautiously added, and the mixture was extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford 2-(5-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1H-indol-1-yl)- N,N-dimethylacetamide (26.0 mg, 69 μmol, 63 %, 95% Purity) as a pale yellow solid.

[0658] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0659] 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.43 (s, 1H), 7.42 – 7.37 (m, 2H), 7.31 (d, J = 3.1 Hz, 1H), 7.00 (dd, J = 8.7, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 5.16 (s, 2H), 3.59 (s, 3H), 3.11 (s, 3H), 2.86 (s, 3H).- 147 -

[0660] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-191-1-ms, m / z 360.0 / 362.0 (M+H)+ (ES+) at 1.02 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 28 4-chloro-5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-(methoxymethyl)pyridazin-3-one (Compound 101)

[0661] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (500 mg, 1 Eq, 3.03 mmol), DIPEA (548 mg, 739 μL, 1.4 Eq, 4.24 mmol) and DMAP (37.0 mg, 0.1 Eq, 303 μmol) in dry DCM (3.50 mL) under a nitrogen atmosphere at 0 °C was added chloro(methoxy)methane (293 mg, 276 μL, 1.2 Eq, 3.64 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was diluted with sat. aq. NaHCO3 (25 mL) and DCM (25 mL) and transferred into a separating funnel. The aqueous layer was further extracted with DCM (2 x 25 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-30% EtOAc : DCM) to afford 4,5-dichloro- 2-(methoxymethyl)pyridazin-3(2H)-one (418 mg, 2.0 mmol, 65 %, 99% Purity) as a white crystalline solid.

[0662] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 5.34 (s, 2H), 3.33 (s, 3H).

[0663] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-23-1-ms-2, m / z 209.0 / 211.1 (M+H)+ (ES+) at 0.83 min, 98.8% purity 260nm + / - 90nm.

[0664] Step 2: To a solution of 4,5-dichloro-2-(methoxymethyl)pyridazin-3(2H)-one (100 mg, 1 Eq, 478 μmol) in DMSO (1.00 mL), DIPEA (124 mg, 167 μL, 2 Eq, 957 μmol) and- 148 - 1-(2-methoxyethyl)-1H-indol-5-amine (109 mg, 1.2 Eq, 574 μmol) were added. The mixture was stirred at 90 °C for 2.5 hours. The mixture was cooled to rt and the reaction mixture was dry loaded onto silica gel. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-30% [3:1 EtOAc / EtOH]: isohexane to afford the desired product (396 mg) as an orange oil. Significant DMSO was found to be present. The residue was diluted with EtOAc (25 mL) and 50 v% Brine (50 mL) and transferred into a separating funnel. The separated organic layer was further extracted with 50 v% Brine (1 x 50 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to afford 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2- (methoxymethyl)pyridazin-3(2H)-one (144 mg, 0.39 mmol, 82 %, 99% Purity) as a thick red gum.

[0665] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity (<1 w% DCM).1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 3.1 Hz, 1H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 6.45 (dd, J = 3.1, 0.8 Hz, 1H), 5.25 (s, 2H), 4.35 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.30 (s, 3H), 3.23 (s, 3H).

[0666] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-26-1-ms-2, m / z 363.3; 365.3 (M+H)+ (ES+) at 1.21 min, 99.2% purity 210-400nm. EXAMPLE 29 4-[[1-(2-methoxyethyl)indol-5-yl]amino]-2,5-dimethyl-pyridazin-3-one (Compound 102)

[0667] Step 1: Pd dppf.dcm (228 mg, 0.05 Eq, 279 μmol) was added to a sparged solution (Sonicating with bubbling N2for 2 min) of 4,5-dichloro-2-methylpyridazin-3(2H)-one (1.00 g, 1 Eq, 5.59 mmol), methylboronic acid (334 mg, 1 Eq, 5.59 mmol) and caesium- 149 - carbonate (5.46 g, 3 Eq, 16.8 mmol) in 1,4-Dioxane (8.00 mL) and Water (800 μL) and the reaction was heated at 100 °C for 3 h. The reaction was cooled and concentrated before being loaded onto silica and purified by column chromatography. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-60% EtOAc / isohexane) to afford 4-chloro-2,5-dimethylpyridazin-3(2H)-one (160 mg, 0.98 mmol, 18 %, 97% Purity) as white crystalline solids.

[0668] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 3.68 (s, 3H), 2.26 (s, 3H).

[0669] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-24-F211587, m / z 161.0 (M+H)+ (ES+) at 0.63 min, 97.4% purity 260nm + / - 90nm.

[0670] Step 2: To a solution of 4-chloro-2,5-dimethylpyridazin-3(2H)-one (100 mg, 1 Eq, 631 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (120 mg, 1 Eq, 631 μmol) in 1,4- Dioxane (3.50 mL), NaOtBu (90.9 mg, 1.5 Eq, 946 μmol), dicyclohexyl(2’,4’,6’- triisopropyl-3,6-dimethoxy-[1,1’-biphenyl]-2-yl)phosphane (33.8 mg, 0.1 Eq, 63.1 μmol) and BrettPhos Pd G3 (57.2 mg, 0.1 Eq, 63.1 μmol) were added. The mixture was sparged (bubbling N2with sonication for 2 min) then stirred at 100 °C for 3 hours. The reaction was cooled and dry loaded onto silica. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% [3:1 EtOAc:EtOH] : isoHexanes), eluting at 25% to afford 4-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2,5-dimethylpyridazin-3(2H)-one (123 mg, 0.38 mmol, 60 %, 96% Purity) as a thick orange gum.

[0671] 1H NMR in DMSO-d6 was consistent with product structure at 96% purity (3.4 w% DCM).1H NMR (400 MHz, DMSO) δ 7.99 (s, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.7, 2.1 Hz, 1H), 6.35 (dd, J = 3.1, 0.8 Hz, 1H), 4.30 (t, J = 5.3 Hz, 2H), 3.67 (s, 3H), 3.66 – 3.63 (m, 2H), 3.22 (s, 3H), 1.58 (s, 3H).

[0672] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-27-1-ms-1, m / z 313.3 (M+H)+ (ES+) at 1.25 min, 97.4% purity 210- 400nm.- 150 - EXAMPLE 30 5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2,4-dimethyl-pyridazin-3-one (Compound 103)

[0673] Step 1: Pd dppf.dcm (228 mg, 0.05 Eq, 279 μmol) was added to a sparged solution (Sonicating with bubbling N2 for 2 min) of 4,5-dichloro-2-methylpyridazin-3(2H)-one (1.00 g, 1 Eq, 5.59 mmol), methylboronic acid (334 mg, 1 Eq, 5.59 mmol) and caesium carbonate (5.46 g, 3 Eq, 16.8 mmol) in 1,4-Dioxane (8.00 mL) and Water (800 μL) and the reaction was heated at 100 °C for 3 h. The reaction was cooled and concentrated before being loaded onto silica and purified by column chromatography. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-60% EtOAc / isohexane) to afford 5-chloro-2,4-dimethylpyridazin-3(2H)-one (247 mg, 1.5 mmol, 27 %, 96% Purity) as white crystalline solids.

[0674] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 7.99 (s, 1H), 3.64 (s, 3H), 2.15 (s, 3H).

[0675] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-24-F111586, m / z 161.0 (M+H)+ (ES+) at 0.81 min, 96.2% purity 260nm + / - 90nm.

[0676] Step 2: To a solution of 5-chloro-2,4-dimethylpyridazin-3(2H)-one (100 mg, 1 Eq, 631 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (120 mg, 1 Eq, 631 μmol) in 1,4- Dioxane (3.50 mL), NaOtBu (90.9 mg, 1.5 Eq, 946 μmol), dicyclohexyl(2',4',6'- triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (33.8 mg, 0.1 Eq, 63.1 μmol) and BrettPhos Pd G3 (57.2 mg, 0.1 Eq, 63.1 μmol) were added. The mixture was stirred at 100 °C for 1.5 hour. The reaction was cooled and dry loaded onto silica. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% [3:1 EtOAc:EtOH] : isoHexanes) to afford 5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2,4- dimethylpyridazin-3(2H)-one (168 mg, 0.53 mmol, 84 %, 99% Purity) as a dark red solid.- 151 -

[0677] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity (0.9 w%) 1H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.7, 2.1 Hz, 1H), 6.39 (dd, J = 3.1, 0.8 Hz, 1H), 4.33 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.54 (s, 3H), 3.22 (s, 3H), 1.98 (s, 3H).

[0678] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-29-1-ms-1, m / z 313.3 (M+H)+ (ES+) at 1.12 min, 99.0% purity 210- 400nm. EXAMPLE 31 4-chloro-5-[cyclopropylmethyl-[1-(cyclopropylmethyl)indol-5-yl]amino]-2-methyl-pyridazin-3- one (Compound 104)

[0679] Step 1: To a solution of 5-((1H-indol-5-yl)amino)-4-chloro-2-methylpyridazin- 3(2H)-one (50.0 mg, 97% Wt, 1 Eq, 177 μmol) in dry DMF (0.90 mL) at 0 °C, sodium hydride (7.06 mg, 60% Wt, 1 Eq, 177 μmol) was added in portions. The mixture was stirred for 30 minutes at the same temperature and (bromomethyl)cyclopropane (25.0 mg, 1.05 Eq, 185 μmol) in DMF (0.10 mL) was added. The mixture was allowed to warm to rt and was stirred for 20 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with EtOAc (3 x 10 ml). The organic layers were combined, washed with 50 v% brine (2 x 20 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% [3:1 EtOAc / EtOH]: isohexane to afford 4-chloro-5-((cyclopropylmethyl)(1- (cyclopropylmethyl)-1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (16.0 mg, 37 μmol, 21 %, 89% Purity) as a yellow solid.

[0680] 1H NMR in DMSO-d6 was consistent with product structure at ~90% purity.- 152 -

[0681] 1H NMR (400 MHz, DMSO) δ 7.70 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 3.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.7, 2.2 Hz, 1H), 6.39 (dd, J = 3.1, 0.8 Hz, 1H), 4.03 (d, J = 7.0 Hz, 2H), 3.89 – 3.79 (m, 2H), 3.61 (s, 3H), 1.30 – 1.20 (m, 1H), 1.19 – 1.06 (m, 1H), 0.55 – 0.50 (m, 2H), 0.39 (tt, J = 6.2, 4.4 Hz, 4H), 0.22 – 0.07 (m, 2H).

[0682] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-18-F1, m / z 383.3 / 385.3 (M+H)+ (ES+) at 1.75 min, 88.8% purity 210- 400nm. EXAMPLE 32 tert-butyl 5-(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)oxyindole-1-carboxylate (Compound 105)

[0683] Step 1: To a solution of tert-butyl 5-hydroxy-1H-indole-1-carboxylate (156 mg, 1.2 Eq, 670 μmol) in DMF (2.00 mL), 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) and Cs2CO3(364 mg, 2 Eq, 1.12 mmol) were added and the mixture was stirred at 80 °C for 2 hours. The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration. washed with water (5 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to afford tert-butyl 5-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin- 4-yl)oxy)-1H-indole-1-carboxylate (104 mg, 0.26 mmol, 47 %, 95% Purity) as a yellow solid.

[0684] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0685] 1H NMR (400 MHz, DMSO) δ 8.10 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 3.7 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H), 6.72 (dd, J = 3.6, 0.7 Hz, 1H), 3.70 (s, 3H), 1.63 (s, 9H).

[0686] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-205-1-ms, m / z 376.0 / 378.0 (M+H)+ (ES+) at 1.80 min, 100.0% purity 260nm + / - 90nm.- 153 - EXAMPLE 33 4-chloro-5-(1H-indol-5-yloxy)-2-methyl-pyridazin-3-one (Compound 106)

[0687] Step 1: To a solution of tert-butyl 5-((5-chloro-1-methyl-6-oxo-1,6- dihydropyridazin-4-yl)oxy)-1H-indole-1-carboxylate (90.0 mg, 1 Eq, 239 μmol) in DCM (2.00 mL), TFA (819 mg, 553 μL, 30 Eq, 7.18 mmol) was added. The mixture was stirred at rt for 4 hours. The mixture was concentrated in vacuo and the residue was dissolved in Sat. Aq. NaHCO3 solution and was extracted with EtOAc (3 x 10 ml). The organic layers were combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford 5-((1H-indol-5-yl)oxy)-4-chloro-2-methylpyridazin-3(2H)-one (46.0 mg, 0.16 mmol, 66 %, 95% Purity) as a tan solid.

[0688] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0689] 1H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 7.51 (s, 1H), 7.49 – 7.44 (m, 2H), 7.40 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.7, 2.5 Hz, 1H), 6.45 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H), 3.68 (s, 3H).

[0690] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water):3917-206-1-ms, m / z 276.1 / 278.2 (M+H)+ (ES+) at 1.16 min, 96.4% purity 210-400nm. EXAMPLE 34 4-chloro-5-[1-(2-methoxyethyl)indol-5-yl]oxy-2-methyl-pyridazin-3-one (Compound 107)- 154 -

[0691] Step 1: To a solution of 5-((1H-indol-5-yl)oxy)-4-chloro-2-methylpyridazin-3(2H)- one (40.0 mg, 1 Eq, 145 μmol) in dry DMF (1.00 mL) at 0 °C, NaH (6.96 mg, 60% Wt, 1.2 Eq, 174 μmol) was added. The mixture was stirred for 30 minutes at the same temperature and 1-bromo-2-methoxyethane (24.2 mg, 16.5 μL, 1.2 Eq, 174 μmol) was added dropwise in DMF (1.00 mL) over 5 minutes. The mixture was warmed to rt and was stirred for 2 hours. Water (20 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo.

[0692] The crude product was purified by chromatography on silica gel (24 g cartridge, 0- 100% EtOAc / isohexane) to afford 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)oxy)-2- methylpyridazin-3(2H)-one (23.0 mg, 65 μmol, 45 %, 95% Purity) as a white solid.

[0693] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0694] 1H NMR (400 MHz, DMSO) δ 7.59 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 3.1 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.8, 2.4 Hz, 1H), 6.45 (dd, J = 3.1, 0.8 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.68 (s, 3H), 3.66 (t, J = 5.3 Hz, 2H), 3.23 (s, 3H).

[0695] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-208-1-ms, m / z 334.0 / 336.0 (M+H)+ (ES+) at 1.38 min, 97.4% purity 260nm + / - 90nm. EXAMPLE 35 4-chloro-5-[[1-[2-(dimethylamino)ethyl]indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 108)

[0696] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) in dry DMF (10.0 mL) at rt, K2CO3 (1.3 g, 3 Eq, 9.3 mmol) and 2-chloro-N,N-dimethylethan-1-amine, HCl (0.58 g, 1.3 Eq, 4.0 mmol) were added. The mixture was warmed to 80 °C and was stirred for 2 hours. Water (20 ml) was added and the mixture was extracted with EtOAc (3- 155 - x 20 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc in isohexane) to afford N,N- dimethyl-2-(5-nitro-1H-indol-1-yl)ethan-1-amine (0.547 g, 2.2 mmol, 72 %, 95% Purity) as a yellow solid.

[0697] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0698] 1H NMR (400 MHz, DMSO) δ 8.56 (d, J = 2.3 Hz, 1H), 8.01 (dd, J = 9.1, 2.3 Hz, 1H), 7.71 (dt, J = 9.2, 0.7 Hz, 1H), 7.66 (d, J = 3.2 Hz, 1H), 6.73 (dd, J = 3.2, 0.8 Hz, 1H), 4.34 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.17 (s, 6H).

[0699] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water):3917-200-1- ms, m / z 234.3 (M+H)+ (ES+) at 1.31 min, 100.0% purity 210-400nm.

[0700] Step 2: A solution of N,N-dimethyl-2-(5-nitro-1H-indol-1-yl)ethan-1-amine (0.10 g, 1 Eq, 0.43 mmol) in MeOH (5.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 1 pass). The residue was concentrated in vacuo to afford 1-(2-(dimethylamino)ethyl)- 1H-indol-5-amine (88.0 mg, 0.39 mmol, 92 %, 91% Purity) as a purple oil.

[0701] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water):3917-213-1- ms, m / z 204.0 (M+H)+ (ES+) at 0.85 min, 91.4% purity 210-400nm.

[0702] 1H NMR in DMSO-d6 was consistent with product structure at 95% purity.

[0703] 1H NMR (400 MHz, DMSO) δ 7.17 – 7.09 (m, 2H), 6.66 (dd, J = 2.1, 0.6 Hz, 1H), 6.51 (dd, J = 8.6, 2.1 Hz, 1H), 6.09 (dd, J = 3.0, 0.8 Hz, 1H), 4.47 (s, 2H), 4.11 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 6.8 Hz, 2H), 2.16 (s, 6H).

[0704] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (60.0 mg, 1 Eq, 335 μmol) in DMSO (1.00 mL), DIPEA (86.6 mg, 117 μL, 2 Eq, 670 μmol) and 1-(2- (dimethylamino)ethyl)-1H-indol-5-amine (81.8 mg, 1.2 Eq, 402 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and EtOAc (10 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (10 ml). The aqueous layer was further extracted with EtOAc (10 ml) and the organic layers were combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo.

[0705] The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 10% (0.7 M Ammonia / MeOH) / DCM) to afford 4-chloro-5-((1-(2-(dimethylamino)ethyl)-- 156 - 1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (24.0 mg, 66 μmol, 20 %, 95% Purity) as a yellow solid.

[0706] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0707] 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.47 – 7.39 (m, 3H), 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.42 (dd, J = 3.1, 0.8 Hz, 1H), 4.26 (t, J = 6.6 Hz, 2H), 3.59 (s, 3H), 2.61 (t, J = 6.6 Hz, 2H), 2.19 (s, 6H).

[0708] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water):3917-216-1- ms, m / z 346.3 / 348.3 (M+H)+ (ES+) at 1.14 min, 97.2% purity 210-400nm. EXAMPLE 36 2-[5-chloro-4-[[1-(2-methoxyethyl)indol-5-yl]amino]-6-oxo-pyridazin-1-yl]-N,N-dimethyl- acetamide (Compound 109)

[0709] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (250 mg, 1 Eq, 1.52 mmol) in dry DMF (3.50 mL) under a nitrogen atmosphere at 0 °C was added NaH (73.0 mg, 60% Wt, 1.20 Eq, 1.82 mmol). The reaction mixture was stirred for 30 min then 2-bromo-N,N-dimethylacetamide (302 mg, 1.2 Eq, 1.82 mmol) was added. The reaction was left to stir overnight (16 h). The reaction mixture was diluted with sat. aq. NaHCO3 (25 mL) and EtOAc (25 mL) and transferred into a separating funnel. The aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. to provide the crude product (299 mg). The crude product was purified by chromatography on silica gel (24 g cartridge, 50- 100% EtOAc : Heptane) to afford 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N,N- dimethylacetamide (206 mg, 0.82 mmol, 54 %, 99% Purity) as a white crystalline solid.

[0710] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 5.03 (s, 2H), 3.04 (s, 3H), 2.84 (s, 3H).- 157 -

[0711] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-36-1-MS-1, m / z 250.1 (M+H)+ (ES+) at 0.70 min, 99.4% purity 210- 400nm.

[0712] Step 2: To a solution of 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N,N- dimethylacetamide (100 mg, 1 Eq, 400 μmol) in DMSO (1.00 mL), DIPEA (103 mg, 139 μL, 2 Eq, 800 μmol) and 1-(2-methoxyethyl)-1H-indol-5-amine (91.3 mg, 1.2 Eq, 480 μmol) were added. The mixture was stirred at 90 °C overnight (16 h). The mixture was cooled to rt and EtOAc (50 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (50 ml). The aqueous layer was further extracted with EtOAc (50 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% [3:1 EtOAc / EtOH]: isohexane, eluting at 70% to afford the desired product 2-(5-chloro-4-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-6-oxopyridazin- 1(6H)-yl)-N,N-dimethylacetamide (118 mg, 0.28 mmol, 69 %, 95% Purity) as a light brown solid.

[0713] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity (2 w% DCM).1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.44 – 7.41 (m, 3H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.45 (dd, J = 3.1, 0.8 Hz, 1H), 4.87 (s, 2H), 4.35 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.23 (s, 3H), 3.01 (s, 3H), 2.82 (s, 3H).

[0714] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-40-1-ms-154084, m / z 404.2 / 406.2 (M+H)+ (ES+) at 1.12 min, 95.2% purity 260nm + / - 90nm. EXAMPLE 37 4-chloro-2-methyl-5-[[1-(2-morpholinoethyl)indol-5-yl]amino]pyridazin-3-one (Compound 110)- 158 -

[0715] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) in dry DMF (10.0 mL) at rt, K2CO3 (1.3 g, 3 Eq, 9.3 mmol) and 4-(2-bromoethyl)morpholine, HBr (1.3 g, 1.5 Eq, 4.6 mmol) were added. The mixture was warmed to 80 °C and was stirred for 4 hours. Water (20 ml) was added and the precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo to afford 4-(2-(5-nitro-1H-indol-1- yl)ethyl)morpholine (510 mg, 1.8 mmol, 57 %, 95% Purity) as a yellow solid.

[0716] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0717] 1H NMR (400 MHz, DMSO) δ 8.56 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 9.1, 2.4 Hz, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 6.74 (dd, J = 3.3, 0.8 Hz, 1H), 4.38 (t, J = 6.4 Hz, 2H), 3.54 – 3.48 (m, 4H), 2.67 (t, J = 6.4 Hz, 2H), 2.41 (t, J = 4.7 Hz, 4H).

[0718] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-210-1-ms, m / z 276.0 (M+H)+ (ES+) at 0.56 min, 96.0% purity 260nm + / - 90nm.

[0719] Step 2: A solution of 4-(2-(5-nitro-1H-indol-1-yl)ethyl)morpholine (0.11 g, 1 Eq, 0.40 mmol) in Methanol (5.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 1 pass). The residue was concentrated in vacuo to afford 1-(2-morpholinoethyl)-1H-indol-5- amine (101 mg, 0.39 mmol, 98 %, 95% Purity) as a purple oil.

[0720] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water):3917-214-1- ms, m / z 246.3 (M+H)+ (ES+) at 0.80 min, 87.5% purity 210-400nm.

[0721] 1H NMR in DMSO-d6 was consistent with product structure at 95% purity.

[0722] 1H NMR (400 MHz, DMSO) δ 7.19 – 7.10 (m, 2H), 6.66 (d, J = 2.1 Hz, 1H), 6.51 (dd, J = 8.6, 2.1 Hz, 1H), 6.10 (dd, J = 3.0, 0.8 Hz, 1H), 4.47 (s, 2H), 4.14 (t, J = 6.8 Hz, 2H), 3.57 – 3.50 (m, 4H), 2.60 (t, J = 6.8 Hz, 2H), 2.40 (m, 4H).

[0723] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (50.0 mg, 1 Eq, 279 μmol) in DMSO (1.00 mL), DIPEA (72.2 mg, 97.3 μL, 2 Eq, 559 μmol) and 1-(2- morpholinoethyl)-1H-indol-5-amine (82.2 mg, 1.2 Eq, 335 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and EtOAc (10 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (10 ml). The aqueous layer was further extracted with EtOAc (10 ml) and the organic layers were combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo.

[0724] The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 10% (0.7 M Ammonia / MeOH) / DCM) to afford the desired product with low purity.- 159 -

[0725] The residue was dissolved in 1.4 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.3% Ammonia in water-MeCN gradient over 8.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 27.5% MeCN; 0.5-5.5 min, ramped from 27.5% MeCN to 57.5% MeCN; 5.5-5.6 min, ramped from 57.5% MeCN to 100% MeCN; 5.6-8.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 4-chloro-2-methyl-5-((1-(2-morpholinoethyl)-1H-indol-5-yl)amino)pyridazin- 3(2H)-one (39.0 mg, 96 μmol, 34 %, 95% Purity) as a pale yellow solid.

[0726] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0727] 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.48 – 7.39 (m, 3H), 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.43 (d, J = 3.1 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.59 (s, 3H), 3.54 (t, J = 4.7 Hz, 4H), 2.69 – 2.63 (m, 2H), 2.43 (s, 4H).

[0728] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-217-1-ms, m / z 388.2 / 390.2 (M+H)+ (ES+) at 0.66 min, 99.1% purity 260nm + / - 90nm. EXAMPLE 38 tert-butyl 4-[2-[5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]indol-1-yl]ethyl]piperidine-1- carboxylate (Compound 111)- 160 -

[0729] Step 1: To a solution of 5-nitro-1H-indole (0.30 g, 1 Eq, 1.9 mmol) in dry DMF (10.0 mL) at rt, K2CO3 (0.77 g, 3 Eq, 5.6 mmol) and tert-butyl 4-(2-bromoethyl)piperidine- 1-carboxylate (0.70 g, 1.3 Eq, 2.4 mmol) were added. The mixture was warmed to 80 °C and was stirred for 4 hours. Water (20 ml) was added, and a brown gum was formed. The water layer was removed, and the gum was dissolved in DCM and concentrated in vacuo to afford tert-butyl 4-(2-(5-nitro-1H-indol-1-yl)ethyl)piperidine-1-carboxylate (0.65 g, 1.5 mmol, 80 %, 85% Purity) as a yellow gum.

[0730] 1H NMR in DMSO-d6 was consistent with product structure at 85% purity.

[0731] 1H NMR (400 MHz, DMSO) δ 8.57 (d, J = 2.2 Hz, 1H), 8.02 (dd, J = 9.1, 2.3 Hz, 1H), 7.74 – 7.65 (m, 2H), 6.75 (dd, J = 3.2, 0.8 Hz, 1H), 4.30 (t, J = 7.4 Hz, 2H), 3.93 – 3.85 (m, 2H), 2.70 – 2.55 (m, 2H), 1.76 – 1.64 (m, 4H), 1.38 (m, 10H), 1.04 (qd, J = 12.2, 4.3 Hz, 2H).

[0732] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-211-1-ms, m / z 318.1 (M- tBu+H)+ (ES+) at 1.92 min, 85.0% purity 260nm + / - 90nm.

[0733] Step 2: A solution of tert-butyl 4-(2-(5-nitro-1H-indol-1-yl)ethyl)piperidine-1- carboxylate (0.15 g, 1 Eq, 0.40 mmol) in MeOH (5.00 mL) was hydrogenated with the H- cube (1 ml / min, 2 bar, 1 pass). The residue was concentrated in vacuo to afford tert-butyl 4-(2-(5-amino-1H-indol-1-yl)ethyl)piperidine-1-carboxylate (137 mg, 0.33 mmol, 81 %, 82% Purity) as a purple oil.

[0734] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water):3917-215-1- ms, m / z 287.9 (M-tBu+H)+ (ES+) at 1.60 min, 82.4% purity 210-400nm.

[0735] 1H NMR in DMSO-d6 at 363 K was consistent with product structure at 85% purity.

[0736] 1H NMR (400 MHz, DMSO) δ 7.17 – 7.05 (m, 2H), 6.72 (dd, J = 2.2, 0.7 Hz, 1H), 6.56 (dd, J = 8.6, 2.2 Hz, 1H), 6.13 (dt, J = 3.1, 1.5 Hz, 1H), 4.24 (s, 2H), 4.07 (dd, J = 8.0, 6.6 Hz, 2H), 3.94 – 3.84 (m, 2H), 3.21 (d, J = 5.2 Hz, 1H), 2.68 (ddd, J = 13.2, 11.8, 2.9 Hz, 2H), 1.75 – 1.61 (m, 4H), 1.40 (s, 9H), 1.14 – 0.99 (m, 2H).

[0737] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (60.0 mg, 1 Eq, 335 μmol) in DMSO (1.00 mL), DIPEA (86.6 mg, 117 μL, 2 Eq, 670 μmol) and tert-butyl 4-(2-(5-amino-1H-indol-1-yl)ethyl)piperidine-1-carboxylate (138 mg, 1.2 Eq, 402 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration, washed- 161 - with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford the desired product with low purity.

[0738] The residue was dissolved in 1.7 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 8.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 52.5% MeCN; 0.5-5.5 min, ramped from 52.5% MeCN to 82.5% MeCN; 5.5-5.6 min, ramped from 82.5% MeCN to 100% MeCN; 5.6-8.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford tert-butyl 4-(2-(5-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)- 1H-indol-1-yl)ethyl)piperidine-1-carboxylate (27.0 mg, 53 μmol, 16 %, 95% Purity) as a yellow solid.

[0739] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0740] 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.47 – 7.40 (m, 3H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.44 (d, J = 3.0 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.90 (d, J = 13.1 Hz, 2H), 3.59 (s, 3H), 2.67 (s, 2H), 1.71 (q, J = 7.2 Hz, 4H), 1.38 (s, 10H), 1.11 – 0.98 (m, 2H).

[0741] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-218-1-ms, m / z 430.0 (M- tBu+H)+ (ES+) at 1.79 min, 97.5% purity 260nm + / - 90nm.- 162 - EXAMPLE 39 4-chloro-2-methyl-5-[[1-(oxetan-3-yl)indol-5-yl]amino]pyridazin-3-one (Compound 112)

[0742] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) in dry DMF (10.0 mL) at rt, K2CO3(1.3 g, 3 Eq, 9.3 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (1.1 g, 1.5 Eq, 4.6 mmol) were added. The mixture was warmed to 80 °C and was stirred for 4 hours. No reaction observed by LCMS. The mixture was heated to 100 °C for 60 hours. Water (20 ml) was added and the precipitate formed was collected by filtration and washed with water (10 ml) to afford 5-nitro-1-(oxetan-3-yl)-1H-indole (0.459 g, 2.0 mmol, 65 %, 95% Purity) as a yellow solid.

[0743] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0744] 1H NMR (400 MHz, DMSO) δ 8.60 (d, J = 2.3 Hz, 1H), 8.10 – 8.02 (m, 2H), 7.80 – 7.73 (m, 1H), 6.89 (dd, J = 3.3, 0.8 Hz, 1H), 5.90 (tt, J = 7.6, 6.2 Hz, 1H), 5.06 (t, J = 7.3 Hz, 2H), 4.93 (d, J = 7.3 Hz, 2H).

[0745] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-212-1-ms, m / z 219.0 (M+H)+ (ES+) at 1.20 min, 100.0% purity 260nm + / - 90nm.

[0746] Step 2: A solution of 5-nitro-1-(oxetan-3-yl)-1H-indole (0.11 g, 1 Eq, 0.50 mmol) in a mixture of MeOH (5.00 mL) and THF (2.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 1 pass). The residue was concentrated in vacuo to afford 1- (oxetan-3-yl)-1H-indol-5-amine (103 mg, 0.42 mmol, 82 %, 76% Purity) as a yellow solid.

[0747] The product was analysed by UPLC (BEH C18^Column, 130Å, 1.7 µm, 2.1 mm x 30 mm, 3 min method, 0.1% Ammonium Hydroxide, 2-100% MeCN / water):3917-221-1- ms, m / z 188.9 (M+H)+ (ES+) at 0.72 min, 76.1% purity 210-400nm.

[0748] 1H NMR in DMSO-d6 was consistent with product structure at 80% purity.

[0749] 1H NMR (400 MHz, DMSO) δ 7.49 (d, J = 3.2 Hz, 1H), 7.23 (dt, J = 8.7, 0.8 Hz, 1H), 6.69 (dd, J = 2.2, 0.6 Hz, 1H), 6.54 (dd, J = 8.7, 2.2 Hz, 1H), 6.24 (dd, J = 3.1, 0.8 Hz,- 163 - 1H), 5.59 (tt, J = 7.7, 6.4 Hz, 1H), 4.99 (t, J = 7.2 Hz, 2H), 4.88 (t, J = 6.6 Hz, 2H), 4.52 (s, 2H).

[0750] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (80.0 mg, 1 Eq, 447 μmol) in DMSO (1.00 mL), DIPEA (116 mg, 156 μL, 2 Eq, 894 μmol) and 1-(oxetan- 3-yl)-1H-indol-5-amine (101 mg, 1.2 Eq, 536 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 100% EtOAc / isohexane) to afford 4-chloro-2-methyl-5-((1-(oxetan-3-yl)-1H-indol-5- yl)amino)pyridazin-3(2H)-one (64.0 mg, 0.18 mmol, 41 %, 95% Purity) as a tan solid.

[0751] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0752] 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.83 (d, J = 3.3 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.07 (dd, J = 8.7, 2.1 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 5.80 (q, J = 7.0 Hz, 1H), 5.05 (t, J = 7.2 Hz, 2H), 4.94 (t, J = 6.6 Hz, 2H), 3.59 (s, 3H).

[0753] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-223-1-ms, m / z 331.0 / 333.0 (M+H)+ (ES+) at 1.11 min, 94.7% purity 260nm + / - 90nm. EXAMPLE 40 tert-butyl 5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]indoline-1-carboxylate (Compound 113)

[0754] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100.0 mg, 1 Eq, 558.7 μmol) in DMSO (1.00 mL), DIPEA (144.4 mg, 195 μL, 2 Eq, 1.117 mmol) and tert-butyl 5-aminoindoline-1-carboxylate (157.1 mg, 1.2 Eq, 670.4 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and EtOAc (10 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (10 ml). The aqueous layer was further extracted with EtOAc (10 ml) and the organic layers were- 164 - combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 100% EtOAc / isohexane) to afford tert-butyl 5-((5-chloro-1-methyl-6-oxo-1,6- dihydropyridazin-4-yl)amino)indoline-1-carboxylate (64.0 mg, 0.15 mmol, 28 %, 91% Purity) as a tan solid.

[0755] 1H NMR in DMSO-d6 at 363 K was consistent with product structure at 95% purity.

[0756] 1H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.08 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.5, 2.3 Hz, 1H), 3.95 (dd, J = 9.2, 8.2 Hz, 2H), 3.61 (s, 3H), 3.09 (t, J = 8.6 Hz, 2H), 1.54 (s, 9H).

[0757] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-225-1-ms, m / z 377.2 / 379.0 (M+H)+ (ES+) at 1.53 min, 91.0% purity 260nm + / - 90nm. EXAMPLE 41 4-chloro-2-(cyclopropylmethyl)-5-[[1-(2-methoxyethyl)indol-5-yl]amino]pyridazin-3-one (Compound 114)

[0758] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (250 mg, 1 Eq, 1.52 mmol) in dry DMF (3.50 mL) under a nitrogen atmosphere at 0 °C was added NaH (73.0 mg, 60% Wt, 1.20 Eq, 1.82 mmol). The reaction mixture was stirred for 30 min then (bromomethyl)cyclopropane (245 mg, 1.2 Eq, 1.82 mmol) was added and the reaction was left to stir for 2 h. Sodium iodide (227 mg, 1 Eq, 1.52 mmol) was added and the reaction left overnight (16 h). The reaction mixture was diluted with sat. aq. NaHCO3 (25 mL) and EtOAc (25 mL) and transferred into a separating funnel. The aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. to provide the crude product (384 mg). The crude product was purified by chromatography on silica gel (24 g cartridge, 0-- 165 - 30% EtOAc : isoHexanes) to afford 4,5-dichloro-2-(cyclopropylmethyl)pyridazin-3(2H)- one (253 mg, 1.1 mmol, 75 %, 98% Purity) as a colourless oil.

[0759] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity. 1H NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 3.96 (d, J = 7.2 Hz, 2H), 1.33 – 1.18 (m, 1H), 0.57 – 0.42 (m, 2H), 0.43 – 0.30 (m, 2H).

[0760] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-39-1-ms-1, m / z 219.0 / 221.0 (M+H)+ (ES+) at 1.26 min, 98.5% purity 260nm + / - 90nm.

[0761] Step 2: To a solution of 4,5-dichloro-2-(cyclopropylmethyl)pyridazin-3(2H)-one (100 mg, 98% Wt, 1 Eq, 447 μmol) in DMSO (1.00 mL), DIPEA (116 mg, 156 μL, 2 Eq, 895 μmol) and 1-(2-methoxyethyl)-1H-indol-5-amine (109 mg, 94% Wt, 1.2 Eq, 537 μmol) were added. The mixture was stirred at 90 °C for 3 h. The mixture was cooled to rt and EtOAc (50 ml) was added. The mixture was washed with sat. aq. NaHCO3 solution (50 ml). The aqueous layer was further extracted with EtOAc (2x 50 ml) and the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% [3:1 EtOAc / EtOH]: isohexane to afford the desired product with low purity. The residue was purified by chromatography on RP Flash C18 (24 g cartridge, 10-60% 0.1 v% formic acid MeCN]: 0.1 v% aq formic acid to afford 4-chloro-2-(cyclopropylmethyl)-5-((1-(2-methoxyethyl)- 1H-indol-5-yl)amino)pyridazin-3(2H)-one (70.0 mg, 0.19 mmol, 42 %, 99% Purity) as a dark red solid.

[0762] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.45 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.04 (dd, J = 8.7, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 3.85 (d, J = 7.1 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.23 (s, 3H), 1.21 – 1.16 (m, 1H), 0.50 – 0.39 (m, 2H), 0.36 – 0.28 (m, 2H).

[0763] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-41-1-ms-2, m / z 373.3 / 375.3 (M+H)+ (ES+) at 0.58 min, 100.0% purity 210-400nm.- 166 - EXAMPLE 42 4-chloro-2-(2-methoxyethyl)-5-[[1-(2-methoxyethyl)indol-5-yl]amino]pyridazin-3-one (Compound 115)

[0764] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (250 mg, 1 Eq, 1.52 mmol) in dry DMF (3.50 mL) under a nitrogen atmosphere at 0 °C was added NaH (73.0 mg, 60% Wt, 1.20 Eq, 1.82 mmol). The reaction mixture was stirred for 30 min then 1-bromo-2-methoxyethane (253 mg, 171 μL, 1.2 Eq, 1.82 mmol) was added and the reaction was left to stir for 16 hours. The reaction mixture was diluted with sat. aq. NaHCO3(25 mL) and EtOAc (25 mL) and transferred into a separating funnel. The aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. to provide the crude product (299 mg). The crude product was purified by chromatography on silica gel (24 g cartridge, 50-100% EtOAc : Heptane) to afford 4,5-dichloro-2-(2-methoxyethyl)pyridazin- 3(2H)-one (44.0 mg, 0.19 mmol, 12 %, 94% Purity) as a colourless oil.

[0765] 1H NMR in DMSO-d6 was consistent with product structure at 94% purity (5 w% DCM). 1H NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 4.27 (t, J = 5.5 Hz, 2H), 3.68 (t, J = 5.5 Hz, 2H), 3.23 (s, 3H).

[0766] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-36-2-ms-254088, m / z 223.0 / 225.0 (M+H)+ (ES+) at 0.87 min, 96.3% purity 260nm + / - 90nm.

[0767] Step 2: To a solution of 4,5-dichloro-2-(2-methoxyethyl)pyridazin-3(2H)-one (35.0 mg, 1 Eq, 157 μmol) in DMSO (1.00 mL), DIPEA (40.6 mg, 54.7 μL, 2 Eq, 314 μmol) and 1-(2-methoxyethyl)-1H-indol-5-amine (35.8 mg, 1.2 Eq, 188 μmol) were added. The mixture was stirred at 90 °C for 3. The mixture was cooled to rt and EtOAc (50 ml) was added. The mixture was washed with sat. aq. NaHCO3solution (50 ml). The aqueous layer was further extracted with EtOAc (2x 50 ml) and the organic layers were combined, dried- 167 - over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-40% [3:1 EtOAc / EtOH]: isohexane to afford 4-chloro-2-(2-methoxyethyl)-5-((1-(2-methoxyethyl)-1H-indol-5- yl)amino)pyridazin-3(2H)-one (22.0 mg, 57 μmol, 36 %, 98% Purity) as a light brown solid.

[0768] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 4.16 (t, J = 5.6 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.23 (s, 3H), 3.22 (s, 3H).

[0769] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-42-1-ms-154301, m / z 377.0 / 379.2 (M+H)+ (ES+) at 1.26 min, 97.9% purity 260nm + / - 90nm. EXAMPLE 43 4-chloro-2-[2-(dimethylamino)ethyl]-5-[[1-(2-methoxyethyl)indol-5-yl]amino]pyridazin-3-one (Compound 116)

[0770] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (250 mg, 1 Eq, 1.52 mmol) in dry DMF (3.50 mL) under a nitrogen atmosphere at 0 °C was added NaH (152 mg, 60% Wt, 2.5 Eq, 3.79 mmol). The reaction mixture was stirred for 30 min then 2- chloro-N,N-dimethylethan-1-amine, HCl (262 mg, 1.2 Eq, 1.82 mmol) and the reaction was left to stir for 24 hours. The reaction mixture was diluted with sat. aq. NaHCO3 (25 mL) and EtOAc (25 mL) and transferred into a separating funnel. The aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. to provide the crude product. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% [3:1 EtOAc:- 168 - EtOH] : isohexane) to afford 4,5-dichloro-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one (47.0 mg, 0.20 mmol, 13 %, 99% Purity) as a yellow oil.

[0771] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 4.19 (t, J = 6.5 Hz, 2H), 2.60 (t, J = 6.5 Hz, 2H), 2.15 (s, 6H).

[0772] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-37-1-ms-1, m / z 236.2 / 238.2 (M+H)+ (ES+) at 0.91 min, 100.0% purity 210-400nm.

[0773] Step 2: To a solution of 4,5-dichloro-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)- one (50.0 mg, 1 Eq, 212 μmol) in DMSO (1.00 mL), DIPEA (54.7 mg, 73.8 μL, 2 Eq, 424 μmol) and 1-(2-methoxyethyl)-1H-indol-5-amine (48.3 mg, 1.2 Eq, 254 μmol) were added. The mixture was stirred at 90 °C overnight (18 h). The mixture was cooled to rt and EtOAc (50 ml) was added. The mixture was washed with sat. aq. NaHCO3solution (50 ml). The aqueous layer was further extracted with EtOAc (50 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0- 100% [3:1 EtOAc / EtOH+ 5 v% aq. NH4OH]: Ethyl Acetate to afford 4-chloro-2-(2- (dimethylamino)ethyl)-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)pyridazin-3(2H)-one (12.0 mg, 29 μmol, 14 %, 95% Purity) as a thick brown gum.

[0774] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.44 (dd, J = 3.2, 0.8 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 4.08 (t, J = 6.6 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.22 (s, 3H), 2.53 (t, J = 6.6 Hz, 2H), 2.14 (s, 6H).

[0775] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-44-1-ms-1, m / z 390.3 / 392.3 (M+H)+ (ES+) at 1.22 min, 95.3% purity 210-400nm.- 169 - EXAMPLE 44 2-[5-chloro-4-[[1-(2-methoxyethyl)indol-5-yl]amino]-6-oxo-pyridazin-1-yl]ethyl acetate (Compound 117)

[0776] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (250 mg, 1 Eq, 1.52 mmol) in dry DMF (3.50 mL) under a nitrogen atmosphere at 0 °C was added NaH (72.7 mg, 60% Wt, 1.2 Eq, 1.82 mmol). The reaction mixture was stirred for 30 min then 2-bromoethyl acetate (304 mg, 201 μL, 1.2 Eq, 1.82 mmol) was added and the reaction was left to stir overnight (16 h). The reaction mixture was diluted with sat. aq. NaHCO3(25 mL) and EtOAc (25 mL) and transferred into a separating funnel. The aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. to provide the crude product. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-60% EtOAc : isoHexanes) to afford 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)ethyl acetate (292 mg, 1.1 mmol, 72 %, 94% Purity) as a clear colourless oil.

[0777] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (500 MHz, DMSO) δ 8.23 (s, 1H), 4.39 – 4.30 (m, 4H), 1.94 (s, 3H).

[0778] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-47-1-ms-1, m / z 251.0 / 253.0 (M+H)+ (ES+) at 0.94 min, 93.8% purity 260nm + / - 90nm.

[0779] Step 2: To a solution of 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)ethyl acetate (100.0 mg, 94% Wt, 1 Eq, 374.4 μmol) in DMSO (1.00 mL), DIPEA (96.79 mg, 130 μL, 2 Eq, 748.8 μmol) and 1-(2-methoxyethyl)-1H-indol-5-amine (90.93 mg, 94% Wt, 1.2 Eq, 449.3 μmol) were added. The mixture was stirred at 90 °C overnight (18 h). The mixture was cooled to rt and EtOAc (50 ml) was added. The mixture was washed with sat. aq. NaHCO3solution (50 ml). The aqueous layer was further extracted with EtOAc (50 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4,- 170 - filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% [3:1 EtOAc / EtOH]: isohexane to afford the desired product 2-(5-chloro-4-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-6-oxopyridazin-1(6H)-yl)ethyl acetate (111 mg, 0.26 mmol, 70 %, 96% Purity) as a thick brown gum.

[0780] 1H NMR in DMSO-d6 was consistent with product structure at 96% purity (1.9 w% EtOAc; 0.3 w% DCM; baseline impurities).1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.47 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 4.32 – 4.28 (m, 2H), 4.25 – 4.20 (m, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.22 (s, 3H), 1.94 (s, 3H).

[0781] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-46-1-ms-1, m / z 405.3 / 407.3 (M+H)+ (ES+) at 1.25 min, 95.9% purity 210-400nm. EXAMPLE 45 5-[[1-[2-(1-acetyl-4-piperidyl)ethyl]indol-5-yl]amino]-4-chloro-2-methyl-pyridazin-3-one (Compound 118)

[0782] Step 1: To a solution of tert-butyl 4-(2-(5-((5-chloro-1-methyl-6-oxo-1,6- dihydropyridazin-4-yl)amino)-1H-indol-1-yl)ethyl)piperidine-1-carboxylate (100.0 mg, 1 Eq, 205.8 μmol) in DCM (2.00 mL), Hydrogen chloride (3 M in CPME) (225.1 mg, 245 μL, 30 Eq, 6.173 mmol) was added. The mixture was stirred at rt for 18 hours. The mixture was concentrated in vacuo to afford 4-chloro-2-methyl-5-((1-(2-(piperidin-4-yl)ethyl)-1H- indol-5-yl)amino)pyridazin-3(2H)-one, HCl (90.0 mg, 0.13 mmol, 62 %, 60% Purity) as a tan solid.- 171 -

[0783] 1H NMR in DMSO-d6 at 363 K was consistent with product structure at 60% purity.

[0784] NMR not assigned due to low purity.

[0785] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water):3917-236-1-ms-basic, m / z 386.4 / 388.4 (M+H)+ (ES+) at 1.30 min, 86.0% purity 210-400nm.

[0786] Step 2: To a solution of 4-chloro-2-methyl-5-((1-(2-(piperidin-4-yl)ethyl)-1H- indol-5-yl)amino)pyridazin-3(2H)-one (30.0 mg, 1 Eq, 77.7 μmol) in DCM (1.00 mL), DIPEA (30.1 mg, 40.6 μL, 3 Eq, 233 μmol) and acetic anhydride (8.73 mg, 8.07 μL, 1.1 Eq, 85.5 μmol) were added. The mixture was stirred at rt for 1 hour. Sat. aq. NH4Cl (10 ml) was added, and the mixture was extracted with DCM (3 x 5 ml). The organic layers were combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford 5-((1-(2-(1-acetylpiperidin-4-yl)ethyl)-1H-indol-5-yl)amino)-4-chloro-2- methylpyridazin-3(2H)-one (18.0 mg, 40 μmol, 51 %, 95% Purity) as a pale yellow solid.

[0787] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0788] 1H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.46 – 7.38 (m, 3H), 7.04 (dd, J = 8.6, 2.1 Hz, 1H), 6.45 (dd, J = 3.1, 0.8 Hz, 1H), 4.27 – 4.19 (m, 2H), 3.61 (s, 3H), 1.97 (s, 3H), 1.85 – 1.67 (m, 5H), 1.62 – 1.44 (m, 1H), 1.27 (s, 2H), 1.23 – 1.01 (m, 2H), 0.87 (t, J = 7.2 Hz, 1H).

[0789] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-240-1-ms, m / z 428.2 / 430.2 (M+H)+ (ES+) at 1.30 min, 96.3% purity 260nm + / - 90nm. EXAMPLE 46 5-chloro-4-[[1-(2-methoxyethyl)indol-5-yl]amino]-1H-pyridazin-6-one (Compound 119)- 172 -

[0790] Step 1: To 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2-(tetrahydro- 2H-pyran-2-yl)pyridazin-3(2H)-one (25.0 mg, 90% Wt, 1 Eq, 55.8 μmol), 3M HCl in CPME (55 mg, 0.50 mL, 3.00 molar, 27 Eq, 1.5 mmol) was added and the reaction left to stir overnight (16 h).

[0791] The reaction mixtures were combined and diluted with sat. aq. NaHCO3 (25 mL) and EtOAc (25 mL) and transferred into a separating funnel. The aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to provide the crude product. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% [3:1 EtOAc / EtOH]: isohexane to afford, after freeze drying, the desired product 4-chloro-5-((1- (2-methoxyethyl)-1H-indol-5-yl)amino)pyridazin-3(2H)-one (2.00 mg, 6.0 μmol, 11 %, 96% Purity) as a light yellow solid.

[0792] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity. 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 8.64 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.43 – 7.40 (m, 3H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.22 (s, 3H).

[0793] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water): 4036-45-1-ms-1, m / z 319.3 / 321.3 (M+H)+ (ES+) at 0.97 min, 95.7% purity 210-400nm. EXAMPLE 47 4-chloro-2-(2-hydroxyethyl)-5-[[1-(2-methoxyethyl)indol-5-yl]amino]pyridazin-3-one (Compound 120)

[0794] Step 1: To a stirred solution of 2-(5-chloro-4-((1-(2-methoxyethyl)-1H-indol-5- yl)amino)-6-oxopyridazin-1(6H)-yl)ethyl acetate (25.0 mg, 96% Wt, 1 Eq, 59.3 μmol) in- 173 - dry THF (0.60 mL) and Water (0.20 mL) at rt was added LiOH, monohydrate (6.00 mg, 2.41 Eq, 143 μmol). The reaction mixture was stirred for 2 hours wherein complete conversion was seen. The reaction mixture was diluted with EtOAc (25 mL) and 50 v% Brine (25 mL) and transferred into a separating funnel. The separated aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were collected, dried over Sodium sulfate, filtered and concentrated in vacuo to provide 4-chloro-2-(2- hydroxyethyl)-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)pyridazin-3(2H)-one (19.0 mg, 51 μmol, 86 %, 97% Purity) as a dark brown solid.

[0795] 1H NMR in DMSO-d6 was consistent with product structure at 97% purity .1H NMR (500 MHz, DMSO) δ 8.63 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.45 (s, 1H), 7.43 – 7.40 (m, 2H), 7.02 (dd, J = 8.7, 2.1 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 4.76 (s, 1H), 4.35 (t, J = 5.3 Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 3.69 – 3.64 (m, 4H), 3.22 (s, 3H).

[0796] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-48-1-ms-155500, m / z 363.0 / 365.0 (M+H)+ (ES+) at 1.06 min, 97.0% purity 260nm + / - 90nm. EXAMPLE 48 3-chloro-4-[[1-(2-methoxyethyl)indol-5-yl]amino]-1-methyl-pyridin-2-one (Compound 121)

[0797] Step 1: To a solution of 4-bromo-3-chloro-1-methylpyridin-2(1H)-one (100 mg, 1 Eq, 449 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (85.5 mg, 1 Eq, 449 μmol) in 1,4- Dioxane (3.50 mL), NaOtBu (64.8 mg, 1.5 Eq, 674 μmol), dicyclohexyl(2',4',6'- triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (24.1 mg, 0.1 Eq, 44.9 μmol) and BrettPhos Pd G3 (40.7 mg, 0.1 Eq, 44.9 μmol) were added. The mixture was sparged (bubbling N2 while sonicating for 2 mins) and stirred at 100 °C for 1 hour. The reaction was cooled and dry loaded onto silica. The crude product was purified by- 174 - chromatography on silica gel (24 g cartridge, 50-100% [3:1 EtOAc:EtOH] : isoHexanes) to afford the desired product with low purity.

[0798] A second reverse-phase column was carried out. The impure product was loaded onto celite and purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 3-chloro-4-((1-(2- methoxyethyl)-1H-indol-5-yl)amino)-1-methylpyridin-2(1H)-one (11.0 mg, 33 μmol, 7.3 %, 99% Purity) as a purple solid.

[0799] 1H NMR in DMSO-d6 was consistent with product structure at >99% purity . 1H NMR (500 MHz, DMSO) δ 8.13 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.38 – 7.35 (m, 2H), 6.97 (dd, J = 8.6, 2.1 Hz, 1H), 6.42 (d, J = 3.1 Hz, 1H), 5.73 (d, J = 7.6 Hz, 1H), 4.34 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.35 (s, 3H), 3.23 (s, 3H).

[0800] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-50-RP-1-ms-155557, m / z 332.0 / 334.0 (M+H)+ (ES+) at 1.18 min, 100.0% purity 260nm + / - 90nm.

[0801] Another reverse-phase column was carried out to obtain the des-Cl product. The impure des-Cl product was loaded onto celite and purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) eluting at 50% to afford the des-Cl product, 4-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-1- methylpyridin-2(1H)-one (8.00 mg, 26 μmol, 5.9 %, 98% Purity) as a brown solid.

[0802] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity (2 w% DCM).1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.40 – 7.33 (m, 2H), 7.30 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.7, 2.1 Hz, 1H), 6.39 (dd, J = 3.1, 0.8 Hz, 1H), 5.85 (dd, J = 7.5, 2.5 Hz, 1H), 5.51 (d, J = 2.5 Hz, 1H), 4.31 (t, J = 5.3 Hz, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.25 (s, 3H), 3.22 (s, 3H).

[0803] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-50-3-RP-ms-1, m / z 298.2 (M+H)+ (ES+) at 1.03 min, 99.4% purity 260nm + / - 90nm.- 175 - EXAMPLE 49 4-[[1-(2-methoxyethyl)indol-5-yl]amino]-1-methyl-pyridin-2-one (Compound 122)

[0804] Step 1: To a solution of 4-bromo-3-chloro-1-methylpyridin-2(1H)-one (100 mg, 1 Eq, 449 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (85.5 mg, 1 Eq, 449 μmol) in 1,4- Dioxane (3.50 mL), NaOtBu (64.8 mg, 1.5 Eq, 674 μmol), dicyclohexyl(2',4',6'- triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (24.1 mg, 0.1 Eq, 44.9 μmol) and BrettPhos Pd G3 (40.7 mg, 0.1 Eq, 44.9 μmol) were added. The mixture was sparged (bubbling N2while sonicating for 2 mins) and stirred at 100 °C for 1 hour. The reaction was cooled and dry loaded onto silica. The crude product was purified by chromatography on silica gel (24 g cartridge, 50-100% [3:1 EtOAc:EtOH] : isoHexanes) to afford the desired product with low purity.

[0805] The impure des-Cl product was loaded onto celite and purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 4-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-1-methylpyridin-2(1H)-one (8.00 mg, 26 μmol, 5.9 %, 98% Purity) as a brown solid.

[0806] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity (2 w% DCM).1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.40 – 7.33 (m, 2H), 7.30 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.7, 2.1 Hz, 1H), 6.39 (dd, J = 3.1, 0.8 Hz, 1H), 5.85 (dd, J = 7.5, 2.5 Hz, 1H), 5.51 (d, J = 2.5 Hz, 1H), 4.31 (t, J = 5.3 Hz, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.25 (s, 3H), 3.22 (s, 3H).

[0807] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-50-3-RP-ms-1, m / z 298.2 (M+H)+ (ES+) at 1.03 min, 99.4% purity 260nm + / - 90nm.- 176 - EXAMPLE 50 2-[5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]indol-1-yl]ethyl acetate (Compound 123)

[0808] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) in dry DMF (10.0 mL) at rt, K2CO3(1.3 g, 3 Eq, 9.3 mmol) and 2-bromoethyl acetate (0.77 g, 0.51 mL, 1.5 Eq, 4.6 mmol) were added. The mixture was warmed to 80 °C and was stirred for 2 hours. Water (20 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc in isohexane) to afford 2-(5-nitro-1H-indol-1- yl)ethyl acetate (0.431 g, 1.6 mmol, 51 %, 90% Purity) as a yellow solid.

[0809] 1H NMR in DMSO-d6 was consistent with product structure at 90% purity.

[0810] 1H NMR (400 MHz, DMSO) δ 8.57 (d, J = 2.3 Hz, 1H), 8.05 (dd, J = 9.1, 2.3 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 3.2 Hz, 1H), 6.76 (dd, J = 3.3, 0.8 Hz, 1H), 4.53 (dd, J = 5.7, 4.7 Hz, 2H), 4.35 (dd, J = 5.7, 4.6 Hz, 2H), 1.90 (s, 3H).

[0811] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-209-2-ms, m / z 249.0 (M+H)+ (ES+) at 1.32 min, 89.4% purity 260nm + / - 90nm.

[0812] Step 2: A solution of 2-(5-nitro-1H-indol-1-yl)ethyl acetate (0.20 g, 90% Wt, 1 Eq, 0.73 mmol) in a mixture of MeOH (5.00 mL) and THF (2.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 3 pass). The residue was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) to afford 2-(5-amino-1H-indol-1-yl)ethyl acetate (103 mg, 0.42 mmol, 59 %, 90% Purity) as a pale yellow solid.

[0813] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-226-2-ms, m / z 219.2 (M+H)+ (ES+) at 0.25 min, 64.3% purity 260nm + / - 90nm.- 177 -

[0814] 1H NMR in DMSO-d6 was consistent with product structure at 90% purity.

[0815] 1H NMR (400 MHz, DMSO) δ 7.18 – 7.12 (m, 2H), 6.67 (dd, J = 2.2, 0.6 Hz, 1H), 6.53 (dd, J = 8.6, 2.1 Hz, 1H), 6.12 (dd, J = 3.0, 0.8 Hz, 1H), 4.47 (s, 2H), 4.32 – 4.18 (m, 4H), 1.93 (s, 3H).

[0816] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (70.0 mg, 1 Eq, 391 μmol) in DMSO (1.00 mL), DIPEA (101 mg, 136 μL, 2 Eq, 782 μmol) and 2-(5-amino- 1H-indol-1-yl)ethyl acetate (102 mg, 1.2 Eq, 469 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The mixture was extracted with EtOAc (3 x 10 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo.The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford the desired product with low purity.

[0817] The residue was dissolved in 1.4 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 15% MeCN; 0.5-15.5 min, ramped from 15% MeCN to 45% MeCN; 15.5-15.6 min, ramped from 45% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 2-(5-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1H-indol-1- yl)ethyl acetate (52.0 mg, 0.14 mmol, 35 %, 95% Purity) as a pale yellow solid.

[0818] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0819] 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.43 (q, J = 1.8 Hz, 3H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 6.46 (dd, J = 3.1, 0.8 Hz, 1H), 4.45 (t, J = 5.2 Hz, 2H), 4.33 (t, J = 5.2 Hz, 2H), 3.59 (s, 3H), 1.93 (s, 3H).

[0820] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-229-2-ms, m / z 361.0 / 363.0 (M+H)+ (ES+) at 1.23 min, 98.9% purity 260nm + / - 90nm.- 178 - EXAMPLE 51 4-chloro-2-methyl-5-[(2-methylindazol-5-yl)amino]pyridazin-3-one (Compound 124)

[0821] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (150 mg, 1 Eq, 838 μmol) in DMSO (3.00 mL), DIPEA (217 mg, 292 μL, 2 Eq, 1.68 mmol) and 2-methyl- 2H-indazol-5-amine (148 mg, 1.2 Eq, 1.01 mmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The mixture was extracted with EtOAc (3 x 10 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford the desired product with low purity.

[0822] The residue was dissolved in 1.9 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 10% MeCN; 0.5-15.5 min, ramped from 10% MeCN to 30% MeCN; 15.5-15.6 min, ramped from 30% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 4-chloro-2-methyl-5-((2-methyl-2H-indazol-5-yl)amino)pyridazin-3(2H)-one (56.0 mg, 0.18 mmol, 22 %, 95% Purity) as a pale yellow solid.

[0823] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0824] 1H NMR (500 MHz, DMSO) δ 8.68 (s, 1H), 8.32 (s, 1H), 7.63 (dt, J = 9.0, 0.9 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.13 (dd, J = 9.0, 2.1 Hz, 1H), 4.17 (s, 3H), 3.60 (s, 3H).- 179 -

[0825] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-232-2-ms, m / z 290.0 / 292.0 (M+H)+ (ES+) at 0.90 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 52 5-[(1-acetylindol-5-yl)amino]-4-chloro-2-methyl-pyridazin-3-one (Compound 125)

[0826] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) and DIPEA (1.2 g, 1.6 mL, 3 Eq, 9.3 mmol) in DCM (8.00 mL) at 0 °C, acetyl chloride (0.29 g, 0.26 mL, 1.2 Eq, 3.7 mmol) was added dropwise in DCM (2.00 mL). DMAP (38 mg, 0.1 Eq, 0.31 mmol) was added and the mixture was warmed to rt and stirred for 18 hours. Water (10 ml) was added and the mixture was extracted with EtOAc (2 x 10 ml). The organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0- 100% EtOAc / isohexane) to afford 1-(5-nitro-1H-indol-1-yl)ethan-1-one (595 mg, 2.8 mmol, 90 %, 95% Purity) as a yellow solid.

[0827] 1H NMR in DMSO-d6 was consistent with product structure at 95% purity.

[0828] 1H NMR (400 MHz, DMSO) δ 8.59 (d, J = 2.4 Hz, 1H), 8.50 (dt, J = 9.1, 0.6 Hz, 1H), 8.21 (dd, J = 9.1, 2.4 Hz, 1H), 8.11 (d, J = 3.8 Hz, 1H), 6.98 (dd, J = 3.8, 0.7 Hz, 1H), 2.71 (s, 3H).

[0829] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-220-1-ms, m / z 205.2 (M+H)+ (ES+) at 1.28 min, 100.0% purity 254 nm.

[0830] Step 2: A solution of 1-(5-nitro-1H-indol-1-yl)ethan-1-one (0.20 g, 1 Eq, 0.98 mmol) in a mixture of MeOH (5.00 mL) and THF (2.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 2 pass). The residue was concentrated in vacuo to afford 1-(5- amino-1H-indol-1-yl)ethan-1-one (110 mg, 0.47 mmol, 48 %, 74% Purity) as a yellow solid.- 180 -

[0831] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water):3917-228-1-ms, m / z 175.7 (M+H)+ (ES+) at 0.76 min, 73.8% purity 210- 400nm.

[0832] 1H NMR in DMSO-d6 was consistent with product structure at 75% purity.

[0833] 1H NMR (400 MHz, DMSO) δ 7.98 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 6.59 (dd, J = 8.7, 2.3 Hz, 1H), 6.49 (dd, J = 3.7, 0.8 Hz, 1H), 4.99 (s, 2H), 2.55 (s, 3H).

[0834] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (90.0 mg, 1 Eq, 503 μmol) in DMSO (1.00 mL), DIPEA (130 mg, 175 μL, 2 Eq, 1.01 mmol) and 1-(5- amino-1H-indol-1-yl)ethan-1-one (105 mg, 1.2 Eq, 603 μmol) were added. The mixture was stirred at 110 °C for 18 hours. Water (10 ml) was added and the precipitate was collected by filtration, washed with water (5 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford the desired product with low purity.

[0835] The residue was dissolved in 2.1 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 17.5% MeCN; 0.5-10.5 min, ramped from 17.5% MeCN to 47.5% MeCN; 10.5-10.6 min, ramped from 47.5% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were collected and extracted with EtOAc (3 x 10 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to afford 5-((1-acetyl-1H-indol-5-yl)amino)-4-chloro-2- methylpyridazin-3(2H)-one (6.00 mg, 18 μmol, 3.6 %, 95% Purity) as a pale yellow solid.

[0836] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0837] 1H NMR (500 MHz, DMSO) δ 8.76 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 3.7 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.7, 2.2 Hz, 1H), 6.75 (d, J = 3.7 Hz, 1H), 3.61 (s, 3H), 2.66 (s, 3H).- 181 -

[0838] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-231-2-ms, m / z 317.0 / 319.0 (M+H)+ (ES+) at 1.13 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 53 4-chloro-2-methyl-5-[(1-methylindazol-5-yl)amino]pyridazin-3-one (Compound 126)

[0839] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) in DMSO (3.00 mL), DIPEA (144 mg, 195 μL, 2 Eq, 1.12 mmol) and 1-methyl- 1H-indazol-5-amine (98.7 mg, 1.2 Eq, 670 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The mixture was extracted with EtOAc (3 x 10 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford the desired product with low purity. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 5-50% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 4-chloro-2-methyl-5-((1-methyl-1H-indazol-5- yl)amino)pyridazin-3(2H)-one (11.0 mg, 36 μmol, 6.5 %, 95% Purity) as a pale yellow solid.

[0840] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0841] 1H NMR (500 MHz, DMSO) δ 8.73 (s, 1H), 8.04 (d, J = 1.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.49 (s, 1H), 7.31 (dd, J = 8.8, 2.0 Hz, 1H), 4.06 (s, 3H), 3.60 (s, 3H).

[0842] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-244-2-ms, m / z 290.0 / 292.0 (M+H)+ (ES+) at 0.99 min, 100.0% purity 260nm + / - 90nm.- 182 - EXAMPLE 54 4-chloro-5-[[1-(2-hydroxyethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 127)

[0843] Step 1: To a solution of 2-(5-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1H-indol-1-yl)ethyl acetate (30.0 mg, 1 Eq, 83.1 μmol) in THF (0.60 mL) and Water (0.20 mL), Lithium hydroxide monohydrate (4.19 mg, 1.2 Eq, 99.8 μmol) was added. the mixture was warmed to 45 °C and stirred for 1 hour. The mixture was cooled to rt. Water (10 ml) and 1 M HCl solution (2 ml) were added. The mixture was extracted with EtOAc ( 3 x 10 ml). the organic layers were combined, washed with brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford 4-chloro-5-((1-(2-hydroxyethyl)- 1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (21.0 mg, 63 μmol, 75 %, 95% Purity) as a pale yellow solid.

[0844] 1H NMR in DMSO-d6 consistent with product structure at >95% purity.

[0845] 1H NMR (500 MHz, DMSO) δ 8.63 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.45 – 7.39 (m, 3H), 7.02 (dd, J = 8.7, 2.1 Hz, 1H), 6.43 (dd, J = 3.2, 0.8 Hz, 1H), 4.89 (t, J = 5.2 Hz, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.73 (q, J = 5.5 Hz, 2H), 3.58 (s, 3H).

[0846] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-248-1-ms, m / z 319.0 / 321.0 (M+H)+ (ES+) at 0.99 min, 100.0% purity 260nm + / - 90nm.- 183 - EXAMPLE 55 4-chloro-2-methyl-5-[[1-(4-piperidyl)indol-5-yl]amino]pyridazin-3-one (Compound 128)

[0847] Step 1: To a solution of 5-nitro-1H-indole (0.20 g, 1 Eq, 1.2 mmol) in dry DMF (4.00 mL), K2CO3(0.51 g, 3 Eq, 3.7 mmol) and tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (0.69 g, 2 Eq, 2.5 mmol) were added. The mixture was warmed to 80 °C and was stirred for 18 hours. Water (20 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc in isohexane) to afford tert-butyl 4-(5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (0.29 g, 0.42 mmol, 34 %, 50% Purity) as a yellow solid.

[0848] 1H NMR in DMSO-d6 was consistent with product structure at 50% purity. 1 / 1 mixture of starting material and product. NMR not described.

[0849] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-219-1-ms, m / z 290.0 (M- tBu+H)+ (ES+) at 1.80 min, 50.5% purity 260nm + / - 90nm.

[0850] Step 2: A solution of tert-butyl 4-(5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (0.29 g, 50% Wt, 1 Eq, 0.42 mmol) in a mixture of MeOH (5.00 mL) and THF (2.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 2 pass). The residue was concentrated in vacuo to afford tert-butyl 4-(5-amino-1H-indol-1-yl)piperidine-1- carboxylate (120 mg, 0.11 mmol, 26 %, 29% Purity) as a yellow solid.

[0851] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-227-1-ms, m / z 316.2 at 0.93 min, 29.4% purity 260nm + / - 90nm.

[0852] 1H NMR in DMSO-d6 was consistent with product structure at 30% purity.- 184 -

[0853] 1H NMR (400 MHz, DMSO) δ 7.26 (d, J = 3.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 8.6, 2.1 Hz, 1H), 6.15 – 6.12 (m, 1H), 4.46 (s, 2H), 4.10 (s, 2H), 2.94 (s, 2H), 1.96 – 1.87 (m, 2H), 1.81 – 1.68 (m, 2H), 1.42 (s, 9H). (1 exchangeable H missing).

[0854] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (60.0 mg, 1 Eq, 335 μmol) in DMSO (1.00 mL), DIPEA (86.6 mg, 117 μL, 2 Eq, 670 μmol) and tert-butyl 4-(5-amino-1H-indol-1-yl)piperidine-1-carboxylate (127 mg, 1.2 Eq, 402 μmol) were added. The mixture was stirred at 110 °C for 18 hours. Water (10 ml) was added and the precipitate was collected by filtration, washed with water (5 ml) and dried in vacuo.

[0855] The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 100% EtOAc / isohexane) to afford tert-butyl 4-(5-((5-chloro-1-methyl-6-oxo-1,6- dihydropyridazin-4-yl)amino)-1H-indol-1-yl)piperidine-1-carboxylate (65.0 mg, 44 μmol, 13 %, 31% Purity) as a tan solid.

[0856] 1H NMR in DMSO-d6 was consistent with product structure at 35% purity.

[0857] NMR not described due to low purity.

[0858] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-230-1-ms, m / z 458.2 / 460.2 at 1.66 min, 61.0% purity 260nm + / - 90nm.

[0859] Step 4: To a solution of tert-butyl 4-(5-((5-chloro-1-methyl-6-oxo-1,6- dihydropyridazin-4-yl)amino)-1H-indol-1-yl)piperidine-1-carboxylate (65.0 mg, 1 Eq, 142 μmol) in DCM (2.00 mL), HCl (3 M in CPME) (103 mg, 946 μL, 3.00 molar, 20 Eq, 2.84 mmol) was added. The mixture was stirred at rt for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in water (5 ml) and was washed with EtOAc (10 ml). The aqueous layer was basified by addition of sat. aq. NaHCO3solution (10 ml) and was extracted with EtOAc (3 x 10 ml). The organic layers were combined, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 1 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.3% Ammonia in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1- 185 - Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 10% MeCN; 0.5-15.5 min, ramped from 10% MeCN to 40% MeCN; 15.5-15.6 min, ramped from 40% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 4-chloro- 2-methyl-5-((1-(piperidin-4-yl)-1H-indol-5-yl)amino)pyridazin-3(2H)-one (5.00 mg, 13 μmol, 9.4 %, 95% Purity) as a pale yellow solid.

[0860] 1H NMR in DMSO-d6 at 363 K was consistent with product structure at >95% purity.

[0861] 1H NMR (500 MHz, DMSO) δ 7.57 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 3.2 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.47 (d, J = 3.2 Hz, 1H), 4.41 (tt, J = 11.7, 4.2 Hz, 1H), 3.61 (s, 3H), 3.21 (s, 1H), 3.11 (dt, J = 12.9, 2.9 Hz, 2H), 2.74 (td, J = 12.2, 2.7 Hz, 2H), 1.97 – 1.80 (m, 4H). (1 NH not shown).

[0862] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water):3917-238-2-ms, m / z 358.3 / 360.3 (M+H)+ (ES+) at 1.04 min, 95.7% purity 254 nm. EXAMPLE 56 4-chloro-5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-(4-pyridyl)pyridazin-3-one (Compound

[0863] Step 1: To a stirred solution of 3,4-dichloro-5-hydroxyfuran-2(5H)-one (250 mg, 1 Eq, 1.48 mmol) in dry Acetic Acid (3.00 mL) under a nitrogen atmosphere at rt was added 4-hydrazineylpyridine (161 mg, 1 Eq, 1.48 mmol). The reaction mixture was heated to 110 °C stirred overnight (18 hours). The reaction mixture was diluted with H2O (50 mL) and transferred to a stirred conical flask and the mixture was quenched with solid K3PO4 until a pH of ~8 was achieved. EtOAc (25 mL) was added, and the resulting fine suspension was- 186 - filtered through a sintered funnel with celite, rinsing with EtOAc. The resulting clear orange biphasic mixture was then transferred into a separating funnel. The separated aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layers were collected, dried over Sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-70% [3:1 EtOAc:EtOH] : isoHexanes) to afford 4,5-dichloro-2-(pyridin-4-yl)pyridazin-3(2H)-one (78.0 mg, 322 μmol, 21.8 %, 100% Purity) as a light yellow solid.

[0864] 1H NMR in DMSO-d6 was consistent with product structure at >99% purity. 1H NMR (400 MHz, DMSO) δ 8.78 – 8.72 (m, 2H), 8.43 (s, 1H), 7.72 – 7.66 (m, 2H).

[0865] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-49-1-ms-1, m / z 242.0 / 244.0 (M+H)+ (ES+) at 0.73 min, 100.0% purity 260nm + / - 90nm.

[0866] Step 2: To a solution of 1-(2-methoxyethyl)-1H-indol-5-amine (65.2 mg, 94% Wt, 1 Eq, 322 μmol) in DMSO (1.00 mL), 4,5-dichloro-2-(pyridin-4-yl)pyridazin-3(2H)-one (78.0 mg, 100% Wt, 1 Eq, 322 μmol) and DIPEA (83.3 mg, 112 μL, 2 Eq, 644 μmol) were added. The mixture was stirred at 90 °C for 1 h. The crude product was purified by chromatography (dry load, silica) on silica gel (24 g cartridge, 0-70% [3:1 EtOAc / EtOH]: isohexane to afford the product and some residual DMSO from the reaction. The residue was diluted with EtOAc (25 mL) and washed with 50 v% brine (2 x 50 mL), the organic layer was dried (Na2SO4), filtered, and concentrated to provide 4-chloro-5-((1-(2- methoxyethyl)-1H-indol-5-yl)amino)-2-(pyridin-4-yl)pyridazin-3(2H)-one (104 mg, 0.25 mmol, 78 %, 96% Purity) as a dark brown solid.

[0867] 1H NMR in DMSO-d6 was consistent with product structure at 96% purity (3.4 w% DCM).1H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.69 – 8.63 (m, 2H), 7.71 (s, 1H), 7.71 – 7.68 (m, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 3.1 Hz, 1H), 7.09 (dd, J = 8.7, 2.1 Hz, 1H), 6.46 (d, J = 3.1 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.2 Hz, 2H), 3.23 (s, 3H).

[0868] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-51-1-ms-1, m / z 396.0 / 398.0 (M+H)+ (ES+) at 1.08 min, 99.0% purity 260nm + / - 90nm.- 187 - EXAMPLE 57 4-chloro-2-methyl-5-[(1-methylpyrrolo[2,3-b]pyridin-5-yl)amino]pyridazin-3-one (Compound 130)

[0869] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) in DMSO (1.00 mL), DIPEA (217 mg, 292 μL, 3 Eq, 1.68 mmol) and 1-methyl- 1H-pyrrolo[2,3-b]pyridin-5-amine (98.7 mg, 1.2 Eq, 670 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford the desired product as a tan solid. The solid was further triturated in Et2O (3 ml), collected by filtration and dried in vacuo to afford 4-chloro-2-methyl-5-((1-methyl-1H-pyrrolo[2,3-b]pyridin-5- yl)amino)pyridazin-3(2H)-one (9.00 mg, 30 μmol, 5.3 %, 95% Purity) as a yellow solid.

[0870] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0871] 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 3.5 Hz, 1H), 7.43 (s, 1H), 6.48 (d, J = 3.4 Hz, 1H), 3.84 (s, 3H), 3.60 (s, 3H).

[0872] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-256-1-ms, m / z 290.0 / 292.0 (M+H)+ (ES+) at 0.98 min, 97.1% purity 260nm + / - 90nm.- 188 - EXAMPLE 58 4-chloro-2-methyl-5-[(1-methylindol-6-yl)amino]pyridazin-3-one (Compound 131)

[0873] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) in DMSO (1.00 mL), DIPEA (217 mg, 292 μL, 3 Eq, 1.68 mmol) and 1-methyl- 1H-indol-6-amine (98.0 mg, 1.2 Eq, 670 μmol) were added. The mixture was stirred at 110 °C for 18 hours.

[0874] The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford 4-chloro-2-methyl-5-((1-methyl-1H-indol-6- yl)amino)pyridazin-3(2H)-one (25.0 mg, 82 μmol, 15 %, 95% Purity) as a tan solid.

[0875] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0876] 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.60 – 7.54 (m, 2H), 7.35 (dd, J = 5.5, 2.5 Hz, 2H), 6.94 (dd, J = 8.3, 1.9 Hz, 1H), 6.44 (dd, J = 3.1, 0.8 Hz, 1H), 3.76 (s, 3H), 3.60 (s, 3H).

[0877] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-258-1-ms, m / z 289.0 / 291.0 (M+H)+ (ES+) at 1.26 min, 98.2% purity 254 nm. EXAMPLE 59 4-ethyl-5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 133)

[0878] Step 1: To a stirred solution of 4,5-dichloropyridazin-3(2H)-one (500 mg, 1 Eq, 3.03 mmol) in dry THF (10.0 mL) under a nitrogen atmosphere at 0 °C was added- 189 - ethylmagnesium bromide 3M in Et2O (1.21 g, 3.03 mL, 3.00 molar, 3 Eq, 9.09 mmol) by dropwise addition. The reaction mixture was stirred at this temperature for 10 min before being allowed to warm to r.t and stir for 2 hours. Saturated aq NH4Cl solution (5 mL) was added slowly. The resulting suspension was transferred to a separating funnel rinsing with EtOAc (25 mL) and 2 M aqueous HCl (25 mL). The separated aqueous layer was further extracted with EtOAc (2x 25 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant oil was dry loaded onto silica and purified by silica chromatography (0−40% EtOAc in isohexane) to afford 5-chloro-4- ethylpyridazin-3(2H)-one (77.0 mg, 0.47 mmol, 16 %, 97% Purity) as a white crystalline solid.

[0879] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity. 1H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 7.93 (s, 1H), 2.58 (q, J = 7.5 Hz, 2H), 1.06 (t, J = 7.5 Hz, 3H).

[0880] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-53-1-ms-1, m / z 161.0 (M+H)+ (ES+) at 0.77 min, 96.7% purity 260nm + / - 90nm.

[0881] Step 2: To a stirred solution of 5-chloro-4-ethylpyridazin-3(2H)-one (77.0 mg, 1 Eq, 486 μmol), Tetrabutylazanium bromide (344 mg, 2.2 Eq, 1.07 mmol) and K2CO3(134 mg, 2 Eq, 971 μmol) in dry MeCN (2.00 mL) under a nitrogen atmosphere at r.t. was added iodomethane (138 mg, 60.5 μL, 2 Eq, 971 μmol). The reaction mixture was stirred for 3. The resultant mixture was filtered under reduced pressure rinsing with EtOAc and transferred to a separating funnel EtOAc (50 mL) was added and washed with 2 M aq HCl (50 mL). The separated aqueous layer was further extracted with EtOAc (2x 25 mL). The combined organic extracts were, dried (Na2SO4) filtered and concentrated to provide the crude product. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-30% EtOAc / isohexane) to afford 5-chloro-4-ethyl-2-methylpyridazin-3(2H)- one (61.0 mg, 0.35 mmol, 72 %, 99% Purity) as a clear colourless oil.

[0882] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 7.99 (s, 1H), 3.64 (s, 3H), 2.62 (q, J = 7.5 Hz, 2H), 1.06 (t, J = 7.5 Hz, 3H).

[0883] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-55-1-ms-1, m / z 173.0 / 175.0 (M+H)+ (ES+) at 1.01 min, 99.0% purity 260nm + / - 90nm.- 190 -

[0884] Step 3: To a solution of 5-chloro-4-ethyl-2-methylpyridazin-3(2H)-one (61.0 mg, 99% Wt, 1 Eq, 350 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (70.8 mg, 94% Wt, 1 Eq, 350 μmol) in 1,4-Dioxane (3.50 mL), NaOtBu (50.4 mg, 1.5 Eq, 525 μmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (18.8 mg, 0.1 Eq, 35.0 μmol) and BrettPhos Pd G3 (31.7 mg, 0.1 Eq, 35.0 μmol) were added. The mixture was sparged (bubbling N2 while sonication for 2 mins) then stirred at 100 °C for 1 hour. The reaction was cooled and dry loaded onto silica. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% [3:1 EtOAc:EtOH] : isoHexanes) to afford slightly impure product. The residue was purified by chromatography on RP Flash C18 (24 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford4-ethyl-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2-methylpyridazin- 3(2H)-one (94.0 mg, 288 μmol, 82.3 %, 100% Purity) as a light tan solid.

[0885] 1H NMR in DMSO-d6 was consistent with product structure at 100% purity. 1H NMR (500 MHz, DMSO) δ 8.04 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.6, 2.1 Hz, 1H), 6.40 (d, J = 3.1 Hz, 1H), 4.33 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.53 (s, 3H), 3.22 (s, 3H), 2.56 (q, J = 7.3 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H).

[0886] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-57-RP-1-ms-1, m / z 327.2 (M+H)+ (ES+) at 1.29 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 60 4-ethyl-5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 134)

[0887] Step 1: To a stirred solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (500 mg, 1 Eq, 2.79 mmol) in dry THF (10.00 mL) under a nitrogen atmosphere at 0 °C was added isopropylmagnesium bromide 2M in THF (576 mg, 1.30 mL, 3.00 molar, 1.4 Eq, 3.91- 191 - mmol) by dropwise addition. The reaction mixture was stirred at this temperature for 10 min before being allowed to warm to r.t and stir for 2 hours. Saturated aq NH4Cl solution (5 mL) was added slowly. The resulting suspension was transferred to a separating funnel rinsing with EtOAc (25 mL) and 2 M aqueous HCl (25 mL). The separated aqueous layer was further extracted with EtOAc (2x 25 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant oil was dissolved in minimal DCM and purified by silica chromatography (0−40% EtOAc in isohexane) to afford 5- chloro-4-isopropyl-2-methylpyridazin-3(2H)-one (333 mg, 1.78 mmol, 63.9 %, 100% Purity) as a colourless oil.

[0888] 1H NMR in DMSO-d6 was consistent with product structure at 100% purity. 1H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 3.62 (s, 3H), 3.45 – 3.31 (m, 1H), 1.27 (d, J = 7.0 Hz, 6H).

[0889] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-56-1-ms-1, m / z 187.0 / 189.0 (M+H)+ (ES+) at 1.25 min, 100.0% purity 260nm + / - 90nm.

[0890] Step 2: To a solution of 5-chloro-4-isopropyl-2-methylpyridazin-3(2H)-one (80.0 mg, 100% Wt, 1 Eq, 429 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (86.8 mg, 94% Wt, 1 Eq, 429 μmol) in 1,4-Dioxane (3.50 mL), NaOtBu (61.8 mg, 1.5 Eq, 643 μmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (23.0 mg, 0.1 Eq, 42.9 μmol) and BrettPhos Pd G3 (38.9 mg, 0.1 Eq, 42.9 μmol) were added. The mixture was sparged (bubbling N2while sonicating for 2 min) then stirred at 100 °C for 1 hour. The reaction was cooled and dry loaded onto celite. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 4-isopropyl-5-((1-(2-methoxyethyl)-1H- indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (142 mg, 0.41 mmol, 96 %, 99% Purity) as a dark brown glass.

[0891] 1H NMR in DMSO-d6 was consistent with product structure at 100% purity. 1H NMR (400 MHz, DMSO) δ 8.01 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.40 – 7.33 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.6, 2.1 Hz, 1H), 6.38 (dd, J = 3.1, 0.8 Hz, 1H), 4.32 (t, J = 5.3 Hz, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.50 (s, 3H), 3.22 (s, 3H), 3.28 – 3.16 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H).- 192 -

[0892] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-58-RP-1-ms-1, m / z 341.2 (M+H)+ (ES+) at 1.42 min, 99.1% purity 260nm + / - 90nm. EXAMPLE 61 6-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 135)

[0893] Step 1: To a solution of 6-bromo-2-methylpyridazin-3(2H)-one (80.0 mg, 1 Eq, 423 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (82.2 mg, 98% Wt, 1 Eq, 423 μmol) in 1,4- Dioxane (3.50 mL), NaOtBu (61.0 mg, 1.5 Eq, 635 μmol), dicyclohexyl(2',4',6'- triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (22.7 mg, 0.1 Eq, 42.3 μmol) and BrettPhos Pd G3 (38.4 mg, 0.1 Eq, 42.3 μmol) were added. The mixture was stirred at 100 °C for 1 hour. The reaction was left to cool and the reaction mixture loaded onto Celite. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 6-((1-(2- methoxyethyl)-1H-indol-5-yl)amino)-2-methylpyridazin-3(2H)-one (34.0 mg, 0.11 mmol, 26 %, 98% Purity) as a brown solid.

[0894] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 3.1 Hz, 1H), 7.21 – 7.11 (m, 2H), 6.83 (d, J = 9.7 Hz, 1H), 6.34 (dd, J = 3.1, 0.8 Hz, 1H), 4.28 (t, J = 5.4 Hz, 2H), 3.64 (t, J = 5.4 Hz, 2H), 3.54 (s, 3H), 3.21 (s, 3H).

[0895] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-60-RP-1-ms-156581, m / z 299.2 (M+H)+ (ES+) at 1.09 min, 98.0% purity 260nm + / - 90nm.- 193 - EXAMPLE 62 4-bromo-5-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 136)

[0896] Step 1: To a solution of 4,5-dibromopyridazin-3(2H)-one (0.65 g, 1 Eq, 2.6 mmol) in DMF (10.0 mL), potassium carbonate (0.53 g, 1.5 Eq, 3.8 mmol) and iodomethane (0.55 g, 0.24 mL, 1.5 Eq, 3.8 mmol) were added. The mixture was warmed to 50 °C and stirred for 1 hour.

[0897] The mixture was cooled to rt and water (30 ml) was added. The mixture was extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (50 ml) dried over Na2SO4, filtered and concentrated in vacuo to afford 4,5-dibromo-2- methylpyridazin-3(2H)-one (0.57 g, 2.0 mmol, 79 %, 95% Purity) as a white solid.

[0898] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0899] 1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 3.67 (s, 3H).

[0900] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-247-1-ms, m / z 266.8 / 268.8 (M+H)+ (ES+) at 0.85 min, 100.0% purity 260nm + / - 90nm.

[0901] Step 2: To a solution of 4,5-dibromo-2-methylpyridazin-3(2H)-one (100 mg, 95% Wt, 1 Eq, 355 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (71.8 mg, 94% Wt, 1 Eq, 355 μmol) in 1,4-Dioxane (3.50 mL), PdOAc2(7.96 mg, 0.1 Eq, 35.5 μmol), 2,2'- bis(diphenylphosphaneyl)-1,1'-binaphthalene (33.1 mg, 0.15 Eq, 53.2 μmol) and NaOtBu (51.1 mg, 1.5 Eq, 532 μmol) were added. The mixture was sparged (bubbling N2 while sonication for 2 mins) then stirred at 100 °C overnight (20 h). The reaction was left to cool and the reaction mixture loaded onto Celite. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 4-bromo-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2- methylpyridazin-3(2H)-one (9.00 mg, 24 μmol, 6.7 %, 99% Purity) as a light brown solid.- 194 -

[0902] 1H NMR in DMSO-d6 was consistent with product structure at >99% purity. 1H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.32 (s, 1H), 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.43 (d, J = 3.1 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.59 (s, 3H), 3.22 (s, 3H).

[0903] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-59-RP-1-ms-156882, m / z 377.0 / 379.0 (M+H)+ (ES+) at 1.27 min, 99.2% purity 260nm + / - 90nm. EXAMPLE 63 4-chloro-5-[[1-(2-methoxyethyl)indol-5-yl]methylamino]-2-methyl-pyridazin-3-one (Compound 137)

[0904] Step 1: To a solution of 1H-indole-5-carbonitrile (0.50 g, 1 Eq, 3.5 mmol) in dry DMF (10.0 mL) at 0 °C, NaH (0.17 g, 60% Wt, 1.2 Eq, 4.2 mmol) was added. The mixture was stirred for 30 minutes at the same temperature and 1-bromo-2-methoxyethane (0.59 g, 0.40 mL, 1.2 Eq, 4.2 mmol) was added dropwise over 5 minutes. The mixture was warmed to rt and was stirred for 3 hours. Water (20 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml). The organic layers were combined, washed with brine (2 x 50 ml) dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to afford 1-(2- methoxyethyl)-1H-indole-5-carbonitrile (671 mg, 3.2 mmol, 91 %, 95% Purity) as a white solid.

[0905] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.- 195 -

[0906] 1H NMR (400 MHz, DMSO) δ 8.10 – 8.05 (m, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 3.2 Hz, 1H), 7.47 (dd, J = 8.5, 1.6 Hz, 1H), 6.59 (dd, J = 3.1, 0.8 Hz, 1H), 4.40 (t, J = 5.2 Hz, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.20 (s, 3H).

[0907] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-201-1-ms, m / z 201.0 (M+H)+ (ES+) at 1.24 min, 100.0% purity 260nm + / - 90nm.

[0908] Step 2: A solution of 1-(2-methoxyethyl)-1H-indole-5-carbonitrile (0.10 g, 1 Eq, 0.50 mmol) in MeOH (NH3) (0.7 M) (5.00 mL) was hydrogenated with the H-cube (1 ml / min, 2 bar, 3 passes). The residue was concentrated in vacuo to afford (1-(2- methoxyethyl)-1H-indol-5-yl)methanamine (0.10 g, 0.47 mmol, 93 %, 95% Purity) as a yellow solid.

[0909] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-233-1-ms, m / z 205.2 (M+H)+ (ES+) at 0.41 min, 97.1% purity 260nm + / - 90nm.

[0910] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0911] 1H NMR (400 MHz, DMSO) δ 7.44 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 7.09 (dd, J = 8.4, 1.6 Hz, 1H), 6.34 (dd, J = 3.0, 0.8 Hz, 1H), 4.29 (t, J = 5.4 Hz, 2H), 3.76 (s, 2H), 3.63 (t, J = 5.4 Hz, 2H), 3.20 (s, 3H), 1.77 (d, J = 12.7 Hz, 2H).

[0912] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (70.0 mg, 1 Eq, 391 μmol) in DMSO (1.00 mL), DIPEA (101 mg, 136 μL, 2 Eq, 782 μmol) and (1-(2- methoxyethyl)-1H-indol-5-yl)methanamine (95.9 mg, 1.2 Eq, 469 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The mixture was extracted with EtOAc (3 x 10 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 100% EtOAc in isohexane) to afford the desired product with low purity. The residue was dissolved in DMSO (1 mL), filtered and was then purified by chiral SFC on a Waters Prep 15 with a PDA detector, 40 °C, 120 bar. The column was a Chiralpak IG, 10 x 250mm, 5µm, flow rate 15mL / min at 60% MeOH (no modifier), 40% CO2. The clean fractions were collected and concentrated in vacuo to afford 4-chloro-5-(((1-(2-methoxyethyl)-1H- indol-5-yl)methyl)amino)-2-methylpyridazin-3(2H)-one (28.0 mg, 77 μmol, 20 %, 95% Purity) as a pale yellow solid.

[0913] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.- 196 -

[0914] 1H NMR (400 MHz, DMSO) δ 7.75 (s, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.12 (dd, J = 8.5, 1.7 Hz, 1H), 6.38 (dd, J = 3.1, 0.8 Hz, 1H), 4.61 (d, J = 6.5 Hz, 2H), 4.29 (t, J = 5.4 Hz, 2H), 3.62 (t, J = 5.3 Hz, 2H), 3.52 (s, 3H), 3.20 (s, 3H).

[0915] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-234-2-ms, m / z 347.0 / 349.0 (M+H)+ (ES+) at 1.24 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 64 4-chloro-2-methyl-5-[(1-methylindol-4-yl)amino]pyridazin-3-one (Compound 138)

[0916] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100.0 mg, 1 Eq, 558.7 μmol) in DMSO (2.00 mL), DIPEA (216.6 mg, 292 μL, 3 Eq, 1.676 mmol) and 1-methyl-1H-indol-4-amine (98.00 mg, 1.2 Eq, 670.4 μmol) were added. The mixture was stirred at 110 °C for 48 hours. The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0- 100% EtOAc / isohexane) to afford the desired product with low purity. The residue was dissolved in 1.6 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 25% MeCN; 0.5-10.5 min, ramped from 25% MeCN to- 197 - 55% MeCN; 10.5-10.6 min, ramped from 55% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 4-chloro- 2-methyl-5-((1-methyl-1H-indol-4-yl)amino)pyridazin-3(2H)-one (19.0 mg, 63 μmol, 11 %, 95% Purity) as a pale yellow solid.

[0917] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0918] 1H NMR (500 MHz, DMSO) δ 8.79 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 3.1 Hz, 1H), 7.23 – 7.16 (m, 2H), 6.94 (d, J = 7.4 Hz, 1H), 6.24 (dd, J = 3.1, 0.9 Hz, 1H), 3.82 (s, 3H), 3.59 (s, 3H).

[0919] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-251-2-ms, m / z 289.0 / 291.0 (M+H)+ (ES+) at 1.23 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 65 4-chloro-2-methyl-5-[[1-(3-pyridyl)indol-5-yl]amino]pyridazin-3-one (Compound 139)

[0920] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) in DMF (10.0 mL), m-Bromopyridine (0.58 g, 0.36 mL, 1.2 Eq, 3.7 mmol), Potassium phosphate, tribasic (1.4 g, 0.54 mL, 2.1 Eq, 6.5 mmol), Methyl[2-(methylamino)ethyl]amine (54 mg, 66 μL, 0.2 Eq, 0.62 mmol) and CuI (29 mg, 0.05 Eq, 0.15 mmol) were added and the mixture was degassed (Vac / N2). The mixture was heated to 150 °C for 14 hours under microwave irradiation. The mixture was cooled to rt and water (30 ml) was added. The mixture was extracted with EtOAc (3 x 20 ml). the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford 5-nitro-1-(pyridin-3-yl)-1H-indole (230 mg, 0.89 mmol, 29 %, 93% Purity) as a yellow solid.

[0921] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.- 198 -

[0922] 1H NMR (400 MHz, DMSO) δ 8.91 (dd, J = 2.7, 0.8 Hz, 1H), 8.73 – 8.67 (m, 2H), 8.18 – 8.06 (m, 2H), 8.01 (d, J = 3.3 Hz, 1H), 7.74 – 7.64 (m, 2H), 7.06 (dd, J = 3.4, 0.8 Hz, 1H).

[0923] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-239-1-ms, m / z 240.0 (M+H)+ (ES+) at 1.32 min, 93.1% purity 260nm + / - 90nm.

[0924] Step 2: To a solution of 5-nitro-1-(pyridin-3-yl)-1H-indole (0.11 g, 1 Eq, 0.46 mmol) in a mixture of MeOH (5.00 mL) and THF (5.00 mL), Pd / C (49 mg, 10% Wt, 0.1 Eq, 46 μmol) was added. The mixture was hydrogenated under 1 bar of hydrogen for 4 hours. The mixture was filtered, washed with MeOH (5 ml) and the filtrate was concentrated in vacuo to afford 1-(pyridin-3-yl)-1H-indol-5-amine (100 mg, 0.45 mmol, 99 %, 95% Purity) as a white solid.

[0925] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0926] 1H NMR (500 MHz, DMSO) δ 8.80 (dd, J = 2.7, 0.8 Hz, 1H), 8.52 (dd, J = 4.7, 1.4 Hz, 1H), 8.00 (ddd, J = 8.2, 2.8, 1.5 Hz, 1H), 7.61 – 7.52 (m, 2H), 7.32 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.60 (dd, J = 8.7, 2.2 Hz, 1H), 6.47 (dd, J = 3.2, 0.8 Hz, 1H), 4.71 (s, 2H).

[0927] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 1 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-249-1-ms, m / z 210.0 (M+H)+ (ES+) at 0.17 min, 98.6% purity 254nm.

[0928] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (70.0 mg, 1 Eq, 391 μmol) in DMSO (1.00 mL), DIPEA (152 mg, 204 μL, 3 Eq, 1.17 mmol) and 1-(pyridin- 3-yl)-1H-indol-5-amine (98.2 mg, 1.2 Eq, 469 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0- 100% 3 / 1 EtOAc / EtOH in isohexane) to afford the desired product with low purity.

[0929] The residue was dissolved in 3.2 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all- 199 - wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 20% MeCN; 0.5-10.5 min, ramped from 20% MeCN to 50% MeCN; 10.5-10.6 min, ramped from 50% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac 4- chloro-2-methyl-5-((1-(pyridin-3-yl)-1H-indol-5-yl)amino)pyridazin-3(2H)-one (13.0 mg, 35 μmol, 9.0 %, 95% Purity) as a pale yellow solid.

[0930] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0931] 1H NMR (500 MHz, DMSO) δ 8.88 (d, J = 2.6 Hz, 1H), 8.73 (s, 1H), 8.62 (dd, J = 4.7, 1.4 Hz, 1H), 8.11 (ddd, J = 8.2, 2.7, 1.5 Hz, 1H), 7.81 (d, J = 3.3 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.13 (dd, J = 8.8, 2.2 Hz, 1H), 6.77 (dd, J = 3.3, 0.8 Hz, 1H), 3.60 (s, 3H).

[0932] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-253-2-ms, m / z 352.0 / 354.0 (M+H)+ (ES+) at 1.17 min, 98.7% purity 260nm + / - 90nm. EXAMPLE 66 4-chloro-2-methyl-5-[[1-(2-pyridyl)indol-5-yl]amino]pyridazin-3-one (Compound 140)

[0933] Step 1: To a solution of 5-nitro-1H-indole (0.50 g, 1 Eq, 3.1 mmol) in DMF (10.0 mL) at 0 °C, NaH (0.19 g, 60% Wt, 1.5 Eq, 4.6 mmol) was added. The mixture was stirred for 30 minutes and 2-bromopyridine (0.73 g, 0.44 mL, 1.5 Eq, 4.6 mmol) was added. The mixture was heated to 130 °C and stirred for 18 hours. The mixture was cooled to rt and water (30 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) wand dried in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to afford 5-nitro-1-(pyridin-2-yl)-1H- indole (0.549 g, 2.1 mmol, 69 %, 93% Purity) as a yellow solid.

[0934] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.- 200 -

[0935] 1H NMR (400 MHz, DMSO) δ 8.68 – 8.61 (m, 2H), 8.56 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 3.5 Hz, 1H), 8.15 (dd, J = 9.2, 2.4 Hz, 1H), 8.07 (ddd, J = 8.3, 7.4, 1.9 Hz, 1H), 7.86 (dt, J = 8.4, 0.9 Hz, 1H), 7.43 (ddd, J = 7.4, 4.8, 0.9 Hz, 1H), 7.06 (dd, J = 3.5, 0.8 Hz, 1H).

[0936] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-243-1-ms, m / z 240.0 (M+H)+ (ES+) at 1.56 min, 93.2% purity 260nm + / - 90nm.

[0937] Step 2: To a solution of 5-nitro-1-(pyridin-2-yl)-1H-indole (0.10 g, 1 Eq, 0.42 mmol) in a mixture of MeOH (5.00 mL) and THF (5.00 mL), Pd / C (44 mg, 10% Wt, 0.1 Eq, 42 μmol) was added. The mixture was hydrogenated under 1 bar of hydrogen for 4 hours. The mixture was filtered, washed with MeOH (5 ml) and the filtrate was concentrated in vacuo to afford 1-(pyridin-2-yl)-1H-indol-5-amine (95.0 mg, 0.43 mmol, 100 %, 95% Purity) as a white solid.

[0938] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0939] 1H NMR (500 MHz, DMSO) δ 8.50 (ddd, J = 4.8, 2.0, 0.9 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.90 (ddd, J = 8.4, 7.3, 2.0 Hz, 1H), 7.86 (d, J = 3.5 Hz, 1H), 7.67 (dt, J = 8.4, 0.9 Hz, 1H), 7.20 (ddd, J = 7.3, 4.9, 0.9 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 6.60 (dd, J = 8.8, 2.2 Hz, 1H), 6.48 (dd, J = 3.5, 0.8 Hz, 1H), 4.73 (s, 2H).

[0940] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-250-1-ms, m / z 210.0 (M+H)+ (ES+) at 0.50 min, 99.4% purity 254 nm.

[0941] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (70.0 mg, 1 Eq, 391 μmol) in DMSO (1.00 mL), DIPEA (152 mg, 204 μL, 3 Eq, 1.17 mmol) and 1-(pyridin- 2-yl)-1H-indol-5-amine (98.2 mg, 1.2 Eq, 469 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The precipitate formed was collected by filtration, washed with water (10 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc / isohexane) to afford the desired product with low purity.

[0942] The residue was dissolved in 1.5 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all- 201 - wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 30% MeCN; 0.5-10.5 min, ramped from 30% MeCN to 60% MeCN; 10.5-10.6 min, ramped from 60% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to afford 4-chloro-2-methyl-5-((1-(pyridin-2-yl)-1H-indol-5-yl)amino)pyridazin-3(2H)-one (14.0 mg, 38 μmol, 9.7 %, 95% Purity) as a pale yellow solid.

[0943] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0944] 1H NMR (500 MHz, DMSO) δ 8.73 (s, 1H), 8.58 (dd, J = 5.2, 1.8 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 3.5 Hz, 1H), 8.04 – 7.97 (m, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.57 – 7.51 (m, 2H), 7.32 (dd, J = 7.4, 4.8 Hz, 1H), 7.18 (dd, J = 8.9, 2.2 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H), 3.60 (s, 3H).

[0945] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-254-2-ms, m / z 352.0 / 354.0 (M+H)+ (ES+) at 1.40 min, 98.3% purity 260nm + / - 90nm. EXAMPLE 67 4-chloro-2-methyl-5-[(1-methylbenzimidazol-5-yl)amino]pyridazin-3-one (Compound 141)

[0946] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100.0 mg, 1 Eq, 558.7 μmol) in DMSO (2.00 mL), DIPEA (216.6 mg, 292 μL, 3 Eq, 1.676 mmol) and 1-methyl-1H-benzo[d]imidazol-5-amine (98.67 mg, 1.2 Eq, 670.4 μmol) were added. The mixture was stirred at 110 °C for 7 hours. Water (10 ml) was added and the precipitate was collected by filtration, washed with water (5 ml) and dried in vacuo to afford 4-chloro-2- methyl-5-((1-methyl-1H-benzo[d]imidazol-5-yl)amino)pyridazin-3(2H)-one (24.0 mg, 79 μmol, 14 %, 95% Purity) as a tan solid.

[0947] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0948] 1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 8.23 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.47 (s, 1H), 7.19 (dd, J = 8.5, 2.0 Hz, 1H), 3.86 (s, 3H), 3.60 (s, 3H).- 202 -

[0949] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-265-1-ms, m / z 290.0 / 292.0 (M+H)+ (ES+) at 0.49 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 68 4-chloro-2-methyl-5-[(1-methylbenzimidazol-5-yl)amino]pyridazin-3-one (Compound 142)

[0950] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100.0 mg, 1 Eq, 558.7 μmol) in DMSO (2.00 mL), DIPEA (216.6 mg, 292 μL, 3 Eq, 1.676 mmol) and 1-methyl-1H-benzo[d]imidazol-6-amine (98.67 mg, 1.2 Eq, 670.4 μmol) were added. The mixture was stirred at 110 °C for 7 hours. The mixture was cooled to rt and water (10 ml) was added. The mixture was extracted with EtOAc (3 x 10 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 100% 3 / 1 EtOAc / EtOH in isohexane) to afford the desired product with low purity.

[0951] The residue was dissolved in 1.3 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130Å, 5 µm, 30 mm X 100 mm, flow rate 40 mL min-1eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 10% MeCN; 0.5-10.5 min, ramped from 10% MeCN to 20% MeCN; 10.5-10.6 min, ramped from 20% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated to afford 4- chloro-2-methyl-5-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyridazin-3(2H)-one (12.0 mg, 39 μmol, 7.0 %, 95% Purity) as a pale yellow solid.

[0952] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.- 203 -

[0953] 1H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.19 (m, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 8.5, 2.0 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 3H).

[0954] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water):3917-266-2-ms-b, m / z 290.2 / 292.2 (M+H)+ (ES+) at 0.75 min, 95.9% purity 210-400nm. EXAMPLE 69 6-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-3-methyl-1,3-benzoxazol-2-one (Compound 143)

[0955] Step 1: To a solution of 6-nitrobenzo[d]oxazol-2(3H)-one (0.60 g, 1 Eq, 3.3 mmol) in DMF (10.0 mL), potassium carbonate (0.92 g, 2 Eq, 6.7 mmol) and iodomethane (0.71 g, 0.31 mL, 1.5 Eq, 5.0 mmol) were added. The mixture was stirred at rt for 3 hours. Water (30 ml) was added and the precipitate was collected by filtration, washed with water (10 ml) and dried in vacuo to afford 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (0.626 g, 3.1 mmol, 92 %, 95% Purity) as a white solid.

[0956] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0957] 1H NMR (400 MHz, DMSO) δ 8.29 – 8.20 (m, 2H), 7.48 (d, J = 8.6 Hz, 1H), 3.41 (s, 3H).

[0958] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-259-1-ms, m / z 195.0 (M+H)+ (ES+) at 0.91 min, 100.0% purity 260nm + / - 90nm.

[0959] Step 2: To a solution of 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (0.20 g, 1 Eq, 1.0 mmol) in a mixture of Methanol (5.00 mL) and THF (5.00 mL), Pd / C (0.11 g, 10% Wt, 0.1 Eq, 0.10 mmol) was added. The mixture was hydrogenated under 1 bar of hydrogen for 6 hours. The mixture was filtered, washed with MeOH (5 ml) and the filtrate was concentrated in vacuo to afford 6-amino-3-methylbenzo[d]oxazol-2(3H)-one (0.158 g, 0.82 mmol, 79 %, 85% Purity) as a white solid.- 204 -

[0960] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0961] 1H NMR (400 MHz, DMSO) δ 6.88 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.42 (dd, J = 8.3, 2.0 Hz, 1H), 5.02 (s, 2H), 3.24 (s, 3H).

[0962] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water):3917-262-1-ms-b, m / z 165.5 at 0.57 min, 84.7% purity 210-400nm

[0963] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (80.0 mg, 1 Eq, 447 μmol) in DMSO (1.00 mL), DIPEA (173 mg, 234 μL, 3 Eq, 1.34 mmol) and 6-amino- 3-methylbenzo[d]oxazol-2(3H)-one (88.0 mg, 1.2 Eq, 536 μmol) were added. The mixture was stirred at 110 °C for 18 hours. Water (10 ml) was added and the precipitate was collected by filtration, washed with water (5 ml) and dried in vacuo The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford 6-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-3- methylbenzo[d]oxazol-2(3H)-one (12.0 mg, 37 μmol, 8.2 %, 94% Purity) as a yellow solid.

[0964] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0965] 1H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 7.55 (s, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.14 (dd, J = 8.3, 2.0 Hz, 1H), 3.60 (s, 3H), 3.35 (s, 3H).

[0966] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-267-1-ms, m / z 307.0 / 309.0 (M+H)+ (ES+) at 0.92 min, 94.2% purity 254 nm. EXAMPLE 70 6-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3,4-dihydroquinolin-2-one (Compound 144)

[0967] Step 1: To a solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (0.62 g, 1 Eq, 3.2 mmol) in DMF (10.0 mL), potassium carbonate (0.89 g, 2 Eq, 6.5 mmol) and iodomethane (0.69 g, 0.30 mL, 1.5 Eq, 4.8 mmol) were added. The mixture was stirred at rt for 18 hours. Water (30 ml) was added and the precipitate was collected by filtration, washed with water- 205 - (10 ml) and dried in vacuo to afford 1-methyl-6-nitro-3,4-dihydroquinolin-2(1H)-one (0.512 g, 2.4 mmol, 73 %, 95% Purity) as a tan solid.

[0968] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0969] 1H NMR (400 MHz, DMSO) δ 8.19 – 8.12 (m, 2H), 7.33 – 7.26 (m, 1H), 3.31 (s, 3H), 3.01 (dd, J = 8.6, 6.3 Hz, 2H), 2.63 (dd, J = 8.7, 6.3 Hz, 2H).

[0970] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-260-1-ms, m / z 207.0 (M+H)+ (ES+) at 1.02 min, 100.0% purity 260nm + / - 90nm.

[0971] Step 2: To a solution of 1-methyl-6-nitro-3,4-dihydroquinolin-2(1H)-one (0.20 g, 1 Eq, 0.97 mmol) in a mixture of Methanol (5.00 mL) and THF (5.00 mL), Pd / C (0.10 g, 10% Wt, 0.1 Eq, 97 μmol) was added. The mixture was hydrogenated under 1 bar of hydrogen for 6 hours.

[0972] The mixture was filtered, washed with MeOH (10 ml) and the filtrate was concentrated in vacuo to afford 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.183 g, 0.87 mmol, 90 %, 84% Purity) as a tan solid.

[0973] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0974] 1H NMR (400 MHz, DMSO) δ 6.76 (d, J = 8.4 Hz, 1H), 6.48 – 6.40 (m, 2H), 4.84 (s, 2H), 3.15 (s, 3H), 2.69 (dd, J = 8.6, 6.1 Hz, 2H), 2.43 (dd, J = 8.6, 6.0 Hz, 2H).

[0975] The product was analysed by UPLC (Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40 °C, 3 min method, 0.2% Ammonium Hydroxide, 2-100% MeCN / water):3917-263-1-ms-b, m / z 177.3 (M+H)+ (ES+) at 0.61 min, 83.8% purity 210- 400nm.

[0976] Step 3: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (80.0 mg, 1 Eq, 447 μmol) in DMSO (1.00 mL), DIPEA (173 mg, 234 μL, 3 Eq, 1.34 mmol) and 6-amino- 1-methyl-3,4-dihydroquinolin-2(1H)-one (94.5 mg, 1.2 Eq, 536 μmol) were added. The mixture was stirred at 110 °C for 18 hours. The mixture was cooled to rt and water (10 ml) was added. The mixture extracted with EtOAc (3 x 10 ml) and the organic layers were combined, washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0- 100% 3 / 1 EtOAc / EtOH in isohexane) to afford the desired product with low purity.

[0977] The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 5- 50% (0.1 % Formic acid in MeCN) / (0.1% Formic Acid in Water)) to afford 6-((5-chloro-- 206 - 1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methyl-3,4-dihydroquinolin-2(1H)- one (25.0 mg, 75 μmol, 17 %, 95% Purity) as a yellow solid.

[0978] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0979] 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.60 (s, 1H), 7.19 – 7.08 (m, 3H), 3.60 (s, 3H), 3.26 (s, 3H), 2.90 – 2.82 (m, 2H), 2.55 (dd, J = 8.7, 6.2 Hz, 2H).

[0980] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-268-2-ms, m / z 319.0 / 321.0 (M+H)+ (ES+) at 0.96 min, 98.3% purity 260nm + / - 90nm. EXAMPLE 71 6-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-3,4-dihydro-1H-quinolin-2-one (Compound 145)

[0981] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (90.0 mg, 1 Eq, 503 μmol) in DMSO (1.00 mL), DIPEA (195 mg, 263 μL, 3 Eq, 1.51 mmol) and 6-amino- 3,4-dihydroquinolin-2(1H)-one (97.9 mg, 1.2 Eq, 603 μmol) were added. The mixture was stirred at 110 °C for 18 hours. Water (10 ml) was added, and the precipitate was collected by filtration, washed with water (5 ml) and dried in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% 3 / 1 EtOAc / EtOH in isohexane) to afford 6-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-3,4- dihydroquinolin-2(1H)-one (31.0 mg, 97 μmol, 19 %, 95% Purity) as a tan solid.

[0982] 1H NMR in DMSO-d6 was consistent with product structure at >95% purity.

[0983] 1H NMR (400 MHz, DMSO) δ 10.14 (s, 1H), 8.57 (s, 1H), 7.55 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.3, 2.5 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.59 (s, 3H), 2.87 (t, J = 7.5 Hz, 2H), 2.49 – 2.41 (m, 2H).

[0984] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):3917-269-1-ms, m / z 305.0 / 307.0 (M+H)+ (ES+) at 0.84 min, 100.0% purity 260nm + / - 90nm.- 207 - EXAMPLE 72 4-chloro-5-(indan-5-ylamino)-2-methyl-pyridazin-3-one (Compound 146)

[0985] Step 1: To a solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 559 μmol) in DMSO (1.00 mL), DIPEA (144 mg, 195 μL, 2 Eq, 1.12 mmol) and 2,3- dihydro-1H-inden-5-amine (89.3 mg, 1.2 Eq, 670 μmol) were added. The reaction mixture was heated to 120 °C for 24 hours. The reaction was cooled and dry loaded onto Celite. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 10- 100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 4-chloro-5-((2,3-dihydro- 1H-inden-5-yl)amino)-2-methylpyridazin-3(2H)-one (52.0 mg, 0.18 mmol, 32 %, 95% Purity) as a light brown solid.

[0986] 1H NMR in DMSO-d6 was consistent with product structure at ~95% purity (1.7 w% DCM; baseline impurities).1H NMR (500 MHz, DMSO) δ 8.61 (s, 1H), 7.57 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.10 (s, 1H), 7.00 (dd, J = 8.0, 2.1 Hz, 1H), 3.60 (s, 3H), 2.89 – 2.78 (m, 4H), 2.03 (p, J = 7.4 Hz, 2H).

[0987] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-62-1-ms-157086, m / z 276.0 / 278.0 (M+H)+ (ES+) at 1.42 min, 97.6% purity 260nm + / - 90nm. EXAMPLE 73 4-[[1-(2-methoxyethyl)indol-5-yl]amino]-1-methyl-pyrimidin-2-one (Compound 147)

[0988] Step 1: To a solution of 4-chloro-1-methylpyrimidin-2(1H)-one (50.0 mg, 1 Eq, 346 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (70.0 mg, 94% Wt, 1 Eq, 346 μmol) in 1,4- Dioxane (3.50 mL), NaOtBu (49.9 mg, 1.5 Eq, 519 μmol), dicyclohexyl(2',4',6'-- 208 - triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (18.6 mg, 0.1 Eq, 34.6 μmol) and BrettPhos Pd G3 (31.4 mg, 0.1 Eq, 34.6 μmol) were added. The mixture was sparged (Bubbling N2 with sonication for 2 min) then stirred at 100 °C for 1 hour. The reaction was cooled and dry loaded onto celite. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 4-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-1-methylpyrimidin-2(1H)- one (65.0 mg, 0.21 mmol, 62 %, 98% Purity) as a light brown solid.

[0989] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity (1.9 w% EtOAc, trace DCM).1H NMR (500 MHz, DMSO) δ 9.40 (s, 1H), 8.07 (s, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 3.1 Hz, 1H), 7.26 (s, 1H), 6.39 (d, J = 3.1 Hz, 1H), 5.86 (s, 1H), 4.30 (t, J = 5.3 Hz, 2H), 3.64 (t, J = 5.3 Hz, 2H), 3.26 (s, 3H), 3.21 (s, 3H).

[0990] The product was analysed by LCMS (Cortecs C18+, 90Å, 30 x 2.1 mm, 2.7μm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-65-1-ms-257067, m / z 299.2 (M+H)+ (ES+) at 0.67 min, 100.0% purity 260nm + / - 90nm. EXAMPLE 74 6-[[1-(2-methoxyethyl)indol-5-yl]amino]-1,3-dimethyl-pyrimidine-2,4-dione (Compound 148)

[0991] Step 1: To a solution of 6-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (50.0 mg, 1 Eq, 286 μmol), 1-(2-methoxyethyl)-1H-indol-5-amine (58.0 mg, 94% Wt, 1 Eq, 286 μmol) in 1,4-Dioxane (3.50 mL), NaOtBu (41.3 mg, 1.5 Eq, 430 μmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (15.4 mg, 0.1 Eq, 28.6 μmol) and BrettPhos Pd G3 (26.0 mg, 0.1 Eq, 28.6 μmol) were added. The mixture was sparged (Bubbling N2 with sonication for 2 min) then stirred at 100 °C for 1.5 hour. The reaction was cooled and dry loaded onto celite. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 6-((1-(2-methoxyethyl)-1H-indol-5-- 209 - yl)amino)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (37.0 mg, 0.11 mmol, 39 %, 99% Purity) as a light cream solid.

[0992] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (500 MHz, DMSO) δ 8.50 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 8.6, 2.1 Hz, 1H), 6.45 (d, J = 3.1 Hz, 1H), 4.39 (s, 1H), 4.35 (t, J = 5.3 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.46 (s, 3H), 3.22 (s, 3H), 3.10 (s, 3H).

[0993] The product was analysed by UPLC (CSH C18 Column, 130Å, 1.7 µm, 2.1 x 30 mm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-66-1-ms-157385, m / z 329.0 (M+H)+ (ES+) at 0.99 min, 99.1% purity 210-400nm. EXAMPLE 75 6-[[1-(2-methoxyethyl)indol-5-yl]amino]-2-methyl-pyridazin-3-one (Compound 149)

[0994] Step 1: To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole (224 mg, 1.65 Eq, 873 μmol) in MeCN (24.00 mL) was added 6-bromo-2- methylpyridazin-3(2H)-one (100 mg, 1 Eq, 529 μmol) and K2CO3 (219 mg, 3 Eq, 1.59 mmol). The reaction mixture was degassed, Pd(dppf)Cl2(5.81 mg, 0.015 Eq, 7.94 μmol) added, the reaction degassed once more, then heated to 80 °C. After 1 hour the reaction was allowed to cool to r.t., diluted with water (25 mL), filtered and the filtered solid washed with water (25 mL), followed by MeCN (40 mL). The solid was dried in vacuo to afford the crude product. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-50% [3:1 EtOAc:EtOH]: EtOAc) to afford 2-methyl-6-(1-methyl-1H- indol-5-yl)pyridazin-3(2H)-one (66.0 mg, 276 μmol, 52.1 %, 100% Purity) as a white solid.

[0995] 1H NMR in DMSO-d6 was consistent with product structure at >99% purity. 1H NMR (500 MHz, DMSO) δ 8.13 – 8.06 (m, 2H), 7.72 (dd, J = 8.7, 1.8 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.01 (d, J = 9.7 Hz, 1H), 6.51 (dd, J = 3.1, 0.9 Hz, 1H), 3.82 (s, 3H), 3.74 (s, 3H).- 210 -

[0996] The product was analysed by UPLC (CSH C18 Column, 130Å, 1.7 µm, 2.1 x 30 mm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-70-1-ms-157601, m / z 240.0 (M+H)+ (ES+) at 1.25 min, 100.0% purity 210-400nm. EXAMPLE 76 4-chloro-5-[[1-(2-methoxyethyl)indol-5-yl]-methyl-amino]-2-methyl-pyridazin-3-one

[0997] Step 1: To a solution of 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)amino)-2- methylpyridazin-3(2H)-one (57.0 mg, 95% Wt, 1 Eq, 163 μmol) in dry DMF (1.00 mL) at 0 °C, NaH (9.76 mg, 60% Wt, 1.5 Eq, 244 μmol) was added and the reaction was left to stir for 15 min. After this time iodomethane (24.3 mg, 10.6 μL, 1.05 Eq, 171 μmol) was added, and the mixture was allowed to warm to r.t. and stirred for 1 hour. The reaction mixture was cooled and loaded onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% [3:1 EtOAc:EtOH]: EtOAc) to afford 4-chloro-5-((1-(2-methoxyethyl)-1H-indol-5-yl)(methyl)amino)-2-methylpyridazin- 3(2H)-one (56.0 mg, 0.16 mmol, 97 %, 98% Purity) as a thick dark red gum.

[0998] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity (2 w% DCM).1H NMR (500 MHz, DMSO) δ 7.73 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 6.95 (dd, J = 8.7, 2.2 Hz, 1H), 6.37 (d, J = 3.1 Hz, 1H), 4.32 (t, J = 5.3 Hz, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.62 (s, 3H), 3.47 (s, 3H), 3.22 (s, 3H).

[0999] The product was analysed by LCMS (Waters Cortecs C18, 30 x 2.1 mm, 2.7μm, at 40 °C, 3 min method, 0.1% Formic acid, 5-100% MeCN / water): 4036-71-1-ms-157641, m / z 347.0 / 349.2 (M+H)+ (ES+) at 1.34 min, 98.4% purity at 260nm + / - 90nm.- 211 - EXAMPLE 77 4-chloro-2-methyl-5-[[1-(3-pyridylmethyl)indol-5-yl]amino]pyridazin-3-one (Compound 151)

[1000] Step 1: Under a nitrogen atmosphere, a solution of 5-((1H-indol-5-yl)amino)-4- chloro-2-methylpyridazin-3(2H)-one (100 mg, 1 Eq, 364 μmol) in DMF (5.00 mL) was charged with sodium hydride (32.0 mg, 60% Wt, 2.2 Eq, 801 μmol) at RT. The reaction mixture was stirred for 30 minutes, after which time 3-(bromomethyl)pyridine, HBr (92.1 mg, 1 Eq, 364 μmol) was added. The reaction was stirred at RT for 18 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organics were washed with brine (2 x 20 mL), dried over MgSO4and concentrated in vacuo to give a crude residue that was purified by normal phase column chromatography (Companion, 24 g, Eluent: 0-100% 3:1 ethyl acetate:EtOH in ethyl acetate) to give 4-chloro-2-methyl-5- ((1-(pyridin-3-ylmethyl)-1H-indol-5-yl)amino)pyridazin-3(2H)-one (10.0 mg, 26.1 μmol, 7.17 %, 95.50% Purity) as an orange solid.

[1001] LCMS (Agilent, Cortecs C18+, 90Å, 2.7 µm, 2.1 mm x 30 mm, Acidic (0.1% Formic acid), 3 min method, 2-100% MeCN / water): 4094-003-1, m / z 366.0 / 368.0 (M+H)+ (ES+), at 0.91 min, 96% purity, 254 nm absorbance.

[1002] 1H NMR in DMSO-d6 was consistent with product structure at >96% purity. DMF (~3.5 wt%) observed as the main NMR impurity.

[1003] 1H NMR (500 MHz, DMSO) δ 8.61 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 7.60 (dd, J = 7.6, 2.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 3.9 Hz, 2H), 7.34 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.03 (dd, J = 8.7, 2.1 Hz, 1H), 6.51 (dd, J = 3.2, 0.8 Hz, 1H), 5.49 (s, 2H), 3.58 (s, 3H).- 212 - EXAMPLE 78 5-[(1,4-dimethylindol-5-yl)amino]-2,4-dimethyl-pyridazin-3-one (Compound 152)

[1004] Step 1: To a solution of 1,4-dimethyl-5-nitro-1H-indole (157 mg, 98% Wt, 1 Eq, 809 μmol) in a mixture of Methanol (5.00 mL) and THF (4.00 mL), Pd / C (Type 87) (172 mg, 5% Wt, 0.1 Eq, 80.9 μmol) was added. The mixture was hydrogenated under 1 bar of hydrogen for 4 hours. The mixture was filtered, washed with MeOH (5 ml) and the filtrate was concentrated in vacuo to afford 1,4-dimethyl-1H-indol-5-amine (123 mg, 0.74 mmol, 91 %, 96% Purity) as a dark red gum.

[1005] 1H NMR in DMSO-d6 was consistent with product structure at 96% purity (baseline impurities).1H NMR (500 MHz, DMSO) δ 7.08 (d, J = 3.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 6.21 (d, J = 3.1 Hz, 1H), 4.38 (s, 2H), 3.66 (s, 3H), 2.18 (s, 3H).

[1006] The product was analysed by UPLC (CSH C18 Column, 130Å, 1.7 µm, 2.1 x 30 mm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-72 cr, m / z 161.1 (M+H)+ (ES+) at 0.26 min, 99.0% purity 210-400nm.

[1007] Step 2: To a solution of 1,4-dimethyl-1H-indol-5-amine (40.4 mg, 96% Wt, 1 Eq, 242 μmol), 5-chloro-2,4-dimethylpyridazin-3(2H)-one (40.0 mg, 96% Wt, 1 Eq, 242 μmol) in 1,4-Dioxane (3.00 mL), BrettPhos Pd G3 (21.9 mg, 0.1 Eq, 24.2 μmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (13.0 mg, 0.1 Eq, 24.2 μmol) and NaOtBu (34.9 mg, 1.5 Eq, 363 μmol) were added. The mixture was sparged (Bubbling N2with sonication for 2 min) then stirred at 100 °C for 1 hour. The reaction was cooled and dry loaded onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% [3:1 Ethyl acetate: Ethanol] : Ethyl acetate) eluting at 10% to afford 5-((1,4-dimethyl-1H-indol-5-yl)amino)-2,4- dimethylpyridazin-3(2H)-one (42.0 mg, 0.14 mmol, 60 %, 97% Purity) as a light cream solid.

[1008] 1H NMR in DMSO-d6 was consistent with product structure at 97% purity (2.2w% DCM).1H NMR (500 MHz, DMSO) δ 7.77 (s, 1H), 7.35 (d, J = 3.1 Hz, 1H), 7.32 (d, J =- 213 - 8.4 Hz, 1H), 6.98 – 6.93 (m, 2H), 6.49 (dd, J = 3.1, 0.8 Hz, 1H), 3.80 (s, 3H), 3.51 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H).

[1009] The product was analysed by LCMS (Waters Cortecs C18, 30 x 2.1 mm, 2.7μm, at 40 °C, 3 min method, 0.1% Formic acid, 5-100% MeCN / water): 4036-74-1-ms-258104, m / z 283.2 (M+H)+ (ES+) at 1.27 min, 98.1% purity at 260nm + / - 90nm. EXAMPLE 79 2,4-dimethyl-5-[(4-methyl-1H-indol-5-yl)amino]pyridazin-3-one (Compound 153)

[1010] Step 1: To a solution of 4-methyl-5-nitro-1H-indole (150 mg, 1 Eq, 851 μmol) in a mixture of Methanol (5.00 mL) and THF (4.00 mL), Pd / C (Type 39A) (181 mg, 5% Wt, 0.1 Eq, 85.1 μmol) was added. The mixture was hydrogenated under 1 bar of hydrogen for 3 hours. The mixture was filtered, rinsed with MeOH (5 ml) and the filtrate was concentrated in vacuo to afford 4-methyl-1H-indol-5-amine (119 mg, 0.80 mmol, 94 %, 98% Purity) as a brown solid.

[1011] 1H NMR in DMSO-d6 was consistent with product structure at 98% purity (baseline impurities).1H NMR (500 MHz, DMSO) δ 10.56 (s, 1H), 7.11 (t, J = 2.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.25 – 6.20 (m, 1H), 4.41 (s, 2H), 2.18 (s, 3H).

[1012] The product was analysed by UPLC (CSH C18 Column, 130Å, 1.7 µm, 2.1 x 30 mm, 3 min method, 0.1% Formic acid, 2-100% MeCN / water):4036-73 cr57688, m / z 147.0 (M+H)+ (ES+) at 0.08 min, 98.9% purity 210-400nm.

[1013] Step 2: To a solution of 4-methyl-1H-indol-5-amine (36.1 mg, 98% Wt, 1 Eq, 242 μmol), 5-chloro-2,4-dimethylpyridazin-3(2H)-one (40.0 mg, 96% Wt, 1 Eq, 242 μmol) in 1,4-Dioxane (3.00 mL), BrettPhos Pd G3 (21.9 mg, 0.1 Eq, 24.2 μmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (13.0 mg, 0.1 Eq, 24.2 μmol) and NaOtBu (34.9 mg, 1.5 Eq, 363 μmol) were added. The mixture was sparged (Bubbling N2 with sonication for 2 min) then stirred at 100 °C for 1.5 hour. The reaction was cooled and dry loaded onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% [3:1 Ethyl acetate: Ethanol] : Ethyl acetate) to afford the desired product with low purity. The residue was purified by- 214 - chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 2,4-dimethyl-5-((4-methyl-1H-indol-5-yl)amino)pyridazin- 3(2H)-one, 0.35Formic Acid (24.0 mg, 84 μmol, 34 %, 99% Purity) as a light cream solid.

[1014] 1H NMR in DMSO-d6 was consistent with product structure at 99% purity. 1H NMR (500 MHz, DMSO) δ 11.17 (s, 1H), 8.23 (s, 0.35H), 7.75 (s, 1H), 7.39 – 7.34 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.52 – 6.47 (m, 1H), 3.51 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H). Note: Product is a partial formate salt; 2 protons are exchanging.

[1015] The product was analysed by LCMS (Waters Cortecs C18, 30 x 2.1 mm, 2.7μm, at 40 °C, 3 min method, 0.1% Formic acid, 5-100% MeCN / water): 4036-75-1-ms-258021, m / z 269.2 (M+H)+ (ES+) at 1.08 min, 99.2% purity at 260nm + / - 90nm. EXAMPLE 80 5-[[1-(1,5-dimethyl-6-oxo-pyridazin-4-yl)-4-methyl-indol-5-yl]amino]-2,4-dimethyl-pyridazin-3- one (Compound 154)

[1016] Step 1: To a solution of 4-methyl-1H-indol-5-amine (36.1 mg, 98% Wt, 1 Eq, 242 μmol), 5-chloro-2,4-dimethylpyridazin-3(2H)-one (40.0 mg, 96% Wt, 1 Eq, 242 μmol) in 1,4-Dioxane (3.00 mL), BrettPhos Pd G3 (21.9 mg, 0.1 Eq, 24.2 μmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (13.0 mg, 0.1 Eq, 24.2 μmol) and NaOtBu (34.9 mg, 1.5 Eq, 363 μmol) were added. The mixture was sparged (Bubbling N2with sonication for 2 min) then stirred at 100 °C for 1.5 hour. The reaction was cooled and dry loaded onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% [3:1 Ethyl acetate: Ethanol] : Ethyl acetate) to afford the desired product with low purity. The residue was purified by chromatography on RP Flash C18 (12 g cartridge, 10-100% [0.1% formic acid MeCN] : 0.1% aq formic acid) to afford 5-((1-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)-4-- 215 - methyl-1H-indol-5-yl)amino)-2,4-dimethylpyridazin-3(2H)-one (9.00 mg, 22 μmol, 8.8 %, 96% Purity) as a light tan solid.

[1017] 1H NMR in DMSO-d6 was consistent with product structure at 96% purity. 1H NMR (500 MHz, DMSO) δ 8.05 (s, 1H), 7.80 (s, 1H), 7.62 (d, J = 3.3 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.04 – 6.99 (m, 2H), 6.87 (d, J = 3.3 Hz, 1H), 3.75 (s, 3H), 3.52 (s, 3H), 2.38 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H).

[1018] The product was analysed by LCMS (Waters Cortecs C18, 30 x 2.1 mm, 2.7μm, at 40 °C, 3 min method, 0.1% Formic acid, 5-100% MeCN / water): :4036-75-2-ms-258105, m / z 391.2 (M+H)+ (ES+) at 1.23 min, 96.5% purity at 260nm + / - 90nm. EXAMPLE 81 5-[[1-(2-methoxyethyl)indol-5-yl]amino]-1,6-dimethyl-pyridazin-4-one (Compound 155)

[1019] Step 1: To a stirred solution of 4,5-dichloro-2-methylpyridazin-3(2H)-one (1.00 g, 1 Eq, 5.59 mmol) in dry THF (20.00 mL) under a nitrogen atmosphere at 0 °C was added methylmagnesium bromide 3M in Et2O (933 mg, 2.61 mL, 3.00 molar, 1.4 Eq, 7.82 mmol) by dropwise addition. The reaction mixture was stirred at this temperature for 10 min before being allowed to warm to...

Claims

1. - 479 - WHAT IS CLAIMED IS:

1. A compound having Formula (I):or a salt or solvate thereof, wherein: Ring A is selected from optionally substituted C6-C10 aryl, optionally substituted 5- or 6- membered heterocyclo, and optionally substituted 5- or 6-memberered heteroaryl; each is a single or a double bond consistent with the valences of X7, X8, and X9; X5is selected from a bond, -NR16- and -O-; X7is selected from -N- and -NR19-; X8is selected from -N-, -NR20-, and -CR8aR8b-; X9is selected from -N-, -NR25, CR9aR9b, and -C(=O)-; R8aand R9aare each independently selected from hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, -C(=O)OR25, and -C(=O)NR26R27; R8band R9bare each independently absent or are selected from hydrogen and optionally substituted C1-C6 alkyl; R16is selected from hydrogen and optionally substituted C1-C6 alkyl; R19is selected from hydrogen, optionally substituted C1-C6alkyl, -C(=O)R19a, -C(=O)OR19a, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl; R19ais selected from hydrogen and C1-C6alkyl; R20is selected from hydrogen and C1-C6 alkyl; R21is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, and C2-C6alkenyl; R22is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted C6- C10aryl;- 480 - R23is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6alkyl, and C2-C6 alkenyl; R24is selected from hydrogen, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, C2-C6alkenyl, optionally substituted 5- or 6-membered heterocyclo, and optionally substituted C6- C10 aryl; one of R21, R22, R23, and R24is absent; R25is selected from hydrogen and C1-C6alkyl; and R26and R27are each independently selected from hydrogen and C1-C6alkyl. The compound of claim 1, having formula (I-A):(I-A), wherein: X6is selected from -N- and -CH-; R17is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy- C1-C6alkyl-, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6- membered heteroaryl; and R18is selected from hydrogen, halo, optionally substituted C1-C6alkyl, and C2-C3alkynyl.

3. The compound of claim 1 or 2 having Formula (I-B):or a salt or solvate thereof, wherein: each is a single or a double bond consistent with the valences of X7and X8; X5is selected from -NR16- and -O-; X7is selected from -N- and -NR19-; X8is selected from -N-, -NR20-, and -CH-;- 481 - R16is selected from hydrogen and optionally substituted C1-C6alkyl; R19is selected from hydrogen, optionally substituted C1-C6 alkyl, -C(=O)R19a, -C(=O)OR19a, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo; R19ais selected from hydrogen and C1-C6 alkyl; and R20is selected from hydrogen and C1-C6 alkyl; wherein when X5is -NH-, X6is -N-, R18is chloro, X7is -NR19-, and X8is -N-, R19is not 2-methoxyethyl.

4. The compound of claim 3, having Formula (I-C):

5. The compound of claim 3, having Formula (I-D):

6. The compound of claim 3, having Formula (I-E):

7. The compound of claim 3, having Formula (I-F):(I-F).- 482 - 8. The compound of claim 3, having Formula (I-G):

9. The compound of claim 3, having Formula (I-H):(I-H).

10. The compound of claim 3, having Formula (I-I):(I-I).

11. The compound of claim 1, having Formula (I-J):(I-J), wherein R22is selected from optionally substituted 5- or 6-membered heterocyclo and optionally substituted C6-C10 aryl.

12. The compound of any one of claims 1-11, wherein X5is -NR16-.

13. The compound of claim 12, wherein R16is hydrogen, methyl, or cyclopropylmethyl.- 483 - 14. The compound of claim 13, wherein R16is hydrogen.

15. The compound of any one of claims 1-11, wherein X5is -O-.

16. The compound of any one of claims 2-10, wherein X6is -N-.

17. The compound of any one of claims 2-10, wherein R17is hydrogen or methyl.

18. The compound of claim 17, wherein R17is methyl.

19. The compound of any one of claims 2-10, wherein R17is optionally substituted C1-C6alkyl.

20. The compound of any one of claims 2-10 and 19, wherein R17is C1-C6 alkyl substituted with amino, hydroxy, C1-C6alkoxy, -C(=O)R18a, -C(=O)OR18a, or C3-C7cycloalkyl, wherein R18ais selected from hydrogen and C1-C6 alkyl.

21. The compound of claim 20, wherein R17is:

22. The compound of any one of claims 2-10, wherein R17is optionally substituted 5- or 6- membered heterocyclo or optionally substituted 5- or 6-membered heteroaryl.

23. The compound of claim 22, wherein R17is:.

24. The compound of any one of claims 2-10, wherein R18is hydrogen, methyl, or chloro.

25. The compound of claim 24, wherein R18is methyl.- 484 - 26. The compound of any one of claims 2-25, wherein R19is hydrogen or methyl.

27. The compound of claim 26, wherein R19is hydrogen.

28. The compound of any one of claims 2-25, wherein R19is -C(=O)CH3 or -C(=O)OC(CH3)3.

29. The compound of any one of claims 2-25, wherein R19is optionally substituted C1-C6alkyl.

30. The compound of any one of claims 2-25 or 29, wherein R19is C1-C6 alkyl substituted with amino, hydroxy, C1-C6alkoxy, C3-C7cycloalkyl, optionally substituted 5- or 6 membered heterocyclo, -OC(=O)R19b, or -C(=O)NR19bR19c, wherein R19band R19care each independently selected from hydrogen and C1-C6 alkyl.

31. The compound of claim 30, wherein R19is:.

32. The compound of claim 31, wherein R19is:.- 485 - 33. The compound of any one of claims 2-25, wherein R19is optionally substituted 5- or 6 membered heterocyclo.

34. The compound of claim 33, wherein R19is:

35. The compound of claim 34, wherein R19is:.

36. The compound of claim 6, wherein R20is hydrogen or methyl.

37. The compound of any one of claims 2-36, wherein R21is hydrogen.

38. The compound of any one of claims 2-37, wherein R22is hydrogen or halo.

39. The compound of claim 38, wherein R22is chloro.

40. The compound of any one of claims 2-39, wherein R23is hydrogen or halo.

41. The compound of claim 40, wherein R23is chloro.

42. The compound of any one of claims 2-41, wherein R24is hydrogen, halo, or optionally substituted phenyl.

43. The compound of claim 42, wherein R24is chloro.- 486 - 44. The compound of claim 42, wherein R24is 3-hydroxyphenyl.

45. The compound of claim 1, selected from the group consisting of the compounds listed in Table 1.

46. The compound of claim 1, selected from the group consisting of: ,47. The compound of claim 1, selected from the group consisting of:- 487 -- 488 -- 489 -- 490 -48. The compound of claim 1, selected from the group consisting of:- 491 -- 492 -- 493 -- 494 -- 495 -- 496 - , , ,- 497 -49. A compound having Formula (II):or a salt or solvate thereof, wherein: X1is absent or is selected from -NR1a-, -^(CH2)n-NR1a-, and -^NR1a-(CH2)n-, wherein the bond marked with a “^” is attached to R1; n is selected from 1, 2, 3, and 4; R1ais selected from hydrogen and optionally substituted C1-C6 alkyl; R1is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy- C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6- membered heteroaryl; R2is selected from hydrogen, optionally substituted C1-C6alkyl, optionally substituted C3- C7 cycloalkyl, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6- membered heteroaryl; R3is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C3-C7 cycloalkyl; X10is selected from -NR6- and -O-; R6is selected from hydrogen, optionally substituted C1-C4alkyl, and optionally substituted 5- to 10-membered heteroaryl;- 498 - X11is selected from -N- and -CR11x; X12is selected from -N- and -CR12x; X13is selected from -N- and -CR13x; X14is selected from -N- and -CR14x; with the proviso that no more than two of X11, X12, X13, and X14are -N-; and R11x, R12x, R13x, and R14xare each independently selected from hydrogen, halo, C1-C4 alkyl, optionally substituted C3-C7cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

50. The compound of claim 49, having Formula (II-A):(II-A), or a salt or solvate thereof, wherein: R4is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C3-C7 cycloalkyl; R5is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C3-C7cycloalkyl; Y1is selected from -NR7- and -O-; and R7is selected from hydrogen and C1-C4 alkyl; wherein when X1is absent, R2is methyl, R3is hydrogen, R4is methyl, R5is methyl, and Y1is -O-, R1is not:- 499 - 51. The compound of claim 49, having Formula (II-B):(II-B), wherein: R14xis selected from optionally substituted 5- or 6-membered aryl and optionally substituted 5- or 6-membered heteroaryl; X15is selected from -N- and -CH-; R28is selected from hydrogen, halo, optionally substituted C1-C6 alkyl, and C2-C3 alkynyl; and R29is selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy- C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6- membered heteroaryl.

52. The compound of claim 49, wherein: R1ais selected from hydrogen and C1-C6alkyl; R1is selected from C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl-, optionally substituted C3-C7 cycloalkyl, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6- membered aryl, and optionally substituted 5- or 6-membered heteroaryl; R2is selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, 5- or 6-membered aryl, and 5- or 6-membered heteroaryl; R3is selected from hydrogen, C1-C6alkyl, and C3-C7cycloalkyl; R4is selected from hydrogen, C1-C6alkyl, and C3-C7cycloalkyl; and R5is selected from hydrogen, C1-C6 alkyl, and C3-C7 cycloalkyl.

53. The compound of claim 49 or 50, wherein X1is absent.- 500 - 54. The compound of claim 49 or 50, wherein R1is selected from C1-C6alkoxy-C1-C6alkyl-, optionally substituted 5- or 6-membered heterocyclo, optionally substituted 5- or 6-membered aryl, and optionally substituted 5- or 6-membered heteroaryl.

55. The compound of claim 54, wherein R1is selected from:wherein R1bis selected from hydrogen, C1-C4alkyl, -C(=O)O(CH3)3, and -C(=O)CH3.

56. The compound of claim 49 or 50, wherein X1is -NR1a-.

57. The compound of claim 56, wherein R1ais selected from hydrogen and methyl.

58. The compound of claim 56 or 57, wherein R1is selected from:

59. The compound of claim 49 or 50, wherein X1is -^NR1a-(CH2)n-.

60. The compound of claim 59, wherein R1ais selected from hydrogen and methyl.

61. The compound of claim 59 or 60, wherein n is 1.

62. The compound of any one of claims 59-61, wherein R1is:- 501 -.

63. The compound of any one of claims 49-62, wherein R2is C1-C6 alkyl.

64. The compound of any one of claims 49-62, wherein R2is methyl, ethyl, or isopropyl.

65. The compound of any one of claims 49-62, wherein R2is phenyl.

66. The compound of any one of claims 49-62, wherein R3is hydrogen.

67. The compound of any one of claims 49-62, wherein R4is C1-C6alkyl.

68. The compound of any one of claims 50-67, wherein R4is methyl.

69. The compound of any one of claims 50-68, wherein R5is C1-C6alkyl.

70. The compound of any one of claims 50-69, wherein R5is methyl.

71. The compound of any one of claims 50-70, wherein Y1is -O-.

72. The compound of any one of claims 50-71, wherein Y1is -NR7-.

73. The compound of claim 72, wherein R7is hydrogen or methyl.

74. The compound of any one of claims 49-73, wherein R6is hydrogen or methyl.

75. The compound of claim 49, wherein the compound is selected from the group consisting of the compounds listed in Table 2.

76. The compound of claim 49, selected from the group consisting of:- 502 -77. A pharmaceutical composition comprising the compound of any one of claims 1-76, and a pharmaceutically acceptable excipient.- 503 - 78. A method of promoting thymus regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-76 or the pharmaceutical composition of claim 77.

79. The method of claim 78, wherein the subject is in need of thymus regeneration due to hematopoietic stem cell transplantation, immune deficiency due to HIV, HIV therapy, autoimmune disease, inborn errors of thymic development, administration of a vaccine, age-related immune senescence, administration of exogenous glucocorticoids, bacterial or viral infections, radiation, immunotherapy, or cytoreductive treatments, zinc deficiency, thymus involution, or a combination thereof.

80. A method of promoting immune reconstitution in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-76 or the pharmaceutical composition of claim 78.

81. The method of claim 80, wherein the subject is in need of immune reconstitution due to hematopoietic stem cell transplantation, immune deficiency due to HIV, HIV therapy, autoimmune disease, inborn errors of thymic development, administration of a vaccine, age-related immune senescence, administration of exogenous glucocorticoids, bacterial or viral infections, radiation, immunotherapy, or cytoreductive treatments, zinc deficiency, thymus involution, or a combination thereof.

82. A method of activating FOXN1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-76 or the pharmaceutical composition of claim 77.

83. The method of claim 82, wherein the subject is in need of FOXN1 activation due to hematopoietic stem cell transplantation, immune deficiency due to HIV, HIV therapy, autoimmune disease, inborn errors of thymic development, administration of a vaccine, age-related immune senescence, administration of exogenous glucocorticoids, bacterial or viral infections, radiation, immunotherapy, or cytoreductive treatments, zinc deficiency, thymus involution, diabetes-related ulcers, foot ulcers, chronic wounds, alopecia, or a combination thereof.- 504 - 84. A method of promoting skin wound healing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-76 or the pharmaceutical composition of claim 77.

85. The method of claim 84, wherein the subject has a diabetes-related ulcer, a foot ulcer, a chronic wound, or a combination thereof.

86. A method of augmenting hair growth, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-76 or the pharmaceutical composition of claim 77.

87. The method of claim 86, wherein the subject has alopecia.

88. A method of enhancing immune function or promoting thymic regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77, wherein the subject is in need of immune function enhancement or thymic regeneration due to administration of CAR-T cells or other adoptive T-cell therapies, recovery from sepsis or critical illness, idiopathic T-cell lymphopenia, immunosuppression following solid organ transplantation, or a combination thereof.

89. The method of claim 88, wherein the subject is at risk of or recovering from infection due to impaired T-cell function.

90. The method of claim 89, wherein the subject is an elderly individual, an immunocompromised patient, a recipient of immunosuppressive therapy, or a combination thereof.

91. A method of promoting immune tolerance or reducing transplant-related complications in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77, wherein the subject is receiving a hematopoietic stem cell transplant or solid organ transplant.- 505 - 92. The method of claim 91, wherein the method reduces the risk of graft-versus-host disease (GVHD).

93. The method of claim 91, wherein the method enhances immune reconstitution.

94. A method of treating or supporting recovery from a thymic epithelial tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77, wherein the subject has a thymoma or thymic carcinoma.

95. A method of promoting immune surveillance or reducing cancer risk in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77, wherein the subject has an age-related decline in immune function, a personal or familial history of cancer, or a genetic predisposition to immune dysfunction.

96. A method of augmenting hair growth or restoring hair loss in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77, wherein the hair loss is chemotherapy-induced, radiation-induced, or idiopathic in origin.

97. A method of promoting skin repair or regeneration in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77, wherein the subject has a radiation- induced skin injury, a surgical wound, or age-related skin atrophy.

98. A method of promoting dermal regeneration or treating skin aging in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77.- 506 - 99. A method of preconditioning a non-human donor organism for xenotransplantation of a composite organ comprising thymic tissue, comprising administering to the donor a therapeutically effective amount of the compound of any one of claims 1–76 or the pharmaceutical composition of claim 77, wherein the method improves thymic tissue function, promotes immune system development, or enhances compatibility of the graft with the recipient immune system.

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