compounds

Abstract

The present disclosure relates generally to compounds, their methods of synthesis, and their use in the treatment of mental illness or central nervous system disorders.

Description

[0001] Compounds

[0002] Field of the invention

[0003] The present disclosure relates generally to novel compounds, their methods of synthesis, and their use in the treatment of mental illness or central nervous system disorders.

[0004] Background of the invention

[0005] Mental illness covers many neuropsychiatric disorders which cause enormous burden to the lives of their sufferers. Diagnoses such as treatment resistant depression, major depressive disorder, eating disorders, substance abuse disorders, post-traumatic stress disorder, obsessive compulsive disorder, attention deficit disorders, schizophrenia, and others can cause such devastating symptoms that many sufferers lose the capability of leading a normal life.

[0006] A variety of serotonergic drugs such as antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and others are commercially available to treat mental illnesses. Unfortunately, in many indications, these therapeutics provide limited benefit when compared to a placebo. Additionally, these therapeutics can result in a wide range of side effects including loss of libido, insomnia, fatigue, weight gain, and others. In spite of their limited efficacy, these drugs continue to be used to treat neuropsychiatric conditions as well as a broad range of auxiliary medical indications. There have been limited advances in new treatment options since many of these drugs were released, and the pharmaceutical industry has come under increased financial pressure to de-emphasise neuroscience programmes entirely. The unmet need for more efficacious mental health treatment is on the rise, and the global COVID-19 pandemic is likely to increase disease burden around the world.

[0007] In the 1950s and 1960s, the use of psychedelic drugs to treat various mental illnesses was extensively explored, and these substances showed promise as treatments for many diseases of the central nervous system (CNS). Following decades of prohibition, scientific research into the application of psychedelics as treatments for mental illnesses has been gaining momentum. The serotonergic psychedelic agent psilocybin has been designated a Breakthrough Therapy by the FDA for the treatment of major depressive 1006352981disorder (2019) and treatment-resistant depression (2018). Psilocybin is the prodrug compound produced by many species of mushrooms known collectively as psilocybin mushrooms or “magic mushrooms”. Psilocybin is rapidly metabolized to the bioactive compound psilocin, which produces a state of altered consciousness including changes in perception, visual hallucinations, and distorted sense of space, time, and self. Many patients report spiritual or “mystical” experiences which have profound and lasting impact on the patients’ mood and behaviour. Psilocybin has shown promise in more than 50 clinical trials for neuropsychiatric indications, including numerous anxiety disorders, obsessive-compulsive disorder, anorexia nervosa, alcohol dependence, and tobacco addiction. Psilocybin and other psychedelic compounds such as / V, / V-dimethyltryptamine (DMT) and 5-methoxy- / V, / V-dimethyltryptamine (5-MeO-DMT) have both immediate and persistent effects on mental state, with the latter extending far beyond the duration of action, possibly as a result of their ability to incite increased neuroplasticity, promote neural outgrowth, and increase spine density of the synaptic neurons in the brain.

[0008] To date, psilocybin remains classified as a controlled substance and / or drug of abuse in most countries under national drug laws. However, clinical investigations have recently led to increased awareness of the potential for psychedelic drugs as breakthrough therapies to treat CNS diseases of enormous unmet medical need.

[0009] Despite its therapeutic potential, psilocybin and other psychedelics remain scheduled drugs of abuse in most countries and the commercial path to market for these drugs as medicines is uncertain. As an adjunct to psychotherapy, the long duration of action of psilocybin and LSD make treatment sessions costly and impractical for broad implementation. In spite of a long history of safe human use, several adverse events have been reported in clinical trials, and it is possible that these may be attributed to signalling bias at 5-HT2A (the primary target) or off-target activity at, for example, 5-HT2B receptors (a cardiac liability antitarget) or 5-HT1A (an anxiolytic target) or 5-HT2C receptors (a disease-relevant target for obesity and some genetic epilepsies, for example). Naturally-occurring psychedelics provide important lead structures for a new generation of neurotherapeutic agents with novel mechanisms of action and / or superior clinical efficacy to currently available neuropsychiatric medications.

[0010] In view of the foregoing there is an ongoing need to develop new compounds which may be useful in the treatment of mental illness or central nervous system disorders.

[0011] 1006352981Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art.

[0012] Summary of the invention

[0013] In one aspect the present disclosure provides compounds of formula (I):

[0014]

[0015] wherein

[0016] A is a 4-14 membered heterocyclyl optionally substituted with one or more substituents selected from: halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR4;

[0017] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5,

[0018] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0019] 1006352981said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5;

[0020] each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0021] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3;

[0022] R6is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyleneP(O)(OR12)2, C(O)R12, CO2R12, C(O)N(R12)2, S(O)R12and SO2R12, C3-6 cycloalkyl, C6-9 alkylenecycloalkyl, C3-6 heterocyclyl, C6-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl,

[0023] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-9 alkylenecycloalkyl, C3-6 heterocyclyl, C6-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R12, C(O)N(R12)2, OR12, N(R12)2, NO2, SR12and SO2R12,

[0024] said C3-6 cycloalkyl, C6-9 alkylenecycloalkyl, C3-6 heterocyclyl, C6-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being further optionally substituted with a substituent independently selected from (O),

[0025] 1006352981C1-6 alkyl, C1-6haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR12;

[0026] each R12is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,

[0027] said C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3;

[0028] R9is independently selected from halogen, CN, OR13, N(R13)2, SR13, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R13, C(O)R13, C(O)N(R13)2, C(O)C(O)N(R13)2, OC(O)R13, OC(O)OR13, OC(O)N(R13)2, OS(O)R13, OS(O)N(R13)2, OSO2R13, OP(O)(OR13)2, OCi-6alkyleneP(O)(OR13)2, S(O)R13, S(O)N(R13)2, SO2R13, N(R13)2, N(R13)C(O)R13, N(R13)C(O)OR13, N(R13)C(O)N(R13)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,

[0029] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R13, C(O)N(R13)2, OR13, N(R13)2, NO2, SR13and SO2R13,

[0030] 1006352981said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR13;

[0031] each R13is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,

[0032] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3;

[0033] R10is independently selected from H, halogen, CN, OR14, N(R14)2, SR14, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R14, C(O)R14, C(O)N(R14)2, C(O)C(O)N(R14)2, OC(O)R14, OC(O)OR14, OC(O)N(R14)2, OS(O)R14, OS(O)N(R14)2, OSO2R14, OP(O)(OR14)2, OCi-6alkyleneP(O)(OR14)2, S(O)R14, S(O)N(R14)2, SO2R14, N(R14)2, N(R14)C(O)R14, N(R14)C(O)OR14, N(R14)C(O)N(R14)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,

[0034] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from

[0035] 1006352981halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R14, C(O)N(R14)2, OR14, N(R14)2, NO2, SR14and SO2R14,

[0036] said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR14;

[0037] each R14is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,

[0038] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3;

[0039] wherein one of R9and R10is H and the other one of R9and R10is not H.

[0040] Any compound described herein may be provided in a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0041] In embodiments, the compound may be any of compounds S11 to S26, S37 to S46, S57 to S66 and S72 to S132.

[0042] In another aspect, the present disclosure provides a medicament comprising a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

[0043] 1006352981In another aspect the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, and / or a pharmaceutically acceptable excipient.

[0044] In another aspect the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.

[0045] In another aspect the present disclosure provides a method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, a medicament according to any one of the herein disclosed embodiments or a pharmaceutical composition according to any one of the herein disclosed embodiments. In another aspect the present disclosure provides a method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, in combination with another known agent useful for treatment of a disease, disorder or condition by activation of a serotonin receptor.

[0046] In another aspect the present disclosure provides a method of treating a mental illness, the method comprising administering to a subject in need thereof a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, a medicament according to any one of the herein disclosed embodiments or a pharmaceutical composition according to any one of the herein disclosed embodiments.

[0047] 1006352981In another aspect the present disclosure provides a method for treating a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition, the method comprising administering to a subject in need thereof a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, a medicament according to any one of the herein disclosed embodiments or a pharmaceutical composition according to any one of the herein disclosed embodiments.

[0048] In another aspect the present disclosure provides a method for increasing neuronal plasticity and / or increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, a medicament according to any one of the herein disclosed embodiments or a pharmaceutical composition according to any one of the herein disclosed embodiments, in an amount sufficient to increase neuronal plasticity and / or increase dendritic spine density of the neuronal cell.

[0049] In another aspect the present disclosure provides methods of treating weight, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, a medicament according to any one of the herein disclosed embodiments or a pharmaceutical composition according to any one of the herein disclosed embodiments.

[0050] In a further aspect, the present disclosure provides use of a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, in the preparation of a medicament for any one or more of the following:

[0051] • treating a disease, disorder or condition by activation of a serotonin receptor; and / or

[0052] treating a mental illness; and / or

[0053] 1006352981treating a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition; and / or

[0054] • increasing neuronal plasticity and / or increasing dendritic spine density; and / or

[0055] • treating weight.

[0056] In a further aspect, the present disclosure provides use of a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof for any one or more of the following:

[0057] • treating a disease, disorder or condition by activation of a serotonin receptor; and / or

[0058] • treating a mental illness; and / or

[0059] • treating a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition; and / or

[0060] • increasing neuronal plasticity and / or increasing dendritic spine density; and / or

[0061] • treating weight.

[0062] In a further aspect, the present disclosure provides a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof for the use in any one or more of the following:

[0063] • treating a disease, disorder or condition by activation of a serotonin receptor; and / or

[0064] • treating a mental illness; and / or

[0065] • treating a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition; and / or

[0066] • increasing neuronal plasticity and / or increasing dendritic spine density; and / or

[0067] treating weight.

[0068] 1006352981In a further aspect, the present disclosure provides a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof for the use as a medicament.

[0069] In another aspect the present disclosure provides a method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, comprising administering to the cell a compound of formula (I) as defined in any one of the herein disclosed embodiments. In embodiments, the method may be in vitro or ex vivo.

[0070] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only.

[0071] Functionally-equivalent products, compositions and methods are clearly within the scope of the invention, as described herein.

[0072] Detailed description of the embodiments

[0073] Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise. Accordingly, it will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0074] Definitions

[0075] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0076] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0077] The terms "treatment" or "treating" of a subject includes delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the sign or symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition. The term "treating" refers to any indication of success in the treatment or amelioration of an injury,

[0078] 1006352981pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of signs or symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating.

[0079] In particularly preferred embodiments, the methods of the present invention can be to prevent or reduce the severity, or inhibit or minimise progression, of a sign or symptom of a disease or condition as described herein. As such, the methods of the present invention have utility as treatments as well as prophylaxes.

[0080] As used herein, "preventing" or "prevention" is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder (i.e., causing at least one of the clinical signs or symptoms of the disease not to develop in an individual that may be exposed to or predisposed to the disease but does not yet experience or display signs or symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians.

[0081] Herein, the term “subject” or “patient" can be used interchangeably with each other. The term “individual” or “patient” refers to an animal that is treatable by the compound and / or method, respectively, including but not limited to, for example, dogs, cats, horses, sheep, pigs, cows, and the like, as well as human and non-human primates. Unless otherwise specified, the “subject” or “patient” may include both male and female genders. Further, it also includes a subject or patient, preferably a human, suitable for receiving treatment with a pharmaceutical composition and / or method of the present invention.

[0082] The term "selective" means a greater activity against a first target (e.g., a 5-HT receptor subtype) relative to a second target (e.g., a second 5-HT receptor subtype). In some embodiments a compound has a selectivity of at least 1.25-fold, at least 1.5 fold, at least 2- fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold or at least 100-fold greater towards a first target relative to a second target. In some embodiments, a compound described herein is selective towards the 5-HT2A receptor relative to one or more other 5-HT receptor subtypes such as 5-HT2B and / or 5-HT2C, preferably 5-HT2B. In some embodiments, a compound described herein is selective

[0083] 1006352981towards the 5-HT2C receptor relative to one or more other 5-HT receptor subtypes such as 5-HT2A and / or 5-HT2B, preferably 5-HT2B.

[0084] " About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, in some instances ±5%, in some instances ±1%, and in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0085] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0086] As used herein the term "alkyl" refers to a straight or branched chain hydrocarbon radical having from one to twelve carbon atoms, or any range between, i.e. it contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkyl group is optionally substituted with substituents. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.

[0087] As used herein, the terms " C1-C2 alkyl", " C1-C3 alkyl" and " C-i-Ce alkyl" refer to an alkyl group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (eg alkyl groups containing 2-5 carbon atoms are also within the range of C-i-Ce).

[0088] The term “alkylene” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH2)n-, where n is 1, 2, 3, 4, 5 or 6.

[0089] 1006352981Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0090] The term “alkenyl” whether it is used alone or as part of another group, means a straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term C2-6 alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0091] Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1 -pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.

[0092] The term “alkynyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term C2-6 alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1 -butynyl, 2-butynyl, butadiynyl, 1 -pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.

[0093] The term "cycloalkyl" is intended to include mono-, bi- or tricyclic alkyl groups. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the prefix “Cni-n2”. For example, the term C3-8 cycloalkyl means an cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. In some embodiments, cycloalkyl groups have from 3 to 12, from 3 to 10, from 3 to 8, from 3 to 6, from 3 to 5 carbon atoms in the ring(s). In some embodiments, cycloalkyl groups have 5 or 6 ring carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group has from 3 to 8, from 3 to 7, from 3 to 6, from 4 to 6, from 3 to 5, or from 4 to 5 ring carbon atoms. Bi- and tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems. Examples of bi- and tricyclic ring cycloalkyl systems include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.

[0094] 1006352981The term "alkylenecycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment- The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of atachment. In some instances, the alkyl component can be absent. The alkyl component can include any number of carbons, such as Ci -e, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. The cycloalkyl component is as defined herein. The numerical range from x to y in “Cx-y alkylenecycloalkyl” relates to the total number of alkyl carbons and cycloalkyl ring atoms. Exemplary alkylenecycloalkyl groups include, but are not limited to, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl and methylenecyclohexyl.

[0095] The term “aryl” refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. The number of carbon atoms that are possible in the referenced aryl group are indicated by the prefix “Cni-n2”. For example, the term Ce-i2aryl means an aryl group having 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.

[0096] The term “alkylenearyl” refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the aryl component and to the point of attachment. The alkyl component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The aryl component is as defined above. The numerical range from x to y in “Cx-y alkylenearyl” relates to the total number of alkyl carbons and aryl ring atoms. Examples of alkylenearyl groups include, but are not limited to, benzyl and ethylenephenyl.

[0097] 1006352981As used herein, the term “alkoxy” refers to an alkyl group as defined herein covalently bound via an 0 linkage. The alkoxy group is optionally substituted with substituents. Examples of “alkoxy” as used herein include, but are not limited to methoxy, ethoxy, propoxy, isoproxy, butoxy, iso-butoxy, tert-butoxy and pentoxy.

[0098] As used herein, the terms " C1-C2 alkoxy", " C1-C3 alkoxy" and " C-i-Ce alkoxy" refer to an alkoxy group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (eg alkoxy groups containing 2-5 carbon atoms are also within the range of C-i-Ce).

[0099] As used herein, the term “alkylamine” refers to an alkyl group as defined herein having one or more amino groups. The amino groups can be primary, secondary or tertiary. The alkyl amine can be further substituted with a hydroxy group to form an aminohydroxy group. Examples of alkylamines include, but are not limited to, ethyl amine, propyl amine, isopropyl amine, ethylene diamine and ethanolamine. The amino group can link the alkyl amine to the point of attachment with the rest of the compound, be at the omega position of the alkyl group, or link together at least two carbon atoms of the alkyl group.

[0100] As used herein, the terms " C1-C2 alkylamine", " C1-C3 alkylamine" and " C-i-Ce alkylamine " refer to an alkylamine group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (e.g., alkylamine groups containing 2-5 carbon atoms are also within the range of C-i-Ce).

[0101] As used herein, the term “alkylsulfonyl” refers to an alkyl group as defined herein having one or more sulfonyl groups. The sulfonyl group can link the alkylsulfonyl to the point of attachment with the rest of the compound, be at the omega position of the alkyl group, or link together at least two carbon atoms of the alkyl group.

[0102] As used herein, the terms " C1-C2 alkylsulfonyl", " C1-C3 alkylsulfonyl" and " C-i-Ce alkylsulfonyl" refer to an alkylsulfonyl group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (e.g., alkylsulfonyl groups containing 2-5 carbon atoms are also within the range of C-i-Ce).

[0103] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus. Preferred heteroatoms include N, 0 and S, preferably N and 0.

[0104] 1006352981The term “heteromoiety" as used herein means a chemical group comprising a heteroatom. Examples of heteromoieties include 0, S, S(O), SO2, N and NH.

[0105] A "substituent" as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, ie, a compound that can be isolated, characterized and tested for biological activity.

[0106] The terms "optionally substituted" or “may be substituted” and the like, as used throughout the specification, denotes that the group may or may not be further substituted or fused (so as to form a polycyclic system), with one or more non-hydrogen substituent groups. Suitable chemically viable substituents for a particular functional group will be apparent to those skilled in the art.

[0107] Examples of substituents include but are not limited to C-i-Ce alkyl, C-i-Ce haloalkyl, C1-Ce haloalkoxy, C-i-Ce hydroxyalkyl, C3-C7 heterocyclyl, C3-C7 cycloalkyl, C-i-Ce alkoxy, C1-C6 alkylsulfanyl, C-i-Ce alkylsulfenyl, C-i-Ce alkylsulfonyl, C-i-Ce alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino, acyl, carboxy, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, ureido, C-i-Ce perfluoroalkyl. Preferably the substituents include amino, halo, C-i-Ce alkyl, amido, hydroxyl.

[0108] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term "halo" refers to the halogen radicals fluoro (-F), chloro (-CI), bromo (-Br), and iodo (-I). Preferably, ‘halo’ is fluoro or chloro.

[0109] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein in which one or more (up to all) of the available hydrogen atoms have been replacd with a halogen. In some instances, the term“perfluoro” can be used to define a compound or

[0110] 1006352981radical where all the hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1 -trifluoromethyl.

[0111] As used herein, the terms " C1-C2 haloalkyl", " C1-C3 haloalkyl" and " C-i-Ce haloalkyl" refer to a haloalkyl group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (e.g. haloalkyl groups containing 2-5 carbon atoms are also within the range of C-i-Ce).

[0112] For example a Ci haloalkyl group could be, but is not limited to, fluoromethyl, or difluoromethyl, or trifluoromethyl.

[0113] As used herein, the term “haloalkenyl” refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen. Thus, for example, “C1-6 haloalkenyl” (or “C-i-Ce haloalkenyl”) refers to a Ci to Ce linear or branched alkenyl group as defined above with one or more halogen substituents.

[0114] As used herein, the term “haloalkynyl” refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen. Thus, for example, “C1-6 haloalkynyl” (or “C-i-Ce haloalkynyl”) refers to a Ci to Ce linear or branched alkynyl group as defined above with one or more halogen substituents.

[0115] As used herein the term haloalkoxy refers to an alkoxy group as defined herein substituted with at least one halogen.

[0116] The term “amino” or “amine” refers to the group -NH2.

[0117] The term “substituted amino” or “secondary amino” refers to an amino group having a hydrogen replaced with, for example a C-i-Ce alkyl group (“C-i-Ce alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) and so on. C1-C3 alkylamino groups are preferred, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).

[0118] The term “disubstituted amino” or “tertiary amino” refers to an amino group having the two hydrogens replaced with, for example a Ci -Csalkyl group, which may be the same or different (“dialkylamino”), an aryl and alkyl group (“aryl(alkyl)amino”) and so on.

[0119] Di(Ci-C3alkyl)amino groups are preferred, such as for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2) and variations thereof (eg N(Me)(Et) and so on).

[0120] 1006352981The term “nitro” refers to the group -NO2.

[0121] The term “cyano” and “nitrile” refer to the group -CN.

[0122] The term “amido” or “amide” refers to the group -C(O)NH2.

[0123] The term “substituted amido” or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a C1-C6 alkyl group (“C1-C6 alkylamido” or “C1-Ce alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on. C1-C3 alkylamide groups are preferred, such as for example, methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt) and propylamide (-C(O)NHPr) and includes reverse amides thereof (eg NHMeC(O)-, -NHEtC(O)- and -NHPrC(O)-).

[0124] The term “disubstituted amido” or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a C-i-Cealkyl group (“di(Ci-C6alkyl)amido” or “di(Ci-C6alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on. Di(Ci-C3alkyl)amide groups are preferred, such as for example, dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2) and dipropylamide ((-C(O)NPr2) and variations thereof (eg C(O)N(Me)Et and so on) and includes reverse amides thereof.

[0125] The term “sulfonyl” refers to the group -SO2H.

[0126] The term “substituted sulfonyl” refers to a sulfonyl group having the hydrogen replaced with, for example a Ci-Ce alkyl group (“sulfonylCi-Ce alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on. Sulfonyl C1-C3 alkyl groups are preferred, such as for example, -SC Me, -SC Et and -SC Pr.

[0127] The term “sulfonylamido” or “sulfonamide” refers to the group -SO2NH2.

[0128] The term “substituted sulfonamido” or “substituted sulphonamide” refers to an sulfonylamido group having a hydrogen replaced with, for example a Ci-Ce alkyl group (“sulfonylamidoCi-Ce alkyl”), an aryl (“arylsulfonamide”), aralkyl (“aralkylsulfonamide”) and so on. SulfonylamidoC-i-Cs alkyl groups are preferred, such as for example, SC NHMe, SC NHEt and -SC NHPr and includes reverse sulfonamides thereof (e.g. -NHSO2Me, NHSO2Et and -NHSO2Pr).

[0129] The term “disubstituted sufonamido” or “disubstituted sulphonamide” refers to an sulfonylamido group having the two hydrogens replaced with, for example a Ci-Ce alkyl

[0130] 1006352981group, which may be the same or different (“sulfonylamidodi(Ci-C6 alkyl)”), an aralkyl and alkyl group (“sulfonamido(aralkyl)alkyl”) and so on. Sulfonylamidodi(Ci-C3 alkyl) groups are preferred, such as for example, -SO2NMe2, -SO2NEt2 and -SO2NPr2 and variations thereof (eg SO2N(Me)Et and so on) and includes reserve sulfonamides thereof (eg -N(Me)SO2Me and so on).

[0131] The term “sulfate” refers to the group OS(O)2OH and includes groups having the hydrogen replaced with, for example a Ci-Ce alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on. C1-C3 alkylsulfates are preferred, such as for example, OS(O)2OMe, OS(O)2OEt and OS(O)2OPr.

[0132] The term “sulfonate” refers to the group SO3H and includes groups having the hydrogen replaced with, for example a Ci-Ce alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on. C1-C3 alkylsulfonates are preferred, such as for example, SOsMe, SOsEt and SOsPr.

[0133] The term “amino acid” as herein defined refers to a moiety containing an amino group and a carboxyl group linked by at least one carbon. An amino acid may refer a natural or non-natural amino acid, preferably a natural amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, preferably the amino acid is arginine, lysine or histidine, most preferably lysine.

[0134] The term “carboxylate” or “carboxyl” refers to the group -COO- or -COOH.

[0135] The term “carbamate” or “carbomyl” refers to the group -OC(O)NH2. The carbamate may be substituted, or may be disubstituted, for example with an alkyl group such as but not limited to Ci-Ce alkyl.

[0136] The term “carbonate” refers to the group -OC(O)O- or -OC(O)OH.

[0137] The term “alkylcarbonate” as herein defined refers to a carbonate group having the hydrogen replaced with, for example a Ci-Ce alkyl group, an aryl or aralkyl group (“arylcarbonate” or “aralkylcarbonate”) and so on. COsC-i-Csalkyl groups are preferred, such as for example, methylcarbonate (COsMe), ethylcarbonate (COsEt) and propylcarbonate (COsPr).

[0138] 1006352981The term “ester” refers to a carboxyl group having the hydrogen replaced with, for example a C-i-Ce alkyl group (“carboxylC-i-Ce alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. CO2C1-C3 alkyl groups are preferred, such as for example, methylester (CC Me), ethylester (CC Et) and propylester (CC Pr) and includes reverse esters thereof (eg -0C(0)Me, -OC(O)Et and -OC(O)Pr).

[0139] The term “heterocyclyl” refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 12 ring atoms (unless otherwise specified), of which 1, 2, 3, 4 or more are ring heteroatoms, for example independently selected from 0, S and N, or ring heteromoieties, for example independently selected from 0, S, S(O), SO2, N and NH. When a heterocyclyl group contains the prefix Cni-n2 or “n1 to n2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1, 2, 3, 4 or more, of the ring atoms is replaced with a heteroatom or heteromoiety.

[0140] In this context, the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10- membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C3-10 heterocyclyl” or “3-10 membered heterocylyl”, as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples of heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.

[0141] Examples of monocyclic heterocyclyl groups include, but are not limited to, those containing one nitrogen atom such as aziridine (3-membered ring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (eg 3-pyrroline, 2,5-dihydropyrrole), 2Hpyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5-membered rings), piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), and azepine (7membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5-membered rings), piperazine (6membered ring); those containing one oxygen atom such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole (dihydrofuran) (5-membered rings), oxane (tetrahydropyran), dihydropyran, pyran (6-membered rings), oxepin (7membered ring); those containing two oxygen atoms such as dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring); those containing three oxygen atoms such as trioxane (6-membered ring); those containing one sulfur atom such as thiirane (3- 1006352981membered ring), thietane (4-membered ring), thiolane (tetrahydrothiophene) (5-membered ring), thiane (tetrahydrothiopyran) (6-membered ring), thiepane (7-membered ring); those containing one nitrogen and one oxygen atom such as tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5-membered rings), morpholine, tetrahydrooxazine, dihydrooxazine, oxazine (6-membered rings); those containing one nitrogen and one sulfur atom such as thiazoline, thiazolidine (5-membered rings), thiomorpholine (6-membered ring); those containing two nitrogen and one oxygen atom such as oxadiazine (6-membered ring); those containing one oxygen and one sulfur such as: oxathiole (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen, one oxygen and one sulfur atom such as oxathiazine (6-membered ring).

[0142] Heterocyclyls also encompass heteroaryl (aromatic heterocyclyls) and heterocycloalkyl (non-aromatic heterocyclyls). Such groups may be substituted or unsubstituted.

[0143] The term “aromatic heterocyclyl” may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”. The heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and 0. The aromatic heterocyclyl groups may comprise 1, 2, 3, 4 or more ring heteroatoms. When a heteroaryl group contains the prefix Cni-n2 or “n1 to n2” this prefix indicates the number of carbon atoms in the corresponding aryl group, in which one or more, suitably 1, 2, 3, 4 or more, of the ring atoms is replaced with a heteroatom. In the case of fused aromatic heterocyclyl groups, only one of the rings may contain a heteroatom and not all rings must be aromatic.

[0144] “Heteroaryl” is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (eg bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls. The term “pseudoaromatic” refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. The term aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non-aromatic ring.

[0145] 1006352981Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. The heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0146] Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclic aromatic ring systems.

[0147] Examples of 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e. 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like.

[0148] Examples of 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like. Examples of 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens). Aromatic heterocyclyl groups may also be bicyclic or polycyclic heteroaromatic ring systems such as fused ring systems (including purine, pteridiny I, napthyridiny 1, 1 H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like). Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5-membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.

[0149] 1006352981A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; I) a furan ring fused to a 5- or 6membered ring containing 1, 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

[0150] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).

[0151] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1,5-a]pyrimidine), benzodioxole and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups. A further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.

[0152] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

[0153] 1006352981Examples of heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.

[0154] Examples of aromatic heterocyclyls fused to carbocyclic aromatic rings may therefore include but are not limited to benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.

[0155] The term “heterocycloalkyl” or “non-aromatic heterocyclyl” encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom such as N, S and 0, or a heteromoiety such as 0, S, S(O), SO2, N and NH. The ring may contain 1, 2, 3, 4 or more heteroatoms or heteromoieties. When a heterocycloalkyl group contains the prefix Cni-n2 or “n1 to n2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1, 2, 3, 4 or more, of the ring atoms is replaced with a heteroatom or heteromoiety. The ring may be a monocyclic ring or part of a polycyclic ring system. Polycyclic ring systems include fused rings and spirocycles. Not every ring in a non-aromatic heterocyclic polycyclic ring system must contain a heteroatom, provided at least one ring contains one or more heteroatoms.

[0156] Non-aromatic heterocyclyls may be 3-8 membered mono-cyclic rings.

[0157] Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl,

[0158] 1 pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and the like.

[0159] Examples of 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5triozalanyl,

[0160] 10063529811,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4thiazinyl and the like.

[0161] Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl and the like.

[0162] Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems. Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like. Examples of non-aromatic 5-membered, 6-membered or 7membered heterocyclyls fused to carbocyclic aromatic rings include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and the like.

[0163] The term “alkyleneheteroaryl” refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment- The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of atachment. In some instances, the alkyl component can be absent. The alkyl component can include any number of carbons, such as Ci -e, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. The heteroaryl component is as defined herein. The numerical range from x to y in “Cx-y alkylenecycloalkyl” relates to the total number of alkyl carbons and heteroaryl ring atoms (carbon and heteroatoms together).

[0164] The term “alkyleneheterocycloalkyl” refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment- The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of atachment. In some instances, the alkyl component can be absent. The alkyl component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. The heterocycloalkyl component is as defined herein. The numerical range from x to y in “Cx-yalkyleneheterocycloalkyl” relates to the total number of alkyl carbons and heterocycloalkyl ring atoms (carbon and heteroatoms together).

[0165] 1006352981As used herein, the term solvate refers to a complex of the compound and either stoichiometric or non-stoichiometric amounts of a solvent. Solvates are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

[0166] As used herein, the term polymorph refers to the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0167] As used herein, the term “metabolite” refers to a derivative of a compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0168] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. As used herein, the term “stereoisomer” includes but is not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures.

[0169] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the

[0170] 1006352981tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0171] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0172] Compounds

[0173] The present disclosure provides compounds of formula (I):

[0174] N

[0175] R9N

[0176] R10

[0177]

[0178] wherein A, R6, R9and R10are as defined for any aspect or embodiment herein.

[0179] 1006352981In the compounds of formula (I), one of R9and R10is H, and the other of R9and R10is selected from any of the groups specified for either R9or R10that is not H. Put another way, only one of R9and R10is H. And accordingly, only one of R9and R10is substituted with a non-hydrogen substituent.

[0180] Compounds of the present disclosure share a 4-azaindole core, substitution at one of the 5-position (R9) or the 6-position (R10), and a cyclic-aminoethyl moiety at the

[0181] 3-position. Surprisingly at least preferred compounds described herein demonstrate advantageous properties, including demonstrating a desirable selectivity profile across 5HT-2A / 5HT-2B / 5HT-2C serotonin receptors and / or possessing reduced off target liabilities, relative to similar compounds, including non-cyclic aminoethyl analogues at the 3-position with similar number of carbon atoms, and other azaindole regioisomers (eg similarly substituted 7-azaindole compounds). Moreover, the compounds described herein demonstrate improved species differentiation for human, mouse and rat 5HT-2A receptors. For example, for similarly decorated 4-azaindole compounds and 7-azaindole compounds, the 4-azaindole compounds demonstrate significantly better cross species efficacy compared to 7-azaindole analogues (see Example 3) where specific examples demonstrate >13x fold increased activity for human 5HT-2A (h5HT-2A) over murine 5HT-2A (m5HT-2A), and >5x fold 5HT-2A over rat 5HT-2A (r5HT-2A). The activity of the 4-azaindole analogues at h5HT-2A are comparable to those of the 7-azaindole analogues, and the lack of species activity difference can significantly aid in pre-clinical development.

[0182] A-ring

[0183] A is a 4-14 membered heterocyclyl optionally substituted with one or more substituents selected from: halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4;

[0184] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5,

[0185] 1006352981said C-i-6 alkyl, C-i-ehaloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0186] said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5;

[0187] each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0188] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

[0189] In some embodiments, A is a C3-8 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4and SO2R4, (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4, wherein R4is defined as in any one of the foregoing paragraphs.

[0190] In some embodiments, A is a C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4and SO2R4, (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl,

[0191] 1006352981C2-6 alkynyl, C2-6haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4, wherein R4is defined as in any one of the foregoing paragraphs.

[0192] In embodiments, A is a C3-8 heterocycloalkyl including 0, 1 or 2 additional ring heteromoieties selected from 0, S, S(O), SO2, N and NR4,

[0193] said C3-8 heterocycloalkyl being further optionally substituted with one or more substituents selected from halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4.

[0194] In embodiments, A is a C4-8 heterocycloalkyl including 0 or 1 additional ring heteromoieties selected from 0, S, S(O), SO2, N and NR4, wherein the C4-sheterocycloalkyl is optionally substituted with one or more substituents selected from halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4.

[0195] In embodiments, A is an optionally substituted C4-8 heterocycloalkyl. In these embodiments, the compound of formula (I) may be provided as a compound of formula (V) as described herein.

[0196] In embodiments, A is a C4-8 heterocycloalkyl that does not include additional ring heteromoieties other than the nitrogen atom depicted in formula (I) (and any of its subformulas including formulas (la), (lb), (II), (III), (IV), (V), (II*), (III*), (IV*) and (V*)).

[0197] In embodiments, A is a C4-8 heterocycloalkyl that is monocyclic or fused bicyclic.

[0198] In embodiments, A is a monocyclic Ce-8 heterocycloalkyl.

[0199] In embodiments, A is a bicyclic Ce-8 heterocycloalkyl.

[0200] In embodiments, A is a C4-8 heterocycloalkyl that is fused.

[0201] In embodiments, A is a C4-8 heterocycloalkyl that is unsubstituted.

[0202] 1006352981In embodiments, A is a C4-8 heterocycloalkyl that is unsubstituted and moncyclic or fused bicyclic.

[0203] In embodiments, A is a C4-8 heterocycloalkyl that is unsubstituted and moncyclic.

[0204] In embodiments, A is a C4-8 heterocycloalkyl that is unsubstituted and fused bicyclic. In embodiments, A is any one of the following:

[0205]

[0206] In embodiments, A is any one of the following:

[0207]

[0208] In embodiments, A is any one of the following:

[0209]

[0210] 1006352981In embodiments, A is any one of the following:

[0211]

[0212] In some embodiments, A is any one of the following:

[0213]

[0214] In some embodiments, A is any one of the following:

[0215] In some embodiments, is any one of the following:

[0216]

[0217] In embodiments, A is a 4-8 membered heterocyclyl.

[0218] In embodiments, A is a monocyclic heterocyclyl.

[0219] In embodiments, A is substituted.

[0220] In embodiments, A is substituted by an optionally substituted Ci-ealkyl.

[0221] In embodiments, A is a bicyclic heterocyclyl.

[0222] In embodiments, A comprises an optionally substituted 4-, 5- or 6-membered heterocyclyl, optionally as part of a polycyclic ring system.

[0223] 1006352981R6

[0224] In compounds of formula (I), R6is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6 alkyleneP(O)(OR12)2, C(O)R12, CO2R12, C(O)N(R12)2, S(O)R12and SO2R12, C3-6 cycloalkyl, Ce-9 alkylenecycloalkyl, C3-6 heterocyclyl, Ce- 9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl,

[0225] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-9 alkylenecycloalkyl, C3-6 heterocyclyl, C6-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R12, C(O)N(R12)2, OR12, N(R12)2, NO2, SR12and SO2R12,

[0226] said C3-6 cycloalkyl, Ce-9 alkylenecycloalkyl, C3-6 heterocyclyl,

[0227] Ce-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce-i 6 alkyleneheteroaryl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR12;

[0228] each R12is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce-alkyleneheteroaryl,

[0229] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl,

[0230] 1006352981C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

[0231] In embodiments, R6is H or optionally substituted linear Ci-ealkyL

[0232] In embodiments, R6is H or optionally substituted linear Ci-salkyL

[0233] In embodiments, R6is optionally substituted linear Ci-ealkyl. For example, R6may be optionally substituted linear Ci-4alkyl, optionally substituted linear Ci salkyl, optionally substituted Ci-2alkyl, or optionally substituted C-ialkyl.

[0234] In embodiments, R6is selected from optionally substituted methyl, optionally substituted ethyl, and optionally substituted iso-propyl.

[0235] In embodiments, R6is selected from H and optionally substituted methyl.

[0236] In embodiments, R6is H.

[0237] R9

[0238] R9is independently selected from hydrogen, halogen, CN, OR13, N(R13)2, SR13, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R13, C(O)R13, C(O)N(R13)2, C(O)C(O)N(R13)2, OC(O)R13, OC(O)OR13, OC(O)N(R13)2, OS(O)R13, OS(O)N(R13)2, OSO2R13, OP(O)(OR13)2, OCi-6alkyleneP(O)(OR13)2, S(O)R13, S(O)N(R13)2, SO2R13, N(R13)2, N(R13)C(O)R13, N(R13)C(O)OR13, N(R13)C(O)N(R13)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, Ce-i2aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl;

[0239] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R13, C(O)N(R13)2, OR13, N(R13)2, NO2, SR13and SO2R13,

[0240] said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 1006352981alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, Cs-ecycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR13;

[0241] each R13is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, Cs- 10 heteroaryl, and Ce- alkyleneheteroaryl,

[0242] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3.

[0243] In embodiments, R9is selected from: halo, -CN, C2-ealkoxy, C(O)N(R13)2.

[0244] In embodiments, R9is halo. For example, in some embodiments, R9is selected from F, Cl and Br. In some embodiments, R9is F.

[0245] In embodiments, R9is C(O)N(R13)2. In some embodiments, each R13is H.

[0246] In embodiments, R9is an optionally substituted C2-ealkoxy.

[0247] In embodiments, R9is an optionally substituted branched C2-ealkoxy.

[0248] In embodiments, R9is a substituted methoxy. Suitable substituents include one or more groups independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

[0249] 1006352981In some embodiments, R9is selected from F, Cl and Br.

[0250] In some embodiments, R9is not unsubstituted methoxy.

[0251] In some embodiments, R9is not methoxy.

[0252] In some embodiments, R9is methoxy.

[0253] In some embodiments, R9is methoxy and A is selected from:

[0254]

[0255] In embodiments, R9is selected from methoxy, ethoxy, F, Br, and Cl.

[0256] In embodiments, R9is selected from ethoxy, F, Br, and Cl.

[0257] In embodiments, R9is H.

[0258] In embodiments, R9is independently selected from halogen, CN, OR13, N(R13)2, SR13, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R13, C(O)R13, C(O)N(R13)2, C(O)C(O)N(R13)2, OC(O)R13, OC(O)OR13, OC(O)N(R13)2, OS(O)R13, OS(O)N(R13)2, OSO2R13, OP(O)(OR13)2, OCi-6alkyleneP(O)(OR13)2, S(O)R13, S(O)N(R13)2, SO2R13, N(R13)2, N(R13)C(O)R13, N(R13)C(O)OR13, N(R13)C(O)N(R13)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, Ce-i2aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl;

[0259] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R13, C(O)N(R13)2, OR13, N(R13)2, NO2, SR13and SO2R13,

[0260] 1006352981said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, Cs-ecycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from 0, S, S(0), SO2, N, and NR13;

[0261] each R13is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, Cs- 10 heteroaryl, and Ce- alkyleneheteroaryl,

[0262] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3; and

[0263] R10is H. In these embodiments, the compound of formula (I) may be provided as a compound of formula (la):

[0264]

[0265] wherein A and R6are as defined for formula (I), and

[0266] 1006352981R9is independently selected from halogen, CN, OR13, N(R13)2, SR13, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R13, C(O)R13, C(O)N(R13)2, C(O)C(O)N(R13)2, OC(O)R13, OC(O)OR13, OC(O)N(R13)2, OS(O)R13, OS(O)N(R13)2, OSO2R13, OP(O)(OR13)2, OCi-6alkyleneP(O)(OR13)2, S(O)R13, S(O)N(R13)2, SO2R13, N(R13)2, N(R13)C(O)R13, N(R13)C(O)OR13, N(R13)C(O)N(R13)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, Ce-i2aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl;

[0267] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R13, C(O)N(R13)2, OR13, N(R13)2, NO2, SR13and SO2R13,

[0268] said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR13;

[0269] each R13is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, Cs- 10 heteroaryl, and Ce- alkyleneheteroaryl,

[0270] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl

[0271] 1006352981and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

[0272] R10

[0273] R10is independently selected from H, halogen, CN, OR14, N(R14)2, SR14, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R14, C(O)R14, C(O)N(R14)2, C(O)C(O)N(R14)2, OC(O)R14, OC(O)OR14, OC(O)N(R14)2, OS(O)R14, OS(O)N(R14)2, OSO2R14, OP(O)(OR14)2, OCi-6alkyleneP(O)(OR14)2, S(O)R14, S(O)N(R14)2, SO2R14, N(R14)2, N(R14)C(O)R14, N(R14)C(O)OR14, N(R14)C(O)N(R14)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,

[0274] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R14, C(O)N(R14)2, OR14, N(R14)2, NO2, SR14and SO2R14,

[0275] said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR14;

[0276] each R14is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,

[0277] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being

[0278] 1006352981optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C-i-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

[0279] In embodiments, R10is independently selected from halogen, CN, OR14, N(R14)2, SR14, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R14, C(O)R14, C(O)N(R14)2, C(O)C(O)N(R14)2, OC(O)R14, OC(O)OR14, OC(O)N(R14)2, OS(O)R14, OS(O)N(R14)2, OSO2R14, OP(O)(OR14)2, OCi-6alkyleneP(O)(OR14)2, S(O)R14, S(O)N(R14)2, SO2R14, N(R14)2, N(R14)C(O)R14, N(R14)C(O)OR14, N(R14)C(O)N(R14)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-io heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,

[0280] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-io heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R14, C(O)N(R14)2, OR14, N(R14)2, NO2, SR14and SO2R14,

[0281] said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3- heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from 0, S, S(O), SO2, N, and NR14;

[0282] each R14is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3- heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce-alkyleneheteroaryl,

[0283] 1006352981said Ci-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

[0284] In embodiments, R10is selected from: halo, -CN, C2-ealkoxy, C(O)N(R14)2.

[0285] In embodiments, R10is halo. For example, in some embodiments, R10is selected from F, Cl and Br. In some embodiments, R10is F.

[0286] In embodiments, R10is C(O)N(R14)2. In some embodiments, each R14is H.

[0287] In embodiments, R10is an optionally substituted C2-ealkoxy.

[0288] In embodiments, R10is an optionally substituted branched C2-ealkoxy.

[0289] In embodiments, R10is a substituted methoxy. Suitable substituents include one or more groups independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

[0290] In some embodiments, R10is selected from F, Cl and Br.

[0291] In some embodiments, R10is not unsubstituted methoxy.

[0292] In some embodiments, R10is not methoxy.

[0293] In some embodiments, R10is methoxy.

[0294] In embodiments, R10is selected from methoxy, ethoxy, F, Br, and Cl.

[0295] 1006352981In embodiments, R10is selected from methoxy, ethoxy, and F.

[0296] In embodiments, R10is selected from ethoxy, F, Br, and Cl.

[0297] In embodiments, R10is H.

[0298] In embodiments, R9is H; and R10is independently selected from halogen, CN, OR14, N(R14)2, SR14, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R14, C(O)R14, C(O)N(R14)2, C(O)C(O)N(R14)2, OC(O)R14, OC(O)OR14, OC(O)N(R14)2, OS(O)R14, OS(O)N(R14)2, OSO2R14, OP(O)(OR14)2, OCi-6alkyleneP(O)(OR14)2, S(O)R14, S(O)N(R14)2, SO2R14, N(R14)2, N(R14)C(O)R14, N(R14)C(O)OR14, N(R14)C(O)N(R14)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,

[0299] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R14, C(O)N(R14)2, OR14, N(R14)2, NO2, SR14and SO2R14,

[0300] said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR14;

[0301] each R14is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,

[0302] 1006352981said C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N, NH and NCH3.

[0303] In embodiments, R9is H and the compound of formula (I) is provided by a compound of formula (lb):

[0304] N

[0305] N

[0306]

[0307] (lb)

[0308] wherein A and R6are as defined for formula (I), and R10is independently selected from halogen, CN, OR14, N(R14)2, SR14, C1-6 alkyl, Ci-s haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R14, C(O)R14, C(O)N(R14)2, C(O)C(O)N(R14)2, OC(O)R14, OC(O)OR14, OC(O)N(R14)2, OS(O)R14, OS(O)N(R14)2, OSO2R14, OP(O)(OR14)2, OC1-6alkyleneP(O)(OR14)2, S(O)R14, S(O)N(R14)2, SO2R14, N(R14)2, N(R14)C(O)R14, N(R14)C(O)OR14, N(R14)C(O)N(R14)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,

[0309] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from 1006352981halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R14, C(O)N(R14)2, OR14, N(R14)2, NO2, SR14and SO2R14,

[0310] said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR14;

[0311] each R14is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,

[0312] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3.

[0313] In embodiments:

[0314] R9is H and R10is other than H; or

[0315] R10is H and R9is other than H.

[0316] In embodiments, when either of R9and R10is other than H (or specified as “not H”), each of R9and R10may be selected from any non-hydrogen group defined in any aspect or embodiment for either substitutent herein.

[0317] In some embodiments, the compounds of formula (I) exclude any compound disclosed in WO 2023 / 115165 A1.

[0318] 1006352981Further embodiments

[0319] In embodiments, there is provided a compound of formula (I):

[0320]

[0321] wherein

[0322] A is a 4-14 membered heterocyclyl selected from:

[0323]

[0324] R6is selected from hydrogen, and optionally substituted C1-6 alkyl;

[0325] and either:

[0326] a. R9is independently selected from methoxy, ethoxy, F, Br, and Cl, and R10is H;

[0327] or

[0328] b. R10is independently selected from methoxy, ethoxy, F, Br, and Cl, and R9is H.

[0329] In some embodiments, the compound of formula (I) is provided as a compound of formula (II)

[0330] 1006352981

[0331]

[0332] wherein R6, R9and R10are as defined herein

[0333] A1is a covalent bond or C(Rg)(Rh)

[0334] A2is a covalent bond of C(R')(Rj)

[0335] Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R' and Rj(if present) are each independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(0), SO2 and NR4

[0336] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N and NR5,

[0337] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0338] said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N and NR5;

[0339] 1006352981each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0340] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3;

[0341] or alternatively one of Raand Rband one of Rdand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system, the other one of Raand Rb, and Rband Rcis independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4.

[0342] In some embodiments, one of A1and A2is a covalent bond.

[0343] In some embodiments, both of A1and A2are covalent bonds. In these embodiments, the carbon atom bonded to Rcand Rdis directly covalently bonded to the carbon atom bonded to Reand Rfdefining a 4 membered hereocyclic ring.

[0344] In some embodiments of the compound of formula (IV), R6is H.

[0345] In some embodiments of the compound of formula (IV), R9is halo, optionally substituted Ci -ealkoxy.

[0346] In some embodiments, Reis an optionally substituted Ci-ealkyL

[0347] In some embodiments, Reis not H and Rais not H.

[0348] In some embodiments, Reis not H, Rais not H, and each of Rb, Rc, Rd, Rf, Rg, Rh, R' and Rj(if present) is H.

[0349] 1006352981In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0350] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system, and each of Rb, Rd, Rf, Rg, Rh, R' and Rj(if present) is H.

[0351] In some embodiments, Rais methyl.

[0352] In some embodiments, the compound of formula (I) or (II) is provided as a compound of formula (III):

[0353]

[0354] wherein R6, R9and R10are as defined herein

[0355] A1is a covalent bond or CH2

[0356] A2is a covalent bond or CH2

[0357] Ra, Rc, and Reare each independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(0), SO2 and NR4

[0358] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N and NR5,

[0359] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally

[0360] 1006352981substituted with one or more substituents independently selected from halogen, CN, Ci-8 alkoxy, C-i-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0361] said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5;

[0362] each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0363] said C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3;

[0364] or alternatively Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0365] In some embodiments, one of A1and A2is a covalent bond.

[0366] In some embodiments, both of A1and A2are covalent bonds. In these embodiments, the carbon atom bonded to Rcis directly covalently bonded to the carbon atom bonded to Redefining a 4 membered hereocyclic ring.

[0367] In some embodiments of the compound of formula (II), R6is H.

[0368] In some embodiments of the compound of formula (II), R9is halo, or optionally substituted Ci-ealkoxy.

[0369] In some embodiments, Reis an optionally substituted Ci-ealkyL

[0370] In some embodiments, Reis not H and Rais not H.

[0371] 1006352981In some embodiments, Reis not H, Rais not H, and Rcis H.

[0372] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0373] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0374] In some embodiments, Reis H.

[0375] In some embodiments, Reis H and Rais not H.

[0376] In some embodiments, Reis H, Rais not H, and Rcis H.

[0377] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0378] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0379] In some embodiments, Rais not H.

[0380] In some embodiments, Rais an optionally substituted Ci-ealkyL

[0381] In some embodiments, Rais methyl.

[0382] In some embodiments, Rais not H, and Rcis H.

[0383] In some embodiments, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system. In some embodiments, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system. In some embodiments, Raand Rctogether form a Csalkylene or Csheteroalkylene to form a fused ring system.

[0384] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0385] In some embodiments, the compound of formula (I), (II) or (III) is provided as a compound of formula (IV):

[0386] 1006352981

[0387]

[0388] wherein Ra, Rc, A1, A2, R6, R9and R10may be as defined herein.

[0389] In some embodiments, the compound of formula (I) may be provided as a compound of formula (V):

[0390]

[0391] wherein:

[0392] L, R3, R6, R9and R10are as defined for any aspect or embodiment herein;

[0393] n is an integer from 1 to 5, preferably 1, 2 or 3; and

[0394] each R may be the same or different and is independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, or two Rs together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring, which may thus form a fused-, spiro- or bridged-cyclic system.

[0395] In embodiments, 2 Rs bonded to adjacent ring carbon atoms form an optionally substituted C3-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a fused ring system. In some embodiments, one of the adjacent ring carbon atoms forming part of the fused ring system is alpha to the nitrogen atom of the heterocycloalkyl group of formula (V).

[0396] 1006352981In embodiments of the compound of formula (V), 2 Rs bonded to adjacent ring carbon atoms form an optionally substituted C3-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a fused ring system. In some embodiments, one of the adjacent ring carbon atoms forming part of the fused ring system is alpha to the nitrogen atom of the heterocycloalkyl group of formula (V).

[0397] In embodiments, 2 Rs bonded to the same ring carbon atom form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a spirocyclic ring system.

[0398] In embodiments of the compound of formula (V), 2 Rs bonded to the same ring carbon atom form an optionally substituted C4-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a spirocyclic ring system.

[0399] In some embodiments, the compound of formula (I) may be provided as a compound of formula (VI):

[0400]

[0401] wherein:

[0402] L, R3, R6, R9and R10are as defined for any aspect or embodiment herein;

[0403] n is an integer from 1 to 5, preferably 1, 2 or 3; and

[0404] each R and R’ may be the same or different and is independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl,

[0405] or one R and R’ together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring, which may thus form a fused-, spiro- or bridged-cyclic system, and the remaining R

[0406] 1006352981being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0407] In embodiments, R’ is H, one R is H, and the other R is selected from halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0408] In embodiments, R’ is H, one R is H, and the other R is C1-6 alkyl.

[0409] In embodiments, R’ and one R together with the atoms to which they are attached form an optionally substituted C3-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a fused ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0410] In embodiments of the compound of formula (VI), R’ and one R together with the atoms to which they are attached form an optionally substituted C3-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a fused ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0411] In embodiments, R’ and one R together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a spirocyclic ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0412] In embodiments of the compound of formula (VI), R’ and one R together with the atoms to which they are attached form an optionally substituted C4-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a spirocyclic ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0413] In embodiments where R’ and one R together with the atoms to which they are attached form a cyclic group, the remaining R is H.

[0414] In some embodiments, the compound of formula (I) is provided by any one of formulas (II*), (III*), (IV*), (V*) and (VI*) wherein the compound is stereoisomerically enriched at least at one of the carbon atom(s) denoted by *:

[0415] 1006352981

[0416]

[0417] (VI*) wherein variables in formula (II*) are as defined for formula (II), variables in formula (III*) are as defined for formula (III), variables in formula (IV*) are as defined for formula (IV), variables in formula (V*) are as defined for formula (V), variables in formula (VI*) are as defined for formula (VI), and any embodiments thereof.

[0418] In embodiments, each carbon atom denoted by * is independently enriched as the R-stereoisomer or the S-stereoisomer.

[0419] In embodiments, a carbon atom denoted by * is enriched as the R-stereoisomer.

[0420] In embodiments, a carbon atom denoted by * is enriched as the S-stereoisomer.

[0421] 1006352981In embodiments, enriched in a stereoisomer may mean that the enriched compound has an enantiomeric excess (ee) of at least about 51%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.9% ee. In embodiments, the enriched compounds may have an ee from any of these values to any other of these values, for example from about 51 % ee to about 99.9% ee, 65% ee to about 99.9% ee or about 80% ee to about 99% ee.

[0422] In embodiments, enriched in a stereoisomer may mean that the enriched compound has a diastereomeric excess (de) of at least about 51%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.9% de. In embodiments, the enriched compounds may have a de from any of these values to any other of these values, for example from about 51 % de to about 99.9% de, 65% de to about 99.9% de or about 80% de to about 99% de.

[0423] In some embodiments, R10is H, and the compound of formula (I) is provided as a compound of formula (Ila)

[0424]

[0425] wherein R6and R9are as defined herein

[0426] A1is a covalent bond or C(Rg)(Rh)

[0427] A2is a covalent bond of C(R')(Rj)

[0428] Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R' and Rj(if present) are each independently selected from H, halogen, (O), CN, C1-8 alkoxy, C-i-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-ehaloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6

[0429] 1006352981heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2and NR4

[0430] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-ehaloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N and NR5,

[0431] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0432] said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N and NR5;

[0433] each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0434] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3;

[0435] or alternatively one of Raand Rband one of Rdand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system, the other one of Raand Rb, and Rband Rcis independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-8 alkylamino,

[0436] 1006352981Ci-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4.

[0437] In some embodiments, one of A1and A2is a covalent bond.

[0438] In some embodiments, both of A1and A2are covalent bonds. In these embodiments, the carbon atom bonded to Rcand Rdis directly covalently bonded to the carbon atom bonded to Reand Rfdefining a 4 membered hereocyclic ring.

[0439] In some embodiments of the compound of formula (IV), R6is H.

[0440] In some embodiments of the compound of formula (IV), R9is halo, optionally substituted Ci -ealkoxy.

[0441] In some embodiments, Reis an optionally substituted Ci-ealkyL

[0442] In some embodiments, Reis not H and Rais not H.

[0443] In some embodiments, Reis not H, Rais not H, and each of Rb, Rc, Rd, Rf, Rg, Rh, R' and Rj(if present) is H.

[0444] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or C1-sheteroalkylene to form a fused ring system.

[0445] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or C1-sheteroalkylene to form a fused ring system, and each of Rb, Rd, Rf, Rg, Rh, R' and Rj(if present) is H.

[0446] In some embodiments, Rais methyl.

[0447] In some embodiments, the compound of formula (I) or (II) is provided as a compound of formula (Illa):

[0448] 1006352981

[0449]

[0450] wherein R6and R9are as defined herein

[0451] A1is a covalent bond or CH2

[0452] A2is a covalent bond or CH2

[0453] Ra, Rc, and Reare each independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(0), SO2 and NR4

[0454] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N and NR5,

[0455] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0456] said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N and NR5;

[0457] 1006352981each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0458] said C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3;

[0459] or alternatively Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0460] In some embodiments, one of A1and A2is a covalent bond.

[0461] In some embodiments, both of A1and A2are covalent bonds. In these embodiments, the carbon atom bonded to Rcis directly covalently bonded to the carbon atom bonded to Redefining a 4 membered hereocyclic ring.

[0462] In some embodiments of the compound of formula (Ila), R6is H.

[0463] In some embodiments of the compound of formula (Ila), R9is halo, or optionally substituted Ci-ealkoxy.

[0464] In some embodiments, Reis an optionally substituted Ci-ealkyL

[0465] In some embodiments, Reis not H and Rais not H.

[0466] In some embodiments, Reis not H, Rais not H, and Rcis H.

[0467] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0468] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0469] In some embodiments, Reis H.

[0470] 1006352981In some embodiments, Reis H and Rais not H.

[0471] In some embodiments, Reis H, Rais not H, and Rcis H.

[0472] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0473] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0474] In some embodiments, Rais not H.

[0475] In some embodiments, Rais an optionally substituted Ci-ealkyL

[0476] In some embodiments, Rais methyl.

[0477] In some embodiments, Rais not H, and Rcis H.

[0478] In some embodiments, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system. In some embodiments, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system. In some embodiments, Raand Rctogether form a Csalkylene or Csheteroalkylene to form a fused ring system.

[0479] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0480] In some embodiments, the compound of formula (I), (II) or (III) is provided as a compound of formula (IVa):

[0481]

[0482] wherein Ra, Rc, A1, A2, R6and R9may be as defined herein.

[0483] 1006352981In some embodiments, the compound of formula (I) may be provided as a compound of formula (Va):

[0484]

[0485] wherein:

[0486] L, R3, R6and R9are as defined for any aspect or embodiment herein;

[0487] n is an integer from 1 to 5, preferably 1, 2 or 3; and

[0488] each R may be the same or different and is independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, or two Rs together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring, which may thus form a fused-, spiro- or bridged-cyclic system.

[0489] In embodiments, 2 Rs bonded to adjacent ring carbon atoms form an optionally substituted C3-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a fused ring system. In some embodiments, one of the adjacent ring carbon atoms forming part of the fused ring system is alpha to the nitrogen atom of the heterocycloalkyl group of formula (V).

[0490] In embodiments of the compound of formula (V), 2 Rs bonded to adjacent ring carbon atoms form an optionally substituted C3-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a fused ring system. In some embodiments, one of the adjacent ring carbon atoms forming part of the fused ring system is alpha to the nitrogen atom of the heterocycloalkyl group of formula (V).

[0491] In embodiments, 2 Rs bonded to the same ring carbon atom form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a spirocyclic ring system.

[0492] 1006352981In embodiments of the compound of formula (V), 2 Rs bonded to the same ring carbon atom form an optionally substituted C4-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a spirocyclic ring system.

[0493] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Via):

[0494]

[0495] wherein:

[0496] L, R3, R6, and R9are as defined for any aspect or embodiment herein;

[0497] n is an integer from 1 to 5, preferably 1, 2 or 3; and

[0498] each R and R’ may be the same or different and is independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl,

[0499] or one R and R’ together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring, which may thus form a fused-, spiro- or bridged-cyclic system, and the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0500] In embodiments, R’ is H, one R is H, and the other R is selected from halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0501] In embodiments, R’ is H, one R is H, and the other R is C1-6 alkyl.

[0502] In embodiments, R’ and one R together with the atoms to which they are attached form an optionally substituted C3-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a fused ring system, the remaining R being

[0503] 1006352981independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0504] In embodiments of the compound of formula (VI), R’ and one R together with the atoms to which they are attached form an optionally substituted C3-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a fused ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0505] In embodiments, R’ and one R together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a spirocyclic ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0506] In embodiments of the compound of formula (Via), R’ and one R together with the atoms to which they are attached form an optionally substituted C4-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a spirocyclic ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0507] In embodiments where R’ and one R together with the atoms to which they are attached form a cyclic group, the remaining R is H.

[0508] In some embodiments, the compound of formula (I) is provided by any one of formulas (Ila*), (Illa*), (IVa*), (Va*) and (Via*) wherein the compound is stereoisomerically enriched at least at one of the carbon atom(s) denoted by *:

[0509]

[0510] 1006352981(Va*)

[0511]

[0512] wherein variables in formula (Ila*) are as defined for formula (Ila), variables in formula (Illa*) are as defined for formula (Illa), variables in formula (IVa*) are as defined for formula (IVa), variables in formula (Va*) are as defined for formula (Va), variables in formula (Via*) are as defined for formula (Via), and any embodiments thereof.

[0513] In embodiments, each carbon atom denoted by * is independently enriched as the R-stereoisomer or the S-stereoisomer.

[0514] In embodiments, a carbon atom denoted by * is enriched as the R-stereoisomer.

[0515] In embodiments, a carbon atom denoted by * is enriched as the S-stereoisomer.

[0516] In embodiments, enriched in a stereoisomer may mean that the enriched compound has an enantiomeric excess (ee) of at least about 51%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.9% ee. In embodiments, the enriched compounds may have an ee from any of these values to any other of these values, for example from about 51 % ee to about 99.9% ee, 65% ee to about 99.9% ee or about 80% ee to about 99% ee.

[0517] 1006352981In embodiments, enriched in a stereoisomer may mean that the enriched compound has a diastereomeric excess (de) of at least about 51%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.9% de. In embodiments, the enriched compounds may have a de from any of these values to any other of these values, for example from about 51 % de to about 99.9% de, 65% de to about 99.9% de or about 80% de to about 99% de.

[0518] In some embodiments, R9is H, and the compound of formula (I) is provided as a compound of formula (lib)

[0519]

[0520] wherein R6, and R10are as defined herein

[0521] A1is a covalent bond or C(Rg)(Rh)

[0522] A2is a covalent bond of C(R')(Rj)

[0523] Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R' and Rj(if present) are each independently selected from H, halogen, (O), CN, C1-8 alkoxy, C-i-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR4

[0524] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5,

[0525] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally

[0526] 1006352981substituted with one or more substituents independently selected from halogen, CN, Ci-8 alkoxy, C-i-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0527] said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5;

[0528] each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0529] said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3;

[0530] or alternatively one of Raand Rband one of Rdand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system, the other one of Raand Rb, and Rband Rcis independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4.

[0531] In some embodiments, one of A1and A2is a covalent bond.

[0532] In some embodiments, both of A1and A2are covalent bonds. In these embodiments, the carbon atom bonded to Rcand Rdis directly covalently bonded to the carbon atom bonded to Reand Rfdefining a 4 membered hereocyclic ring.

[0533] In some embodiments of the compound of formula (IVb), R6is H.

[0534] 1006352981In some embodiments of the compound of formula (IVb), R10is halo, optionally substituted Ci-ealkoxy.

[0535] In some embodiments, Reis an optionally substituted Ci-ealkyL

[0536] In some embodiments, Reis not H and Rais not H.

[0537] In some embodiments, Reis not H, Rais not H, and each of Rb, Rc, Rd, Rf, Rg, Rh, R' and Rj(if present) is H.

[0538] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0539] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system, and each of Rb, Rd, Rf, Rg, Rh, R' and Rj(if present) is H.

[0540] In some embodiments, Rais methyl.

[0541] In some embodiments, the compound of formula (I) or (II) is provided as a compound of formula (lllb):

[0542]

[0543] wherein R6, and R10are as defined herein

[0544] A1is a covalent bond or CH2

[0545] A2is a covalent bond or CH2

[0546] Ra, Rc, and Reare each independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-ehaloalkynyl, C1-8

[0547] 1006352981alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4

[0548] each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-ehaloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5,

[0549] said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,

[0550] said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N and NR5;

[0551] each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,

[0552] said C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N, NH and NCH3;

[0553] or alternatively Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0554] In some embodiments, one of A1and A2is a covalent bond.

[0555] 1006352981In some embodiments, both of A1and A2are covalent bonds. In these embodiments, the carbon atom bonded to Rcis directly covalently bonded to the carbon atom bonded to Redefining a 4 membered hereocyclic ring.

[0556] In some embodiments of the compound of formula (II), R6is H.

[0557] In some embodiments of the compound of formula (II), R10is halo, or optionally substituted Ci-ealkoxy.

[0558] In some embodiments, Reis an optionally substituted Ci-ealkyL

[0559] In some embodiments, Reis not H and Rais not H.

[0560] In some embodiments, Reis not H, Rais not H, and Rcis H.

[0561] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0562] In some embodiments, Reis not H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0563] In some embodiments, Reis H.

[0564] In some embodiments, Reis H and Rais not H.

[0565] In some embodiments, Reis H, Rais not H, and Rcis H.

[0566] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0567] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0568] In some embodiments, Rais not H.

[0569] In some embodiments, Rais an optionally substituted Ci-ealkyL

[0570] In some embodiments, Rais methyl.

[0571] In some embodiments, Rais not H, and Rcis H.

[0572] 1006352981In some embodiments, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system. In some embodiments, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system. In some embodiments, Raand Rctogether form a Csalkylene or Csheteroalkylene to form a fused ring system.

[0573] In some embodiments, Reis H, Raand Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system.

[0574] In some embodiments, the compound of formula (I), (II) or (III) is provided as a compound of formula (IVb):

[0575]

[0576] wherein Ra, Rc, A1, A2, R6, R9and R10may be as defined herein.

[0577] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Vb):

[0578]

[0579] wherein:

[0580] L, R3, R6, R9and R10are as defined for any aspect or embodiment herein;

[0581] n is an integer from 1 to 5, preferably 1, 2 or 3; and

[0582] each R may be the same or different and is independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, 1006352981or two Rs together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring, which may thus form a fused-, spiro- or bridged-cyclic system.

[0583] In embodiments, 2 Rs bonded to adjacent ring carbon atoms form an optionally substituted C3-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a fused ring system. In some embodiments, one of the adjacent ring carbon atoms forming part of the fused ring system is alpha to the nitrogen atom of the heterocycloalkyl group of formula (V).

[0584] In embodiments of the compound of formula (V), 2 Rs bonded to adjacent ring carbon atoms form an optionally substituted C3-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a fused ring system. In some embodiments, one of the adjacent ring carbon atoms forming part of the fused ring system is alpha to the nitrogen atom of the heterocycloalkyl group of formula (V).

[0585] In embodiments, 2 Rs bonded to the same ring carbon atom form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a spirocyclic ring system.

[0586] In embodiments of the compound of formula (V), 2 Rs bonded to the same ring carbon atom form an optionally substituted C4-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a spirocyclic ring system.

[0587] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Vlb):

[0588]

[0589] wherein:

[0590] L, R3, R6, and R10are as defined for any aspect or embodiment herein;

[0591] 1006352981n is an integer from 1 to 5, preferably 1, 2 or 3; and

[0592] each R and R’ may be the same or different and is independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl,

[0593] or one R and R’ together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring, which may thus form a fused-, spiro- or bridged-cyclic system, and the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0594] In embodiments, R’ is H, one R is H, and the other R is selected from halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0595] In embodiments, R’ is H, one R is H, and the other R is C1-6 alkyl.

[0596] In embodiments, R’ and one R together with the atoms to which they are attached form an optionally substituted C3-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a fused ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0597] In embodiments of the compound of formula (Vlb), R’ and one R together with the atoms to which they are attached form an optionally substituted C3-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a fused ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0598] In embodiments, R’ and one R together with the atoms to which they are attached form an optionally substituted C4-12 cycloalkyl or an optionally substituted 4-12 membered heterocycloalkyl ring such that it forms a spirocyclic ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0599] In embodiments of the compound of formula (Vlb), R’ and one R together with the atoms to which they are attached form an optionally substituted C4-6 cycloalkyl or an optionally substituted 4-6 membered heterocycloalkyl ring such that it forms a

[0600] 1006352981spirocyclic ring system, the remaining R being independently selected from hydrogen, halogen, C1-8 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl.

[0601] In embodiments where R’ and one R together with the atoms to which they are attached form a cyclic group, the remaining R is H.

[0602] In some embodiments, the compound of formula (I) is provided by any one of formulas (lib*), (lllb*), (IVb*), (Vb*) and (Vlb*) wherein the compound is stereoisomerically enriched at least at one of the carbon atom(s) denoted by *:

[0603] (IVb*) (Vb*)

[0604]

[0605] 1006352981wherein variables in formula (lib*) are as defined for formula (lib), variables in formula (lllb*) are as defined for formula (lllb), variables in formula (IVb*) are as defined for formula (IVb), variables in formula (Vb*) are as defined for formula (Vb), variables in formula (Vlb*) are as defined for formula (Vlb), and any embodiments thereof.

[0606] In embodiments, each carbon atom denoted by * is independently enriched as the R-stereoisomer or the S-stereoisomer.

[0607] In embodiments, a carbon atom denoted by * is enriched as the R-stereoisomer.

[0608] In embodiments, a carbon atom denoted by * is enriched as the S-stereoisomer.

[0609] In embodiments, enriched in a stereoisomer may mean that the enriched compound has an enantiomeric excess (ee) of at least about 51%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.9% ee. In embodiments, the enriched compounds may have an ee from any of these values to any other of these values, for example from about 51 % ee to about 99.9% ee, 65% ee to about 99.9% ee or about 80% ee to about 99% ee.

[0610] In embodiments, enriched in a stereoisomer may mean that the enriched compound has a diastereomeric excess (de) of at least about 51%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.9% de. In embodiments, the enriched compounds may have a de from any of these values to any other of these values, for example from about 51 % de to about 99.9% de, 65% de to about 99.9% de or about 80% de to about 99% de.

[0611] In some embodiments, the compound of formula (I) is selected from any one of the following compounds S11 to S26, S37 to S46, S57 to S66 and S72 to S132:

[0612] Compound No. Structure

[0613] V

[0614] Sil

[0615] H

[0616]

[0617] 1006352981Compound No. Structure

[0618] S12

[0619] S13 V

[0620] w

[0621] H

[0622] Pr S14

[0623] H

[0624] S15

[0625] \^''N H

[0626] S16

[0627] H

[0628] p S17

[0629] w

[0630] H

[0631] S18

[0632] ■ C v

[0633] H

[0634]

[0635] 1006352981Compound No. Structure S19

[0636] w

[0637] H

[0638] 5^""' S20

[0639] w

[0640] H

[0641] S21

[0642] T1 H

[0643] Cr'^ S22 IX Xx<

[0644] H

[0645] N

[0646] S23

[0647] H

[0648] S24

[0649] o> S25

[0650]

[0651] 1006352981Compound No. Structure<V^>J

[0652] S26

[0653] PO 'C" S37 o o

[0654] S38

[0655] O o

[0656] > H V

[0657] S39

[0658] p<2):\ H

[0659] S40

[0660] S41

[0661] H

[0662] S42

[0663]

[0664] 1006352981Compound No. Structure

[0665] S43

[0666] H

[0667] S44

[0668] o

[0669] S45

[0670] H

[0671] J

[0672] S46

[0673] H

[0674] c S57

[0675] " 0? H

[0676] i S58

[0677] H

[0678] u S59

[0679] H

[0680]

[0681] 1006352981Compound No. Structure

[0682] S60

[0683] S61

[0684] /

[0685] co m

[0686] H

[0687] '\r^ S62

[0688] \s5#'"'N co CD H

[0689] co.

[0690] S63

[0691] \' > zZ ' Y V

[0692] S64

[0693] / _ J 5^'"" S65

[0694] H

[0695] S66

[0696]

[0697] 1006352981Compound No. Structure o N- S72

[0698] HAd ZI

[0699] \ /

[0700] <\r^ o I S73 o p

[0701] o

[0702] \ \

[0703] H

[0704] S74

[0705] CP* S75

[0706] H

[0707] S76

[0708] S77

[0709] H

[0710] S78 ^CX -hk P^

[0711] H

[0712]

[0713] 1006352981Compound No. Structure

[0714] S79 ^,0.... N

[0715] H

[0716] p. v3

[0717] S80 o

[0718] )

[0719] ' < P ~'N H

[0720] S81

[0721] \

[0722] ( ( O

[0723] o o

[0724] O

[0725] S82 / O H IZIZ

[0726] HxV yo

[0727] S83

[0728] S84

[0729] S85 \ ^0^ J Y T > H

[0730] S86

[0731]

[0732] 1006352981Compound No. Structure

[0733] S87

[0734] Yzxziiz^ ^ 0 d, d,X^Xd.

[0735] S88 0Q Z zH z

[0736] o o o o

[0737] ) ) ) )

[0738] S89

[0739] ( o

[0740] S90 _hk J o m

[0741] H IZ

[0742] p S91

[0743] S92

[0744] S93 F\ J 1 X > H

[0745] \ 1 / ^ N- >^ S94 K J

[0746] H

[0747]

[0748] 1006352981Compound No. Structure

[0749] S95

[0750] S96 J

[0751] 0 S97. N. J rp

[0752] S98 J £ op

[0753] S99

[0754] H

[0755] S100

[0756] jf Y>

[0757] S101 J F^ I^XN>

[0758] S102 / N. J F^ I^TN>

[0759]

[0760] 1006352981Compound No. Structure

[0761] S103 J

[0762] S104 J

[0763] S105. N. J r x>F2

[0764] S106 J I X>

[0765] W"' S107 „Nx

[0766] S108,. AV..... /

[0767] ') \\

[0768] S109 7

[0769] Cr-^: A7

[0770] ■< >.s w- "■ S110 _,, N.

[0771]

[0772] 1006352981Compound No. Structure '"‘X Sill

[0773] C: - P

[0774] S112

[0775] \ J S113 Aj

[0776] V. ■

[0777] S114.

[0778] S115

[0779] .•■' '“x S116 N.. /

[0780] ( T> Ci -' -:::Ji

[0781] S117 A' GAX<-::::'A

[0782] XJ

[0783] S118

[0784] St| \\

[0785]

[0786] 1006352981Compound No. Structure

[0787] S119

[0788] S120 Z

[0789] S121

[0790] UX

[0791] S122

[0792] S123

[0793] S124

[0794] 4

[0795] S125

[0796] S126

[0797] vXv

[0798]

[0799] 1006352981Compound No. Structure

[0800] VJ-,.

[0801] S127

[0802] 'O'

[0803] P v,- S128 _. / .

[0804] S129

[0805] X.. b.

[0806] / ; X

[0807] S130 A- /

[0808] S131 H.. / .

[0809] S132 X. /

[0810] » T’ S

[0811]

[0812] In embodiments, the compound is selected from any one of compounds S11 to S26, S37 to S46, S57 to S66 and S72 to S82.

[0813] Forms of the compound

[0814] In the case of compounds that are solids, it will be understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

[0815] 1006352981The invention includes all crystalline forms of a compound of Formula (I) including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms demonstrates polymorphism, all polymorphs are within the scope of this invention.

[0816] Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, Formula (I) includes compounds having the indicated structures, including the hydrated or solvated forms, as well as the non-hydrated and non-solvated forms.

[0817] The compounds of Formula (I) or salts, tautomers, N-oxides, polymorphs or prodrugs thereof may be provided in the form of solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF), acetic acid, and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the invention.

[0818] Basic nitrogen-containing groups may be quarternised with such agents as Ci-ealkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

[0819] Nitrogen containing groups may also be oxidised to form an N-oxide.

[0820] The compound of Formula (I) or salts, tautomers, N-oxides, solvates and / or prodrugs thereof that form crystalline solids may demonstrate polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides, solvates and / or prodrugs are within the scope of the invention.

[0821] The compound of Formula (I) may demonstrate tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist within an equilibrium. Any tautomers of the compounds of Formula (I) are to be understood as being within the scope of the invention.

[0822] 1006352981The compound of Formula (I) may contain one or more stereocentres. All stereoisomers of the compounds of formula (I) are within the scope of the invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olephinic forms and cis and trans substitution patterns) and atropisomers. In some embodiments, the compound is a stereoisomerically enriched form of the compound of formula (I) at any stereocentre. The compound may be enriched in one stereoisomer over another by at least about 60, 70, 80, 90, 95, 98 or 99%.

[0823] The compound of Formula (I) or its salts, tautomers, solvates, N-oxides, and / or stereoisomers, may be isotopically enriched with one or more of the isotopes of the atoms present in the compound. For example, the compound may be enriched with one or more of the following minor isotopes:2H,3H,13C,14C,15N and / or17O, preferably2H. An isotope may be considered enriched when its abundance is greater than its natural abundance.

[0824] A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.

[0825] Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, and amido groups of compounds of Formula (I). The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are 1006352981covalently bonded to the above substituents of Formula (I) through the carbonyl carbon prodrug sidechain.

[0826] Compositions, formulations and modes of administration

[0827] The compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition. In practice, the compounds of formula (I) are usually administered in the form of pharmaceutical compositions, that is, in admixture with at least one pharmaceutically acceptable excipient. The proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.

[0828] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, and at least one pharmaceutically acceptable excipient.

[0829] Pharmaceutical compositions of the disclosure typically include a therapeutically effective amount of one or more active ingredients in admixture with one or more pharmaceutically and physiologically acceptable formulation materials. Suitable formulation materials include, but are not limited to, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, excipients and / or pharmaceutical adjuvants. For example, a suitable vehicle may be water for injection, physiological saline solution, or artificial perilymph, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.

[0830] Pharmaceutical compositions of the present disclosure additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical

[0831] 1006352981compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; com oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminium hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colouring agents, releasing agents, coating agents, sweetening, flavouring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0832] Various dosage units are each preferably provided as a discrete dosage tablet, capsules, lozenge, dragee, gum, or other type of solid formulation. Capsules may encapsulate a powder, liquid, or gel. The solid formulation may be swallowed, or may be of a suckable or chewable type (either frangible or gum-like). The present invention contemplates dosage unit retaining devices other than blister packs; for example, packages such as bottles, tubes, canisters, packets. The dosage units may further include conventional excipients well-known in pharmaceutical formulation practice, such as binding agents, gellants, fillers, tableting lubricants, disintegrants, surfactants, and colorants; and for suckable or chewable formulations.

[0833] A compound of formula (I) may be administered in any form and route which makes the compound bioavailable.

[0834] Compositions described herein may be administered systemically or directly to the site of condition or disease.

[0835] 1006352981Compositions described herein may be formulated from compounds according to Formula (I) for any appropriate route of administration including, for example, oral, rectal, nasal, vaginal, topical (including transdermal, buccal, ocular and sublingual), parenteral (including subcutaneous, intraperitoneal, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracisternal injection as well as any other similar injection or infusion techniques), inhalation, insufflation, infusion or implantation techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions). In some embodiments, compositions described herein may be administered orally, nasally, intravenously, intramuscularly, topically, subcutaneously, rectally, vaginally or by urethral application.

[0836] Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavouring agents, colouring agents and / or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatine or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

[0837] Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0838] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and / or flavouring agents may be added to provide palatable oral preparations.

[0839] 1006352981Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0840] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavouring and colouring agents, may also be present.

[0841] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, ora mixture thereof. Suitable emulsifying agents include naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate. An emulsion may also comprise one or more sweetening and / or flavouring agents.

[0842] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such Formulations may also comprise one or more demulcents, preservatives, flavouring agents and / or colouring agents.

[0843] A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

[0844] Preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical

[0845] 1006352981stabilizers and antioxidants such as vitamin E, sodium ascorbate / ascorbic acid and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerine, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils. Suitable fragrances and colours include, but are not limited to, FD& C Red No. 40 and FD& C Yellow No. 5. Other suitable additional ingredients that may be included in a topical Formulation include, but are not limited to, abrasives, absorbents, anticaking agents, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herbal extracts such as chamomile extract, binders / excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.

[0846] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0847] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0848] 1006352981The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0849] A pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. For inhalation formulations, the composition or combination provided herein may be delivered via any inhalation methods known to a person skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable. Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.

[0850] Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses. Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs. Suitable Formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

[0851] Compositions suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by at least partially dispersing the active in one or more lipophilic bases and then shaping the mixture.

[0852] Pharmaceutical compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of active following administration. Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may

[0853] 1006352981also be biodegradable. Preferably, the formulation provides a relatively constant level of active release. The amount of active contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated.

[0854] One skilled in the art can readily select the proper form and route of administration depending on the particular characteristics of the compound selected, the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances.

[0855] It will be understood, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, number of doses, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient), and the seventy of the particular disorder undergoing therapy.

[0856] The phrase “therapeutically effective amount” generally refers to an amount of one or more active ingredients of the invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more sign or symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more sign or symptoms of the particular disease, condition, or disorder described herein.

[0857] Typically, a therapeutically effective dosage is formulated to contain a concentration (by weight) of at least about 0.1% up to about 50% or more, and all combinations and subcombinations of ranges therein. The compositions can be formulated to contain one or more actives described herein in a concentration of from about 0.1 to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations of from greater than about 0.1%, for example, about 0.2, 0.3, 0.4 or 0.5%, to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or 30%. Exemplary compositions may contain from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or 20%, with concentrations of from greater than about 0.5%, for example, about 0.6, 0.7, 0.8, 0.9 or 1%, to less than about 20%, for example, about 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10%. The compositions can contain from greater than about 1% for example, about 2%, to less than about 10%, for example about 9 or 8%, including concentrations of greater than about 2%, for example, about 3

[0858] 1006352981or 4%, to less than about 8%, for example, about 7 or 6%. The active agent can, for example, be present in a concentration of about 5%. In all cases, amounts may be adjusted to compensate for differences in amounts of active ingredients actually delivered to the treated cells or tissue.

[0859] The frequency of administration may be once daily, 2, 3 or 4 times daily. The treatment period may be for the duration of the detectable disease.

[0860] In some embodiments, the pharmaceutical composition comprises a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.

[0861] The additional agent may be any suitable agent described herein. In some embodiments, the additional agent is a psychoactive drug, including those described herein. In some embodiments, the additional agent is useful for treatment of a disease, disorder or condition by activation of a serotonin receptor, including those described herein. In some embodiments, the additional agent is selected from any one of the following, including those described herein: an agent for a mental illness and / or a neuropsychiatric condition; an agent for psychosis and / or psychotic symptoms; an agent for attention deficit hyperactivity disorder and / or attention deficit disorder; an agent for dementia and / or Alzheimer’s disease; and an agent for an addiction disorder.

[0862] Applications

[0863] The present disclosure provides methods of using the compounds of formula (I) and compositions as described in any one of the foregoing paragraphs. The present disclosure also provides methods of delivering to a subject in need thereof a compound of formula (I) ora composition (e.g., an effective amount of the compound or composition) of the present disclosure.

[0864] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound or composition (e.g., pharmaceutical composition) of the present disclosure.

[0865] 1006352981In another aspect, the present disclosure provides methods of preventing a disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound of formula (I) or composition (e.g., pharmaceutical composition) of the present disclosure.

[0866] In another aspect, provided herein are uses of the compounds of formula (I) or compositions of the present disclosure in the manufacture of a medicament for use in a method (e.g., method of delivering an active agent to a subject in need thereof, method of treating a disease in a subject in need thereof, method of preventing a disease in a subject in need thereof) of the present disclosure.

[0867] In another aspect, provided herein are uses of the compounds of formula (I) or compositions of the present disclosure in a method (e.g., method of delivering an active agent to a subject in need thereof, method of treating a disease in a subject in need thereof, method of preventing a disease in a subject in need thereof) of the present disclosure.

[0868] In certain embodiments, the effective amount is effective in treating the disease. In certain embodiments, the effective amount is effective in preventing the disease.

[0869] In another aspect, the present disclosure provides a method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0870] In another aspect, the present disclosure provides a method of preventing a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0871] In another aspect, the present disclosure provides method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein, in combination with another known agent useful for treatment of a disease, disorder or condition by activation of a serotonin receptor. The other known agents useful for treatment of a disease, disorder or

[0872] 1006352981condition by activation of a serotonin receptor may be any suitable agents known in the art, including those described herein.

[0873] In another aspect, the present disclosure provides method of preventing a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein, in combination with another known agent useful for prevention of a disease, disorder or condition by activation of a serotonin receptor.

[0874] In certain embodiments, the serotonin receptor is 5-HT2A.

[0875] In certain embodiments, the serotonin receptor is one or both of 5-HT2A and 5-HT2C. Additionally, or alternatively, in some embodiments, the serotonin receptor is not 5-HT2B.

[0876] In some embodiments, the compound of formula (I) of the present disclosure is selective towards the 5-HT2A receptor over one or both of the 5-HT2C receptor and the 5-HT2B receptor, preferably over the 5-HT2B receptor. In some embodiments, the compound of formula (I) is selective towards the 5-HT2C receptor over one or both of the 5-HT2A receptor and the 5-HT2B receptor, preferably over the 5-HT2B receptor. In some embodiments, the compound of formula (I) is selective toward the 5-HT2A receptor and 5-HT2C receptor over the 5-HT2B receptor.

[0877] In some embodiments, the compound of formula (I) of the present disclosure exhibits an ECso value for the 5-HT2A receptor of less than about 1 mM, less than about 100 pM, less than about 10 pM, less than about 1 pM, or less than about 100 nM, or less than about 10 nM, as determined by an assay described herein, for example an assay of calcium flux activity such as measuring changes in intracellular calcium. In some embodiments, the compound of formula (I) exhibits an EC50 for the 5-HT2A receptor of less than about 1 mM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, less than about 9 pM, less than about 8 pM, less than about 7

[0878] 1006352981pM, less than about 6 pM, less than about 5 pM, less than about 4 pM, less than about 3 pM, less than about 2 pM, less than about 1 pM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, or less than about 100 nM, or any equivalent unit of measure (e.g., mol / L), as determined by an assay of calcium flux activity.

[0879] In some embodiments, the compound of formula (I) of the present disclosure exhibits an ECso value for the 5-HT2C receptor of less than about 1 mM, less than about 100 pM, less than about 10 pM, less than about 1 pM, or less than about 100 nM, or less than about 10 nM, as determined by an assay described herein, for example an assay of calcium flux activity such as measuring changes in intracellular calcium. In some embodiments, the compound of formula (I) exhibits an EC50 for the 5-HT2C receptor of less than about 1 mM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, less than about 9 pM, less than about 8 pM, less than about 7 pM, less than about 6 pM, less than about 5 pM, less than about 4 pM, less than about 3 pM, less than about 2 pM, less than about 1 pM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, or less than about 100 nM, or any equivalent unit of measure (e.g., mol / L), as determined by an assay of calcium flux activity.

[0880] In some embodiments, the compound of formula (I) of the present disclosure exhibits an ECso value for the 5-HT2B receptor of greater than about 1 pM, greater than about 10 pM, or greater than about 100 pM, as determined by an assay described herein, for example an assay of calcium flux activity such as measuring changes in intracellular calcium.

[0881] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is a mental illness or a neuropsychiatric condition. Accordingly, the present application also includes a method of treating a mental illness or a neuropsychiatric condition comprising administering to a subject in need thereof a 1006352981compound of formula (I) or a composition as described herein. The present application also includes a use of a compound of formula (I) of the present disclosure for treatment of a mental illness or a neuropsychiatric condition, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of a mental illness or a neuropsychiatric condition. The application further includes a compound of formula (I) of the present disclosure for use in treating a mental illness or a neuropsychiatric condition.

[0882] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is a mental illness or a neuropsychiatric condition and compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for a mental illness or a neuropsychiatric condition. The one or more additional agents for a mental illness or a neuropsychiatric condition may be any suitable agents known in the art, including those described herein. In some embodiments, the additional agents for a mental illness or a neuropsychiatric condition is selected from antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) (e.g. bupropion); anti-anxiety medication including benzodiazepines such as alprazolam; agents for an addiction disorder such as alcohol addiction (e.g., disulfiram), nicotine dependence (e.g., varenicline) and opioid use disorder (e.g., methadone, buprenorphine, buprenorphine-naloxone and buprenorphine long-acting injection); mood stabilizers such as lithium and anticonvulsants such carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin and topiramate.

[0883] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is neurodegeneration. Accordingly, the present application also includes a method of treating neurodegeneration comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein. The present application also includes a use of a compound of formula (I) of the present disclosure for treatment of neurodegeneration, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment neurodegeneration. The application further includes a compound of formula (I) of the present disclosure for use in treating neurodegeneration. In some embodiments, the

[0884] 1006352981disease, disorder or condition that is treated by activation of a serotonin receptor is reduced brain- derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation and / or inflammation.

[0885] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor comprises cognitive impairment; ischemia including stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, nerve pain, referred pain, phantom pain, neuropathic pain, cluster headaches and migraine; obesity and eating disorders; epilepsies and seizure disorders; neuronal cell death; excitotoxic cell death; or a combination thereof.

[0886] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms. Accordingly, the present application also includes a method of treating psychosis or psychotic symptoms comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein. The present application also includes a use of a compound of formula (I) of the present disclosure for treatment of psychosis or psychotic symptoms, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of psychosis or psychotic symptoms. The application further includes a compound of formula (I) of the present disclosure for use in treating psychosis or psychotic symptoms.

[0887] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms and the the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for psychosis or psychotic symptoms. The one or more additional agents for psychosis or psychotic symptoms may be any suitable agents known in the art, including those described herein. In some embodiments, the additional agents for psychosis or psychotic symptoms are selected typical antipsychotics and atypical antipsychotics. The typical antipsychotics may be selected from acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, moperone, oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, 1006352981piperacetazine, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine and zuclopenthixol and combinations thereof. The atypical antipsychotics may be selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone and zotepine, and combinations thereof.

[0888] In some embodiments, administering to said subject in need thereof a therapeutically effective amount of the compound of formula (I) of the present disclosure does not result in a worsening of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions. In some embodiments, administering to said subject in need thereof a therapeutically effective amount of the compound of formula (I) results in an improvement of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions. In some embodiments, administering to said subject in need thereof a therapeutically effective amount of the compounds of formula (I) results in an improvement of psychosis or psychotic symptoms.

[0889] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition. Accordingly, the present application also includes a method of treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition comprising administering a therapeutically effective amount of compound of formula (I) or a composition of the present disclosure to a subject in need thereof. The present application also includes a use of compound of formula (I) of the present disclosure for treatment a CNS disease, disorder or condition and / or a neurological disease, disorder or condition, as well as a use of compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of a CNS disease, disorder or condition and / or a neurological disease, disorder or condition. The application further includes a compound of formula (I) of the present disclosure of the application for use in treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition.

[0890] 1006352981In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition and the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition. The one or more additional agents for a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition may be any suitable agents known in the art, including those described herein. In some embodiments, the additional agents for a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition are selected from lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Non limiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.

[0891] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder and a combination thereof. Accordingly, the present application also includes a method of treating attention deficit hyperactivity disorder and / or attention deficit disorder comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein. The present application also includes a use of a compound of formula (I) of the present disclosure for treatment of attention deficit hyperactivity disorder and / or attention deficit disorder, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of attention deficit hyperactivity disorder and / or attention deficit disorder. The application further includes a compound of formula (I) of the present disclosure for use in treating attention deficit hyperactivity disorder and / or attention deficit disorder. In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is attention deficit hyperactivity disorder and / or attention deficit

[0892] 1006352981disorder and a combination thereof and the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for attention deficit hyperactivity disorder and / or attention deficit disorder and a combination thereof. The one or more additional agents for attention deficit hyperactivity disorder and / or attention deficit disorder may be any suitable agents known in the art, including those described herein. In some embodiments, the additional agents for attention deficit hyperactivity disorder and / or attention deficit disorder and a combination thereof are selected from methylphenidate, dexamphetamine, lisdexamfetine, atomoxetine and amphetamine and a combination thereof.

[0893] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is selected from dementia and Alzheimer’s disease and a combination thereof. Accordingly, the present application also includes a method of treating dementia and / or Alzheimer’s disease comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein. The present application also includes a use of a compound of formula (I) of the present disclosure for treatment of dementia and / or Alzheimer’s disease, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of dementia and / or Alzheimer’s disease. The application further includes a compound of formula (I) of the present disclosure for use in treating dementia and / or Alzheimer’s disease.

[0894] In some embodiments, the disease, disorder or condition that is treated by activation of a serotonin receptor is dementia or Alzheimer’s disease and the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for dementia or Alzheimer’s disease. The one or more additional agents for dementia or Alzheimer’s disease may be any suitable agents known in the art, including those described herein. In some embodiments, the additional agents for dementia and Alzheimer’s disease are selected from acetylcholinesterase inhibitors, NMDA antagonists and nicotinic agonists. The acetylcholinesterase inhibitors may be selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof. The NMDA antagonists may be selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof. The nicotinic agonists may be selected from nicotine, nicotinic acid, nicotinic alpha7 agonists, or alpha2 beta4 agonists or a combination thereof.

[0895] 1006352981In another aspect, the present disclosure provides a method of treating a mental illness, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein. In another aspect, the present disclosure provides a method of preventing a mental illness, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein. The mental illness may be a neuropsychiatric condition.

[0896] In certain embodiments, the mental illness is selected from anxiety disorders such as generalized anxiety disorder, panic disorder, social anxiety disorder and specific phobias; depression such as, hopelessness, loss of pleasure, fatigue and suicidal thoughts; mood disorders, such as depression, bipolar disorder, cancer-related depression, anxiety and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, mania, schizophrenia, schizoaffective disorder, schizophreniform Disorder; impulse control and addiction disorders, such as pyromania (starting fires), kleptomania (stealing) and compulsive gambling; alcohol addiction; drug addiction, such as opioid addiction / dependence, nicotine dependence, cocaine dependence, marijuana abuse and so on; smoking cessation; personality disorders, such as antisocial personality disorder, aggression, obsessive-compulsive personality disorder and paranoid personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that cause a subject to perform certain rituals or routines; post-traumatic stress disorder (PTSD); stress response syndromes (formerly called adjustment disorders); dissociative disorders, formerly called multiple personality disorder, or "split personality," and depersonalization disorder; factitious disorders; sexual and gender disorders, such as sexual dysfunction, gender identity disorder and the paraphilias; somatic symptom disorders, formerly known as a psychosomatic disorder or somatoform disorder.

[0897] In some embodiments, the mental illness is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; drug addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorder; factitious disorders; sexual and gender disorders; somatic symptom disorders; hallucinations; delusions; psychosis; and combinations thereof.

[0898] 1006352981In certain embodiments, the mental illness is selected from hallucinations and delusions and a combination thereof. In these embodiments, the hallucinations may be selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations and chronoceptive hallucinations, and a combination thereof.

[0899] In another aspect, the present disclosure provides a method for treating a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0900] In another aspect, the present disclosure provides a method for preventing a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.

[0901] In some embodiments, the CNS disease, disorder or condition and / or neurological disease, disorder or condition is selected from neurological diseases including neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer’s disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment, Parkinson’s disease and Parkinsonian related disorders such as Parkinson dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infections; CNS inflammation; stroke; multiple sclerosis; Huntington’s disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otological and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesias; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorders; restless leg syndrome; Tourette's syndrome; Tic disorder; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia nervosa and bulimia nervosa; binge eating disorder, trichotillomania, dermotillomania, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0902] In another aspect, the present disclosure provides a method for increasing neuronal plasticity, the method comprising contacting a neuronal cell with a compound of formula

[0903] 1006352981(I) or a pharmaceutical composition as described herein, in an amount sufficient to increase neuronal plasticity of the neuronal cell. “Neuronal plasticity” refers to the ability of the brain to change its structure and / or function continuously throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and / or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.

[0904] In some embodiments, increasing neuronal plasticity can treat neurodegenerative disorder, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.

[0905] In another aspect the present disclosure provides methods of treating weight, comprising administering an effective amount of a compound of the invention to a subject in need thereof. Treatment of weight may include treating weight gain; weight loss; metabolic disorder; weight gain associated with pharmaceutical intervention; weight gain associated with a mental illness (including those described herein); eating disorders such as anorexia, bulimia, cachexia, etc.; eating behaviour; obesity; diabetes; insulin resistance; pre-diabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.

[0906] In another aspect, the present disclosure provides a method for increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of formula (I) or a pharmaceutical composition as described herein, in an amount sufficient to increase dendritic spine density of the neuronal cell.

[0907] In certain embodiments, the compound of formula (I) produces a maximum number of dendritic crossings with an increase of greater than 1.0 fold by a Sholl Analysis.

[0908] 1006352981In another aspect the present disclosure provides a method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, comprising administering a compound of formula (I) as defined in any one of the herein disclosed embodiments to the cell. The serotonin receptor may be a 5-HT receptor subtype, preferably one or both of 5-HT2A and 5-HT2c.

[0909] In some embodiments, effective amounts vary according to factors such as the disease state, age, sex and / or weight of the subject or species. In some embodiments, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated and the like, but can nevertheless be routinely determined by one skilled in the art.

[0910] In some embodiments, the compounds of formula (I) of the present disclosure are administered one, two, three or four times a year. In some embodiments, the compounds of the present disclosure are administered at least once a week. However, in another embodiment, the compounds are administered to the subject from about one time per two weeks, three weeks or one month. In another embodiment, the compounds are administered about one time per week to about once daily. In another embodiment, the compounds are administered 1, 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the seventy of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of the compounds of the application and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject. In some embodiments, the compounds of the application are administered at doses that are hallucinogenic or psychotomimetic and taken in conjunction with psychotherapy or therapy and may occur once, twice, three, or four times a year. However, in some embodiments, the compounds are administered to the subject once daily, once every two days, once every 3 days, once a week, once every two weeks, once a month, once

[0911] 1006352981every two months, or once every three months at doses that are not hallucinogenic or psychotomimetic.

[0912] A compound of formula (I) of the present disclosure may be either used alone or in combination with other known agents useful for treating diseases, disorders or conditions by activation of a serotonin receptor, such as the compounds of the present disclosure. When used in combination with other known agents useful in treating diseases, disorders by activation of a serotonin receptor, it is an embodiment that a compound of formu;a (I) is administered contemporaneously with those agents. As used herein, "contemporaneous administration" of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable.

[0913] Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion. In some embodiments, a compound of formula (I) of the present disclosure is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of formula (I) as described herein, an additional therapeutic agent and a pharmaceutically acceptable carrier.

[0914] In some embodiments, the compounds of the application are used or administered in an effective amount which comprises administration of doses or dosage regimens that are devoid of clinically meaningful psychedelic / psychotomimetic actions. In some embodiments, the compounds of the application are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similar to those exhibited by a human plasma psilocin Cmax of 4 ng / mL or less and / or human 5-HT2A human CNS receptor occupancy of 40% or less or those exhibited by a human plasma psilocin Cmax of 1 ng / mL or less and / or human 5-HT2A human CNS receptor occupancy of 30% or less. In some embodiments, the

[0915] 1006352981compounds of the application are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similar to those exhibited by a human plasma psilocin Tmax in excess of 60 minutes, in excess of 120 minutes or in excess of 180 minutes.

[0916] Kit

[0917] In another embodiment there is provided a kit or article of manufacture including one or more compounds, pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph, and / or pharmaceutical compositions as described above.

[0918] In other embodiments there is provided a kit for use in a therapeutic application mentioned above, the kit including:

[0919] a container holding one or more compounds, pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph and / or pharmaceutical compositions as described herein;

[0920] a label or package insert with instructions for use.

[0921] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or examples. All of these different combinations constitute various alternative aspects of the invention.

[0922] Examples

[0923] General

[0924] Reference will now be made to specific embodiments of the invention. While the synthetic protocols outlined below will describe specific embodiments of the invention, it is understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention and defined by the claims.

[0925] One skilled in the art will recognise numerous methods and materials similar or equivalent to those described herein. The present invention is in no way limited to the materials and methods described. It will be understood that the choice of structural 1006352981features or substitution patterns surrounding the core scaffolds outlined above will influence the selection of one process over another. Starting materials are available from commercial sources or may be readily prepared from available precursors following straightforward transformations that are well known to one skilled in the art.

[0926] In the examples below, unless otherwise stated, temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, “rt,” or “RT,” (typically a range of from about 18-25 °C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (typically, 4.5-30 mm Hg) with a bath temperature of up to 60 °C; the course of reactions was typically followed by thin layer chromatography (TLC); melting points are uncorrected; products exhibited satisfactory1H NMR and / or microanalytical data; and the following conventional abbreviations are also used: L (litres), mL (millilitres), mmol (millimoles), g (grams), mg (milligrams), min (minutes), and h (hours).

[0927] Unless otherwise specified, all solvents and reagents were purchased from suppliers and used without further purification. Reactions were conducted under a nitrogen atmosphere unless otherwise stated. Compounds were visualized under UV lamp (254 nm).1H NMR spectra were recorded on a 300 MHz, 400 MHz, or 600 MHz NMR instrument as indicated. Column and flash chromatography was performed using SiO2 as the stationary phase and “MeOH / NH3” refers to a 9:1 solution of methanol to 15 M aqueous ammonia.

[0928] LCMS was carried out using the following conditions.

[0929] Instrument Column Mobile Phase (A / B) Time Program

[0930] Shimadzu LC- Waters XSelect 0.1% FA in 5-100% B over 20AD XR, 8030 C18 (3.5 pm, H2O / 0.1% FA in 7 minutes (1

[0931] triple quadrupole 1.6 x 150 mm) MeCN mL / min)

[0932] mass spectrometer [25 °C]

[0933]

[0934] 1006352981General Procedure A: / V-alkylation of amines with substituted 3-(2-chloroethyl)-1 H-pyrrolo[3,2-b]pyridine

[0935] The required amine hydrochloride (2.5 - 3 eq.) was added to a stirred suspension of the appropriately substituted 3-(2-chloroethyl)-1 / - / -pyrrolo[3,2-b]pyridine (1.0 eq.) and K2CO3 (10 eq.) in anhydrous MeCN (0.33 M) and the reaction mixture was heated to 80 °C under a reflux condenser and stirred for 16 - 24 h. The reaction mixture was diluted with H2O (4 x reaction volume) and extracted with an equal volume of EtOAc or CHCI3 three times. The combined organic extracts were washed with an equal volume of brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography (0 - 10% MeOH / NH3 in CH2CI2) to afford the desired compound.

[0936] General Procedure B: / V-alkylation of amines with substituted 3-(2-chloroethyl)-1H-pyrrolo[3,2-b]pyridine with in situ Finkelstein halide exchange

[0937] The required amine (3 eq.) was added to a stirred suspension of the appropriately substituted 3-(2-chloroethyl)-1 / - / -pyrrolo[3,2-b]pyridine (1 eq.) and potassium iodide (1 eq.) in anhydrous MeCN (0.2 M) and the reaction mixture was heated to 60 °C and stirred for 8 h. The reaction was then concentrated under a stream of nitrogen gas, before being diluted with H2O (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography (0.5 - 15% MeOH / NH3 in CH2CI2) to afford the desired compound. General Procedure C: Formulation of fumaric acid and oxalic acid salts from amines

[0938] The freebase amine was dissolved in a minimal volume of solvent (acetone or / PrOH) and added to a hot solution of fumaric acid or oxalic acid (acetone or / PrOH, 1 - 3 eq., 0.02 - 0.2 M). The resultant mixture was heated to between 40 - 60 °C and cooled to RT. Precipitation was initiated by addition of Et20 or hexane if necessary and then stood at 4 °C. The precipitate was collected by vacuum filtration and washed with Et20 to give the desired product.

[0939] 1006352981Synthesis of compounds

[0940] Compounds of formula (I) can be synthesised from an appropriately substituted 6,5-aromatic system following the steps outlined in Scheme 1 below or similar as one skilled in the art may consider. Various substituted 6,5-aromatic systems are commercially available or may be prepared by techniques known in the art, for example as described in WO2015 / 158313 and Landagaray E et al (European Journal of Medicinal Chemistry, Volume 127, 15 February 2017, Pages 621-631).

[0941] Scheme 1: Compounds of general formula (I) can be synthesised from an appropriately substituted 1 / - / -pyrrolo[3,2-b]pyridine system following the outlined sequence of steps in Scheme 1 or similar as would be apparent to one skilled in the art. An appropriately substituted 1 / - / -pyrrolo[3,2-b]pyridine system can undergo a Freidel-Crafts acylation with 2-halo acetylhalides followed by reduction to generate alkylhalides that can undergo nucleophilic substitution reactions with various amines allowing access to compounds of general formula (I) (exemplified by compounds S11 to S26, S37 to S46, S57 to S66 and S72 to S132).

[0942]

[0943] Scheme 1

[0944] In Scheme 1, X represents a halogen. In alternatives of the above scheme, X may represent an alternative leaving group, such as mesylate, tosylate or similar as is known in the art.

[0945] Example 1: Syntheses of compounds of formula (I)

[0946] In the following example, the synthesis of a selection of representative compounds of formula (I) are described.

[0947] 1006352981Synthesis of 5-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-6]pyridine (S12)

[0948]

[0949] Step 1: 2-chloro-1-(5-fluoro-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (1)

[0950] A suspension of 5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (9.76 g, 71.7 mmol) in CH2CI2 (180 mL) at 0 °C was treated with powdered AICI3 (47.8 g, 358 mmol) followed by 2-chloroacetyl chloride (14.3 mL, 179 mmol) and the mixture was stirred for 3 h at RT. The reaction was poured into ice water (600 mL) which was stirred vigorously. The resultant precipitate was collected by vacuum filtration and washed with MeOH to afford 2-chloro-1-(5-fluoro-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one as a light yellow solid (11.3 g, 74%).1H NMR (400 MHz, DMSO-56): 512.57 (s, 1H), 8.47 (d, J = 3.5 Hz, 1H), 8.09 (dd, J = 8.7, 7.3 Hz, 1 H), 7.01 (dd, J = 8.7, 1.6 Hz, 1 H), 5.08 (s, 2H);13C NMR (101 MHz, DMSO-de): 5185.7, 159.6 (d, J = 231.2 Hz), 139.4 (d, J = 19.1 Hz), 136.4, 127.8 (d, J = 2.4 Hz), 126.1 (d, J = 10.1 Hz), 113.7, 103.9 (d, J = 42.3 Hz), 48.5.

[0951] Step 2: 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (2)

[0952] To a solution of 2-chloro-1-(5-fluoro-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (11.3 g, 53.1 mmol) in TFA (60 mL) was added EtsSiH (59.4 mL, 372 mmol) and the mixture was stirred at 80 °C for 4 h. The reaction was poured over ice (600 mL), neutralised with 3 M aq. NaOH and extracted with EtOAc (3 x 140 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced

[0953] 1006352981pressure. The solid was triturated with warm hexane and collected by vacuum filtration to afford 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (9.43 g, 89%) as an off-white solid.1H NMR (400 MHz, DMSO-d6): 511.34 (s, 1 H), 7.90 (dd, J = 8.6, 7.4 Hz, 1H), 7.59 (s, 1H), 6.81 (dd, J = 8.7, 1.6 Hz, 1H), 3.88 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H);13C NMR (101 MHz, DMSO-d6): 5158.4 (d, J = 228.0 Hz), 140.9 (d, J = 18.3 Hz), 129.0, 127.1 (d, J = 2.0 Hz), 124.2 (d, J = 9.9 Hz), 110.8, 101.9 (d, J = 42.9 Hz), 44.6, 27.6.

[0954] Step 3: 5-fluoro-3-(2-(pyrrolidin-1 -yl)ethyl)-1 / - / -pyrrolo[3,2-£>]pyridine (S12)

[0955] A solution of 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (500 mg, 2.52 mmol) in pyrrolidine (5 mL) was heated to 55 °C and stirred for 3.5 h. The reaction mixture was diluted with EtOAc (40 mL), washed with water (3 x 15 mL), brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by recrystallisation from CH2CI2 by addition of hexane as antisolvent. The precipitate was collected by vacuum filtration to afford the title compound as off-white crystals (415 mg, 71%).1H NMR (400 MHz, CDCI3): 59.57 (s, 1H), 7.29 (dd, J = 8.6, 7.1 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1 H), 6.51 (dd, J = 8.6, 1.6 Hz, 1 H), 3.04 - 2.92 (m, 4H), 2.73 - 2.63 (m, 4H), 1.88 - 1.75 (m, 4H).

[0956] Step 4: 5-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[0957] (S12-fumarate)

[0958] 5-fluoro-3-(2-(pyrrolidin-1 -yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (410 mg, 1.76 mmol) was formulated as the fumarate salt according to General Procedure C, to afford a white crystalline solid (1:1.4 amine:fumaric acid, 465 mg, 67%).1H NMR (400 MHz, DMSO-d6. 511.39 (s, 1 H), 7.90 (dd, J = 8.6, 7.4 Hz, 1 H), 7.57 (d, J = 2.7 Hz, 1 H), 6.81 (dd, J = 8.6, 1.6 Hz, 1H), 6.53 (s, 2.8H), 3.23 - 3.13 (m, 2H), 3.08 - 3.02 (m, 4H), 3.02 -2.96 (m, 2H), 1.91 - 1.79 (m, 4H);13C NMR (101 MHz, DMSO-d6): 5167.1, 158.1 (d, J = 227.8 Hz), 140.8 (d, J = 18.2 Hz), 134.7, 128.4, 127.0 (d, J = 1.8 Hz), 124.0 (d, J = 9.8 Hz), 110.5, 101.7 (d, J = 42.9 Hz), 54.5, 53.0, 22.9, 21.3;1H qNMR Purity: 97.7% (ERETIC); LCMS: tR(3.888 min) m / z = 234.15 [M+H]+.

[0959] 1006352981Synthesis of 3-(2-(2,2-dimethylpyrrolidin-1 -yl)ethyl)-5-fluoro-1 H-pyrrolo[3,2-b]pyridine (S14)

[0960]

[0961] 2 S14

[0962] Step 1: 3-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (S14)

[0963] A mixture of 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (300 mg, 1.51 mmol) and 2,2-dimethylpyrrolidine (0.37 mL, 3.02 mmol) in a sealed pressure tube was heated at 80 °C for 16 h. The reaction mixture was cooled, diluted with EtOAc (30 mL) and H2O was added under stirring until everything dissolved. The phases were separated and the aqueous layer was further extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (3 * 10 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (0.1% - 8% MeOH / NH3 in CH2CI2) to afford the title compound as a white solid (355 mg, 90%).1H NMR (400 MHz, DMSO-d6. 511.19 (s, 1 H), 7.85 (dd, J = 8.6, 7.5 Hz, 1 H), 7.52 (d, J = 2.7 Hz, 1 H), 6.76 (dd, J = 8.6, 1.6 Hz, 1 H), 2.83 - 2.73 (m, 4H), 2.71 - 2.57 (m, 2H), 1.77 - 1.62 (m, 2H), 1.62 -1.47 (m, 2H), 0.93 (s, 6H);13C NMR (101 MHz, DMSO-d6): 5158.0 (d, J = 226.9 Hz), 141.1 (d, J = 18.3 Hz), 127.9, 126.9 (d, J = 1.8 Hz), 123.7 (d, J = 9.9 Hz), 113.1, 101.4 (d, J = 43.2 Hz), 59.9, 50.3, 48.7, 39.6, 23.9, 22.5, 20.2;19F NMR (376 MHz, DMSO-d6): 5 -76.3.

[0964] Step 2: 3-(2-(2,2-dimethylpyrrolidin-1 -yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S14-fumarate)

[0965] 3-(2-(2,2-dimethylpyrrolidin-1-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (330 mg, 1.26 mmol) was formulated as the fumarate salt according to General Procedure C, to afford a white crystalline solid (1:1 amine:fumaric acid, 412 mg, 87%).1H NMR (400 MHz, DMSO-c / e): 511.47 (s, 1 H), 7.91 (dd, J = 8.6, 7.4 Hz, 1 H), 7.61 (d, J = 2.6 Hz, 1 H), 6.81 (dd, J = 8.6, 1.4 Hz, 1 H), 6.49 (s, 2H), 3.39 - 3.26 (m, 2H), 3.16 - 2.95 (m, 4H), 1.95 -1.73 (m, 4H), 1.21 (s, 6H);13C NMR (101 MHz, DMSO-d6): 5167.9, 158.3 (d, J = 228.1

[0966] 1006352981Hz), 140.9 (d, J = 18.0 Hz), 135.2, 128.7, 127.1, 124.3 (d, J = 9.9 Hz), 110.6, 101.9 (d, J = 42.8 Hz), 66.4, 50.4, 48.0, 37.8, 21.6, 21.4, 19.6;19F NMR (376 MHz, DMSO-56): 5-76.1;1H qNMR Purity: 97.4% (ERETIC).

[0967] Synthesis of (R)-5-fluoro-3-(2-(2-methylpyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S15)

[0968]

[0969] Step 1: (R)-5-fluoro-3-(2-(2-methylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S15)

[0970] General Procedure A using 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (300 mg, 1.51 mmol) and (R)-2-methylpyrrolidine hydrochloride (459 mg, 3.78 mmol) afforded the title compound as an off-white solid (299 mg, 80%).1H NMR (400 MHz, CDCIs): 511.19 (s, 1 H), 7.85 (dd, J = 8.6, 7.4 Hz, 1 H), 7.51 (d, J = 2.5 Hz, 1 H), 6.77 (dd, J = 8.6, 1.6 Hz, 1H), 3.19 - 3.11 (m, 1H), 3.11 - 3.02 (m, 1H), 2.91 -2.81 (m, 1H), 2.80 - 2.70 (m, 1H), 2.35 -2.24 (m, 2H), 2.14 (q, J = 8.7 Hz, 1H), 1.91 - 1.80 (m, 1H), 1.72 - 1.56 (m, 2H), 1.34 - 1.22 (m, 1 H), 1.01 (d, J = 6.0 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5158.2 (d, J = 227.1 Hz), 141.2 (d, J = 18.2 Hz), 128.0, 127.0 (d, J = 2.1 Hz), 123.9 (d, J = 9.9 Hz), 113.1, 101.6 (d, J = 43.1 Hz), 59.5, 53.9, 53.3, 32.6, 23.1, 21.5, 19.0.

[0971] Step 2: (R)-5-fluoro-3-(2-(2-methylpyrrolidin-1 -y l)ethy l)-1 / - / -pyrrolo[3, 2-£>]py rid ine fumarate (S15-fumarate)

[0972] (R)-5-fluoro-3-(2-(2-methylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (242 mg, 0.98 mmol) was formulated as the fumarate salt according to General Procedure C to afford light brown crystals (1:1 amine:fumaric acid, 296 mg, 83%).1H NMR (400 MHz, DMSO-cfe): 511.49 - 11.27 (m, 1 H), 7.89 (dd, J = 8.6, 7.4 Hz, 1 H), 7.58 (d, J = 2.7 Hz, 1 H), 6.80 (dd, J = 8.6, 1.5 Hz, 1 H), 6.51 (s, 2H), 3.48 - 3.40 (m, 1 H), 3.38 - 3.29 (m, 1 H), 3.05 -2.88 (m, 3H), 2.87 - 2.77 (m, 1H), 2.72 (q, J = 8.9 Hz, 1H), 2.10 - 1.97 (m, 1H), 1.87 - 1.76 (m, 2H), 1.56 - 1.42 (m, 1H), 1.20 (d, J = 6.3 Hz, 3H);13C NMR (101 MHz, DMSO-cfe): 5167.3, 158.2 (d, J = 227.8 Hz), 140.9 (d, J = 18.2 Hz), 134.9, 128.3, 127.0

[0973] 1006352981(d, J = 2.0 Hz), 124.1 (d, J = 9.9 Hz), 111.0, 101.7 (d, J = 43.0 Hz), 61.2, 52.6, 52.5, 31.6, 21.4, 21.2, 16.9;1H qNMR Purity: 98.1% (ERETIC).

[0974] Synthesis of (S)-5-fluoro-3-(2-(2-methylpyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S16)

[0975]

[0976] Step 1: (S)-5-fluoro-3-(2-(2-methylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S16)

[0977] General Procedure A using 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-5]pyridine (300 mg, 1.51 mmol) and (S)-2-methylpyrrolidine hydrochloride (459 mg, 3.78 mmol) afforded the title compound as an off-white solid (292 mg, 78%).1H NMR (400 MHz, CDCIs): 59.12 (s, 1H), 7.43 (dd, J = 8.6, 7.1 Hz, 1H), 7.19 (d, J= 2.6 Hz, 1H), 6.59 (dd, J = 8.6, 1.6 Hz, 1H), 3.41 - 3.28 (m, 2H), 3.13 - 3.04 (m, 1H), 3.03 -2.92 (m, 1H), 2.60 - 2.42 (m, 2H), 2.34 (q, J = 8.9 Hz, 1 H), 2.04 - 1.91 (m, 1 H), 1.89 - 1.72 (m, 2H), 1.52 - 1.41 (m, 1 H), 1.19 (d, J = 6.1 Hz, 3H).

[0978] Step 2: (S)-5-fluoro-3-(2-(2-methylpyrrolidin-1 -y I )ethy l)-1 / - / -pyrrolo[3, 2-£>]py ridine fumarate (S16-fumarate)

[0979] (S)-5-fluoro-3-(2-(2-methylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-5]pyridine (260 mg, 1.05 mmol) was formulated as the fumarate salt according to General Procedure C to afford off-white crystals (1:1 amine:fumaric acid, 246 mg, 64%).1H NMR (400 MHz, DMSO-cfe): 511.38 (s, 1 H), 7.90 (dd, J = 8.6, 7.4 Hz, 1 H), 7.58 (d, J = 2.7 Hz, 1 H), 6.80 (dd, J = 8.6, 1.6 Hz, 1 H), 6.51 (s, 2H), 3.50 - 3.41 (m, 1 H), 3.39 - 3.28 (m, 1 H), 3.06 - 2.88 (m, 3H), 2.87 - 2.78 (m, 1H), 2.73 (q, J = 8.8 Hz, 1H), 2.10 - 1.96 (m, 1H), 1.88 - 1.76 (m, 2H), 1.56 - 1.42 (m, 1 H), 1.21 (d, J = 6.3 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5 167.3, 158.2 (d, J = 227.7 Hz), 140.9 (d, J = 18.4 Hz), 134.9, 128.3, 127.0 (d, J = 2.0 Hz), 124.1 (d, J = 9.9 Hz), 111.0, 101.7 (d, J = 43.0 Hz), 61.2, 52.6, 52.5, 31.6, 21.4, 21.2, 16.8;1H qNMR Purity: 98.4% (ERETIC).

[0980] 1006352981Synthesis of 3-(2-(azetidin-1-yl)ethyl)-5-fluoro-1H-pyrrolo[3,2-6]pyridine (S17)

[0981]

[0982] Step 1: 3-(2-(azetidin-1-yl)ethyl)-5-fluoro-1H-pyrrolo[3,2-b]pyridine (S17)

[0983] A solution of 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (1.0 g, 5.03 mmol) in acetonitrile (10 mL) in a pressure tube was treated with sodium iodide (755 mg, 5.03 mmol) and azetidine (1.7 mL, 25.2 mmol) and then the reaction was heated at 40 °C for 36 h. The volatiles were then removed under a stream of nitrogen gas and the residue was purified by flash chromatography (1% - 8% MeOH / NH3 in CH2CI2) to afford the title compound as an off-white solid (527 mg, 48%).1H NMR (400 MHz, DMSO-c / e): 611.19 (s, 1 H), 7.85 (dd, J = 8.6, 7.5 Hz, 1 H), 7.48 (d, J = 2.7 Hz, 1 H), 6.77 (dd, J = 8.6, 1.7 Hz, 1 H), 3.10 (t, J = 6.9 Hz, 4H), 2.69 - 2.53 (m, 4H), 1.94 (p, J = 6.9 Hz, 2H);13C NMR (101 MHz, DMSO-c / e): 5158.1 (d, J = 226.8 Hz), 141.1 (d, J = 18.3 Hz), 128.0, 126.9 (d, J = 1.9 Hz), 123.7 (d, J = 9.8 Hz), 112.6, 101.4 (d, J = 43.2 Hz), 59.5, 54.5, 21.9, 17.2.

[0984] Step 2: 3-(2-(azetidin-1-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[0985] (S17-fumarate)

[0986] 3-(2-(azetidin-1-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (380 mg, 1.73 mmol) was formulated as the fumarate salt according to General Procedure C, to afford a white crystalline solid (1:1 amine:fumaric acid, 366 mg, 63%).1H NMR (400 MHz, DMSO-c / e): 5 11.42 (s, 1 H), 7.90 (dd, J = 8.6, 7.4 Hz, 1 H), 7.55 (d, J = 2.7 Hz, 1 H), 6.81 (dd, J = 8.6, 1.5 Hz, 1 H), 6.51 (s, 2H), 3.72 (t, J = 7.7 Hz, 4H), 3.22 - 3.08 (m, 2H), 2.90 - 2.74 (m, 2H), 2.20 (p, J = 7.7 Hz, 2H);13C NMR (101 MHz, DMSO-c / e): 5167.7, 158.2 (d, J = 227.8 Hz), 140.8 (d, J = 18.2 Hz), 135.0, 128.5, 127.0 (d, J = 1.3 Hz), 124.1 (d, J = 9.8 Hz), 110.2, 101.7 (d, J = 42.9 Hz), 55.6, 53.6, 20.0, 16.4;1H qNMR Purity: 98.9% (ERETIC); LCMS: tR(3.720 min) m / z = 220.15 [M+H]+.

[0987] 1006352981Synthesis of ( / ?)-5-fluoro-3-(2-(2-methylazetidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S19)

[0988]

[0989] Step 1: (R)-5-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S19)

[0990] General Procedure A using 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-5]pyridine (300 mg, I.51 mmol) and (R)-2-methylazetidine hydrochloride (406 mg, 3.78 mmol) afforded the title compound as an off-white solid (56 mg, 16%).1H NMR (400 MHz, DMSO-cfe): 5 I I.18 (s, 1 H), 7.85 (dd, J = 8.6, 7.4 Hz, 1 H), 7.48 (d, J = 2.5 Hz, 1 H), 6.77 (dd, J = 8.6, 1.6 Hz, 1H), 3.28 - 3.20 (m, 1H), 3.14 - 3.00 (m, 1H), 2.85 - 2.72 (m, 1H), 2.70 - 2.60 (m, 3H), 2.53 - 2.45 (m, 1 H), 2.03 - 1.92 (m, 1 H), 1.69 - 1.56 (m, 1 H), 1.11 (d, J = 6.1 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5158.2 (d, J = 227.1 Hz), 141.1 (d, J = 18.2 Hz), 128.0, 127.0 (d, J = 2.1 Hz), 123.9 (d, J = 9.9 Hz), 112.9, 101.5 (d, J = 43.1 Hz), 62.0, 58.4, 51.0, 25.4, 22.3, 21.9;1H qNMR Purity: 98.3% (ERETIC).

[0991] Synthesis of (S)-5-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1H-pyrrolo[3,2-b]pyridine (S20)

[0992]

[0993] 2

[0994] Step 1: (S)-5-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1H-pyrrolo[3,2-£)]pyridine (S20)

[0995] General Procedure A using 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-5]pyridine (300 mg, 1.51 mmol) and (S)-2-methylazetidine hydrochloride (406 mg, 3.78 mmol), afforded the title compound as an off-white solid (65 mg, 18%).1H NMR (400 MHz, CDCIs): 69.46 (s, 1H), 7.38 (dd, J = 8.6, 7.1 Hz, 1H), 7.16 (d, J = 2.6 Hz, 1H), 6.55 (dd, J = 8.6, 1.6 Hz,

[0996] 10063529811 H), 3.48 - 3.42 (m, 1 H), 3.32 - 3.21 (m, 1 H), 3.14 - 3.03 (m, 1 H), 2.92 - 2.83 (m, 3H), 2.82 -2.71 (m, 1H), 2.15 - 2.04 (m, 1 H), 1.90 - 1.75 (m, 1H), 1.27 (d, J = 6.2 Hz, 3H).

[0997] Step 2: (S)-5-fluoro-3-(2-(2-methylazetidin-1 -y I )ethy l)-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S20 -fumarate)

[0998] (S)-5-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (54 mg, 0.23 mmol) was formulated as the fumarate salt according to General Procedure C to afford an off-white solid (1:1.1 amine:fumaric acid, 24 mg, 29%).1H NMR (400 MHz, DMSO-cfe): 511.40 (s, 1 H), 7.90 (dd, J = 8.6, 7.4 Hz, 1 H), 7.55 (d, J = 2.7 Hz, 1 H), 6.81 (dd, J = 8.7, 1.6 Hz, 1H), 6.52 (s, 2H), 4.00 - 3.87 (m, 1H), 3.43 - 3.34 (m, 2H), 3.27 - 3.18 (m, 1 H), 3.10 - 2.99 (m, 1 H), 2.84 (t, J = 7.9 Hz, 2H), 2.30 - 2.20 (m, 1 H), 2.01 - 1.88 (m, 1H), 1.34 (d, J = 6.5 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5167.5, 158.2 (d, J = 227.8 Hz), 140.8 (d, J = 18.2 Hz), 134.9, 128.4, 127.0 (d, J = 2.1 Hz), 124.1 (d, J = 9.9 Hz), 110.5, 101.8 (d, J = 42.9 Hz), 63.6, 54.6, 50.3, 24.4, 20.3, 19.3;1H qNMR Purity: 97.2% (ERETIC).

[0999] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1H-pyrrolo[3,2-b]pyridine (S21)

[1000]

[1001] Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2- £>]pyridine (S21)

[1002] S21 was synthesised and worked up without chromatography according to General Procedure A using 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (5.0 g, 25.2 mmol) and racemic cis 2-azabicyclo[3.1.0]hexane hydrochloride (9.03 g, 75.5 mmol). The concentrated organic phase was washed with hexane and then suspended in CH2CI2 (~60 mL), filtered, and rinsed with CH2CI2 (25 mL). The solid was collected by vacuum filtration to afford the title compound as an off-white solid (3.45 g, 56%).1H NMR (400 MHz, CDCI3): 59.58 (s, 1H), 7.30 (dd, J = 8.6, 7.1 Hz, 1H), 7.14 (d, J = 2.6

[1003] 1006352981Hz, 1H), 6.51 (dd, J = 8.6, 1.6 Hz, 1H), 3.14 - 3.00 (m, 3H), 3.00 - 2.95 (m, 2H), 2.91 (td, J = 5.9, 2.7 Hz, 1 H), 2.07 - 1.82 (m, 3H), 1.51 - 1.41 (m, 1 H), 0.78 - 0.70 (m, 1 H), 0.19 (dt, J = 8.2, 5.8 Hz, 1H);1H qNMR Purity: 98.9% (ERETIC).

[1004] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S21 -fumarate)

[1005] Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (116 mg, 0.47 mmol) was formulated as the fumarate salt according to General Procedure C, to afford an off-white solid (1:1 amine:fumaric acid, 87 mg, 75%).1H NMR (400 MHz, DMSO-c / e): 511.28 (s, 1 H), 7.88 (dd, J = 8.6, 7.4 Hz, 1 H), 7.56 (d, J = 2.7 Hz, 1 H), 6.79 (dd, J = 8.6, 1.6 Hz, 1 H), 6.57 (s, 2H), 3.08 (t, J = 8.8 Hz, 1 H), 2.99 - 2.83 (m, 5H), 2.18 - 2.06 (m, 1H), 1.96 - 1.78 (m, 2H), 1.51 - 1.41 (m, 1H), 0.82 - 0.74 (m, 1H), 0.22 (dt, J = 8.4, 5.9 Hz, 1H);13C NMR (101 MHz, DMSO-d6): 5166.7, 158.1 (d, J = 227.2 Hz), 141.0 (d, J = 18.3 Hz), 134.4, 128.1, 126.9, 123.8 (d, J = 9.8 Hz), 111.9, 101.5 (d, J = 43.1 Hz), 53.9, 47.9, 40.1, 26.0, 22.5, 14.8, 1.9;1H qNMR Purity: 98.8% (ERETIC); LCMS: tR(3.969 min) m / z = 246.15 [M+H]+.

[1006] Synthesis of 3-(2-((1 / ?,5S)-2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1H-pyrrolo[3,2-b]pyridine (S22)

[1007]

[1008] Step 1: 3-(2-((1R,5S)-2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S22-fumarate)

[1009] A suspension of K2CO3 (696 mg, 5.03 mmol) in DMSO (5 mL) was treated with (1R,5S)-2-azabicyclo[3.1.0]hexane hydrochloride (301 mg, 2.52 mmol), followed by 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) and the reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EtOAc (70 mL) and washed with H2O (5 x 5 mL), brine (3 x 5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash

[1010] 1006352981chromatography (0.1% - 5% MeOH / NH3 in CH2CI2) to afford the title compound as an off-white solid (25 mg, 10%) which was then formulated as the fumarate salt according to General Procedure C to afford a white solid (1:1 amine:fumaric acid, 17 mg, 46%).1H NMR (400 MHz, DMSO-d6): 511.27 (s, 1 H), 7.87 (dd, J = 8.6, 7.5 Hz, 1 H), 7.55 (d, J = 2.7 Hz, 1H), 6.79 (dd, J = 8.6, 1.6 Hz, 1H), 6.57 (s, 2H), 3.10 - 3.00 (m, 1H), 2.98 -2.77 (m, 5H), 2.18 - 2.00 (m, 1H), 1.96 - 1.75 (m, 2H), 1.51 - 1.39 (m, 1H), 0.81 - 0.72 (m, 1H), 0.19 (dt, J = 8.1, 5.9 Hz, 1H);13C NMR (101 MHz, DMSO-56): 5166.6, 158.1 (d, J = 227.0 Hz), 141.1, 134.4, 128.1, 126.9 (d, J = 1.7 Hz), 123.8 (d, J = 9.9 Hz), 112.1, 101.5 (d, J = 43.0 Hz), 54.0, 47.9, 40.1, 26.1, 22.7, 14.7, 1.8;1H qNMR Purity: 100% (ERETIC).

[1011] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1-methyl-1 H-pyrrolo[3,2-b]pyridine (S24)

[1012]

[1013] Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-methyl-1 / - / -pyrrolo[3,2-b]pyridine (S24)

[1014] A solution of racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (141 mg, 0.58 mmol) in anhydrous DMF (2 mL) at 0 °C was treated with 60% w / w NaH mineral oil dispersion (30 mg, 0.75 mmol) and the mixture was stirred for 30 min. lodomethane (36 pL, 0.58 mmol) was added dropwise and the reaction was stirred at RT for 1.5 h. The reaction was quenched by dropwise addition of H2O until gas evolution ceased and the reaction mixture was diluted with EtOAc (20 mL) and H2O (10 mL). The aqueous phase was adjusted to pH 13 with 2 M aq. NaOH and the organic phase was separated. The aqueous phase was extracted with EtOAc (2 x 15 mL) and the combined organics were washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0% - 5% MeOH / NH3 in CH2CI2) to afford the title compound as a light brown oil (90 mg, 60%).1H NMR (400 MHz, CDCI3): 57.61 (dd, J = 8.7, 6.9 Hz, 1 H), 10063529817.18 (s, 1 H), 6.73 (dd, J = 8.6, 1.7 Hz, 1 H), 3.77 (s, 3H), 3.08 - 2.99 (m, 3H), 2.96 -2.78 (m, 3H), 2.10 - 1.81 (m, 3H), 1.42 (ddt, J = 8.4, 6.3, 4.5 Hz, 1H), 0.72 - 0.65 (m, 1H), 0.11 (dt, J = 8.3, 5.8 Hz, 1H).

[1015] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-methyl-1 / - / -pyrrolo[3,2-b]pyridine oxalate (S24-oxalate)

[1016] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-methyl-1 / - / -pyrrolo[3,2-b]pyridine (84 mg, 0.32 mmol) was prepared as the oxalate salt according to General Procedure C to afford a white solid (1:1 amine:oxalic acid, 70 mg, 62%).1H NMR (400 MHz, DMSO-cfe): 58.05 (dd, J = 8.7, 7.2 Hz, 1 H), 7.60 (s, 1 H), 6.90 (dd, J = 8.7, 1.5 Hz, 1 H), 3.81 (s, 3H), 3.54 - 3.40 (m, 2H), 3.33 (t, J = 7.9 Hz, 2H), 3.16 - 2.98 (m, 2H), 2.81 - 2.64 (m, 1H), 2.11 - 1.91 (m, 2H), 1.77 - 1.67 (m, 1H), 1.09 (ddd, J = 7.2, 4.7, 2.5 Hz, 1H), 0.64 (dt, J = 8.6, 6.9 Hz, 1H);13C NMR (101 MHz, DMSO-de): 5164.3, 158.3 (d, J = 228.5 Hz), 140.6 (d, J = 18.4 Hz), 132.4, 128.0 (d, J = 1.8 Hz), 122.9 (d, J = 10.0 Hz), 109.0, 101.9 (d, J = 42.9 Hz), 53.0, 48.5, 39.9, 38.1, 25.0, 20.6, 15.5, 3.2;1H qNMR Purity: 98.6% (ERETIC).

[1017] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1-ethyl-1 H-pyrrolo[3,2-b]pyridine (S25)

[1018]

[1019] Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-ethyl-1 / - / -pyrrolo[3,2-b]pyridine (S25)

[1020] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-ethyl-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in the same manner as S24, using S21 (200 mg, 0.82 mmol) and iodoethane (66 pL, 0.82 mmol) to afford a yellow / brown oil (164 mg, 74%).1H NMR (400 MHz, CDCIs): 57.63 (dd, J = 8.7, 7.0 Hz, 1 H), 7.24 (s, 1 H), 6.71 (dd, J = 8.7, 1.7 Hz, 1 H), 4.12 (q, J = 7.3 Hz, 2H), 3.11 - 2.98 (m, 3H), 2.95 - 2.78 (m, 3H), 2.08 - 1.89

[1021] 1006352981(m, 2H), 1.88 - 1.81 (m, 1 H), 1.45 (t, J = 7.3 Hz, 1 H), 1.46 - 1.38 (m, 3H), 0.68 (ddd, J = 6.3, 4.2, 2.7 Hz, 1H), 0.10 (dt, J = 8.3, 5.8 Hz, 1H).

[1022] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-ethyl-1 / - / -pyrrolo[3,2-b]pyridine oxalate (S25-oxalate)

[1023] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-1-ethyl-5-fluoro-1H-pyrrolo[3,2-b]pyridine (155 mg, 0.57 mmol) was formulated as the oxalate salt according to General Procedure C to afford a white solid (1:1 amine:oxalic acid, 151 mg, 73%).1H NMR (400 MHz, DMSO-cfe): 58.10 (dd, J = 8.7, 7.2 Hz, 1H), 7.68 (s, 1H), 6.88 (dd, J = 8.7, 1.5 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.52 - 3.41 (m, 2H), 3.34 (t, J = 8.0 Hz, 2H), 3.15 - 2.99 (m, 2H), 2.74 (q, J = 9.8 Hz, 1H), 2.11 - 1.94 (m, 2H), 1.78 - 1.68 (m, 1H), 1.35 (t, J = 7.2 Hz, 3H), 1.10 (ddd, J = 7.2, 4.8, 2.5 Hz, 1H), 0.65 (dt, J = 8.6, 6.9 Hz, 1H);13C NMR (101 MHz, DMSO-cfe): 5164.3, 158.3 (d, J = 228.7 Hz), 140.7 (d, J = 18.2 Hz), 130.7, 127.0 (d, J = 1.7 Hz), 122.9 (d, J = 9.8 Hz), 109.1, 101.9 (d, J = 42.8 Hz), 53.0, 48.6, 41.1, 40.2, 25.0, 20.7, 15.59, 15.58, 3.3;1H qNMR Purity: 100% (ERETIC).

[1024] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-fluoro-1-isopropyl-1 H-pyrrolo[3,2-b]pyridine (S26)

[1025]

[1026] Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-b]pyridine (S26)

[1027] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in the same manner as S24, using S21 (200 mg, 0.82 mmol) and 2-iodopropane (82 pL, 0.82 mmol) to afford a yellow / brown oil (109 mg, 47%).1H NMR (400 MHz, CDCh): 57.66 (dd, J = 8.7, 7.0 Hz, 1H), 7.31 (s, 1H), 6.71 (dd, J = 8.7, 1.7 Hz, 1 H), 4.57 (hept, J = 6.7 Hz, 1 H), 3.14 - 2.98 (m, 3H), 2.97 - 2.80 (m, 3H), 2.11 - 1.93 (m, 2H), 1.91 - 1.81 (m, 1H), 1.52 (d, J = 6.7 Hz, 6H), 1.43 (ddt, J

[1028] 1006352981= 8.5, 5.9, 4.3 Hz, 1 H), 0.69 (ddd, J = 6.5, 4.3, 2.7 Hz, 1 H), 0.11 (dt, J = 8.3, 5.8 Hz, 1H).

[1029] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-£>]pyridine (S26 oxalate)

[1030] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-b]pyridine (103 mg, 0.36 mmol) was formulated as the oxalate salt according to General Procedure C to afford a white solid (1:1 amine:oxalic acid, 84 mg, 62%).1H NMR (400 MHz, DMSO-de): 58.14 (dd, J = 8.8, 7.2 Hz, 1H), 7.78 (s, 1H), 6.88 (dd, J = 8.8, 1.5 Hz, 1H), 4.77 (hept, J = 6.7 Hz, 1H), 3.50 - 3.30 (m, 2H), 3.36 (t, J = 8.1 Hz, 2H), 3.15 - 2.99 (m, 2H), 2.81 - 2.66 (m, 1H), 2.12 - 1.94 (m, 2H), 1.79 - 1.69 (m, 1H), 1.44 (d, J = 6.6 Hz, 6H), 1.14 - 1.05 (m, 1H), 0.70 - 0.61 (m, 1H);13C NMR (101 MHz, DMSO-de): 5164.3, 158.3 (d, J = 228.8 Hz), 140.6 (d, J = 18.1 Hz), 127.7, 126.7 (d, J = 2.0 Hz), 123.0 (d, J = 9.8 Hz), 109.4, 101.8 (d, J = 42.6 Hz), 53.0, 48.6, 47.6, 40.2, 25.0, 22.55, 22.54, 20.9, 15.6, 3.3;1H qNMR Purity: 100% (ERETIC).

[1031] Synthesis of 3-(2-(2-ethylpyrrolidin-1 -yl)ethyl)-5-fluoro-1 H-pyrrolo[3,2-6]pyridine (S93)

[1032]

[1033] S93

[1034] Step 1: 3-(2-(2-ethylpyrrolidin-1 -yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-£>]pyridine (S93)

[1035] General Procedure A using 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) and 2-ethylpyrrolidine hydrochloride (341 mg, 2.52 mmol) gave the desired product which was recrystallised from EtOAc / hexane to afford the title compound as colourless crystals (96 mg, 36%).1H NMR (400 MHz, DMSO-de): 511.18 (s, 1H), 7.85 (dd, J = 8.6, 7.4 Hz, 1H), 7.57 - 7.47 (m, 1H), 6.76 (dd, J = 8.6, 1.6 Hz, 1H), 3.17 (ddd, J = 8.9, 6.2, 4.0 Hz, 1 H), 3.08 (ddd, J = 11.5, 10.1, 6.6 Hz, 1 H), 2.92 - 2.80 (m, 1 H), 2.80 - 2.68 (m, 1 H), 2.33 (ddd, J = 11.5, 9.7, 4.9 Hz, 1 H), 2.23 - 2.09 (m, 2H), 1.89 -1.76 (m, 1 H), 1.71 - 1.53 (m, 3H), 1.41 - 1.28 (m, 1 H), 1.26 - 1.08 (m, 1 H), 0.80 (t, J =

[1036] 10063529817.4 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5158.0 (d, J = 226.9 Hz), 141.1 (d, J = 18.3 Hz), 127.9, 126.9 (d, J = 2.2 Hz), 123.6 (d, J = 9.8 Hz), 113.0, 101.3 (d, J = 43.3 Hz), 65.3, 54.2, 53.5, 29.4, 26.1, 23.1, 21.8, 10.2;1H qNMR Purity: 99.2% (ERETIC).

[1037] Synthesis of ( / ?)-3-(2-(2-ethylpyrrolidin-1 -yl)ethyl)-5-fluoro-1 H-pyrrolo[3,2-b]pyridine (S94)

[1038]

[1039] Step 1: (R)-3-(2-(2-ethylpyrrolidin-1-yl)ethyl)-5-fluoro-1 / - / -pyrrolo[3,2-5]pyridine (S94)

[1040] General Procedure A using 3-(2-chloroethyl)-5-fluoro-1 / - / -pyrrolo[3,2-5]pyridine (200 mg, 1.01 mmol) and (R)-2-ethylpyrrolidine hydrochloride (341 mg, 2.52 mmol) gave the desired product which was recrystallised from EtOAc / hexane to afford the title compound as off-white crystals (87 mg, 33%).1H NMR (400 MHz, DMSO-cfe): 511.18 (s, 1H), 7.85 (dd, J = 8.6, 7.4 Hz, 1H), 7.52 (s, 1H), 6.76 (dd, J = 8.6, 1.7 Hz, 1H), 3.17 (ddd, J = 8.9, 6.2, 4.0 Hz, 1H), 3.08 (ddd, J = 11.5, 10.1, 6.6 Hz, 1H), 2.92 - 2.80 (m, 1 H), 2.80 - 2.68 (m, 1 H), 2.33 (ddd, J = 11.5, 9.7, 4.9 Hz, 1 H), 2.23 - 2.09 (m, 2H), 1.89 - 1.76 (m, 1H), 1.71 - 1.53 (m, 3H), 1.41 - 1.27 (m, 1H), 1.24 - 1.08 (m, 1H), 0.79 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5 158.0 (d, J = 227.1 Hz), 141.1 (d, J = 18.2 Hz), 127.9, 126.9 (d, J = 1.9 Hz), 123.6 (d, J = 9.8 Hz), 113.0, 101.3 (d, J = 43.2 Hz), 65.3, 54.2, 53.5, 29.4, 26.2, 23.1, 21.8, 10.2;1H qNMR Purity: 100% (ERETIC).

[1041] Synthesis of 5-chloro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-6]pyridine (S38)

[1042]

[1043] 1006352981Step 1: 2-chloro-1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (3)

[1044] To an ice-cold stirred suspension of 5-chloro-1 / - / -pyrrolo[3,2-b]pyridine (1.52 g, 10.0 mmol) in anhydrous CH2CI2 (25 mL) was added powdered AICl3(2.39 g, 17.9 mmol) portion wise over 20 min and the suspension was stirred at RT for 1 h. Chloroacetyl chloride (1.43 mL, 17.9 mmol) was added dropwise and the resultant mixture was stirred for 18 h. The reaction mixture was poured onto ice (~ 50 g) and filtered. The precipitate was washed with H2O (3 x 20 mL) and air dried to give the desired compound as a white powder (1.98 g, 87%).1H NMR (400 MHz, MeOD-ck): 68.36 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 5.12 (s, 2H).

[1045] Step 2: 3-(2-chloroethyl)-5-chloro-1H-pyrrolo[3,2-b]pyridine (4)

[1046] A solution of 2-chloro-1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (1.90 g, 8.30 mmol) in EtsSiH (10 mL) and trifluoroacetic acid (10 mL) was heated to 70 °C and stirred for 12 h. The reaction mixture was poured onto ice (~20 g) and neutralised by portion wise addition of solid K2CO3. The mixture was extracted with CH2CI2 (3 x 25 mL) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexane) to afford the title compound as a white solid (1.08 g, 61%).1H NMR (400 MHz, DMSO-d6): 511.40 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 3.90 (t, J = 7.3 Hz, 2H), 3.22 - 3.10 (m, 2H);13C NMR (101 MHz, DMSO-56): 5144.3, 142.2, 129.0, 127.5, 122.1, 116.0, 110.8, 44.5, 27.4.

[1047] Step 3: 5-chloro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[1048] (S38 -fumarate)

[1049] General Procedure B using 3-(2-chloroethyl)-5-chloro-1 / - / -pyrrolo[3,2-b]pyridine (215 mg, 1.00 mmol) and pyrrolidine (0.25 mL, 3.00 mmol) gave the desired product which was formulated as the fumarate salt according to General Procedure C as an off-white solid (2:1 amine:fumaric acid, 176 mg, 57%).1H NMR (400 MHz, DMSO-56): 5 11.45 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 2.6 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 6.46 (s, 1H), 3.05 - 2.90 (m, 4H), 2.90 - 2.75 (m, 4H), 1.86 - 1.68 (m, 4H);13C NMR (101 MHz, DMSO-de): 5168.1, 144.4, 142.0, 135.2, 128.4, 127.6, 122.0, 115.9, 111.7, 55.2, 53.2,

[1050] 100635298123.0, 22.0;1H qNMR Purity: 98.4% (ERETIC); LCMS: tR(4.157 min) m / z = 250.15, 252.10 [M+H]+.

[1051] Synthesis of (R)-5-chloro-3-(2-(2-methylpyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S40)

[1052]

[1053] Step 1. (R)-5-chloro-3-(2-(2-methylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S40)

[1054] General Procedure A using 3-(2-chloroethyl)-5-chloro-1 / - / -pyrrolo[3,2-b]pyridine (150 mg, 0.7 mmol) and (R)-2-methylpyrrolidine hydrochloride (212 mg, 1.74 mmol) afforded the title compound as a white solid (102 mg, 55%).1H NMR (400 MHz, DMSO-CAJ): 5 11.26 (s, 1H), 7.76 (d, J = 8.5 Hz, 1 H), 7.55 (d, J = 2.6 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1H), 3.21 - 3.14 (m, 1H), 3.13 - 3.05 (m, 1H), 2.96 - 2.84 (m, 1H), 2.84 -2.71 (m, 1H), 2.37 - 2.24 (m, 2H), 2.14 (q, J = 8.7 Hz, 1H), 1.93 - 1.80 (m, 1H), 1.72 - 1.58 (m, 2H), 1.35 - 1.22 (m, 1H), 1.02 (d, J = 6.0 Hz, 3H);13C NMR (101 MHz, DMSO-d6): 5144.6, 141.8, 128.0, 127.4, 121.7, 115.6, 113.2, 59.3, 53.7, 53.2, 32.5, 22.9, 21.4, 19.0;1H qNMR Purity: 98.9% (ERETIC).

[1055] Synthesis of 5-bromo-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-b]pyridine (S58)

[1056]

[1057] Step 1: 2-chloro-1-(5-bromo-1 / - / -pyrrolo[3,2-5]pyridin-3-yl)ethan-1-one (5)

[1058] 1006352981To an ice-cold stirred suspension of 5-bromo-1 / - / -pyrrolo[3,2-b]pyridine (1.97 g, 10.0 mmol) in anhydrous CH2CI2 (25 mL) was added powdered AICl3(2.39 g, 17.9 mmol) portion wise over 20 min and the resultant suspension was stirred at RT for 1 h.

[1059] Chloroacetyl chloride (1.43 mL, 17.9 mmol) was added dropwise and the suspension stirred for 18 h. The reaction mixture was poured onto ice (~50 g) and then filtered. The precipitate was washed with H2O (3 x 20 mL) and air dried to give the desired compound as an off-white powder (2.20 g, 80%).1H NMR (400 MHz, MeOD-ck): 68.34 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 5.12 (s, 2H).

[1060] Step 2: 3-(2-chloroethyl)-5-bromo-1 / - / -pyrrolo[3,2-b]pyridine (6)

[1061] A solution of 2-chloro-1-(5-bromo-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (2.2 g, 8.04 mmol) in EtsSiH (10 mL) and trifluoroacetic acid (10 mL) was heated to 70 °C and stirred for 12 h. The reaction mixture was poured onto ice (~20 g) and neutralised by portionwise addition of solid K2CO3. The mixture was extracted with CH2CI2 (3 x 25 mL) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexane) to afford the title compound as a white solid (1.23 g, 59%).

[1062] Step 3: 5-bromo-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[1063] (S58 -fumarate)

[1064] General Procedure B using 3-(2-chloroethyl)-5-bromo-1 / - / -pyrrolo[3,2-b]pyridine (260 mg, 1.00 mmol) and pyrrolidine (0.25 mL, 3.00 mmol) gave the desired compound which was formulated as the fumarate salt according to General Procedure C as an off-white solid (2:1 amine:fumaric acid, 210 mg, 60%).1H NMR (400 MHz, DMSO-CAJ): 5 11.45 (s, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 2.6 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 6.47 (s, 1 H), 3.05 - 2.91 (m, 4H), 2.90 - 2.77 (m, 4H), 1.88 - 1.67 (m, 4H);13C NMR (101 MHz, DMSO-de): 5167.9, 145.3, 135.1, 132.6, 128.3, 127.7, 122.0, 119.3, 111.7, 55.2, 53.3, 23.0, 22.1;1H qNMR Purity: 96.6% (ERETIC); LCMS: tR(4.275 min) m / z = 294.05, 296.05 [M+H]+.

[1065] 1006352981Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-bromo-1H-pyrrolo[3,2-b]pyridine (S66)

[1066]

[1067] S66

[1068] Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-bromo-1 / - / -pyrrolo[3,2-b]pyridine (S66)

[1069] A solution of 3-(2-chloroethyl)-5-bromo-1 / - / -pyrrolo[3,2-b]pyridine (175 mg, 0.67 mmol) in MeCN (2 mL) was treated with K2CO3 (600 mg, 4.05 mmol) and racemic cis 2-azabicyclo[3.1.0]hexane hydrochloride (202 mg, 1.69 mmol) and the resultant mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was filtered and the filter cake washed with MeCN (20 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (2 - 8% MeOH / NH3 in CH2CI2) to afford the title compound as an off-white solid (30 mg, 15%).

[1070] 1H NMR (400 MHz, DMSO-d6): 511.27 (s, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 2.6 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 3.00 - 2.80 (m, 3H), 2.80 - 2.63 (m, 3H), 1.94 - 1.66 (m, 3H), 1.43 - 1.26 (m, 1 H), 0.71 - 0.60 (m, 1 H), 0.02 (dt, J = 8.2, 5.5 Hz, 1 H);13C NMR (101 MHz, DMSO-cfe): 5145.5, 132.5, 127.9, 127.6, 121.7, 119.0, 113.2, 54.4, 47.7, 40.3, 26.5, 23.3, 14.5, 1.3;1H qNMR Purity: 99.8% (ERETIC).

[1071] Synthesis of 5-methoxy-3-(2-(pyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S73):

[1072]

[1073] 1006352981Step 1: 2-chloro-1-(5-methoxy-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (5)

[1074] To an ice-cold stirred suspension of 5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (5 g, 33.7 mmol) in anhydrous CH2CI2 (100 mL) was added AICI3 (22.5 g, 169 mmol) portion wise. Chloroacetyl chloride (6.7 mL, 84.4 mmol) was added dropwise and the resultant mixture was stirred in an ice-bath for 30 min. The reaction mixture was poured onto ice (~200 g) with vigorous stirring and the pH was adjusted to pH 7-8 using saturated aq. NaHCOs. The suspension was diluted with EtOAc (300 mL) and saturated aq.

[1075] Rochelle’s salt (200 mL) and stirred vigorously for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated with warm CH2CI2 and cooled. The resultant solid was collected by vacuum filtration to afford the title compound as an off-white solid (5.3 g, 70%).1H NMR (400 MHz, DMSO-cfe): 612.29 (s, 1H), 8.23 (d, J = 3.5 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 5.19 (s, 2H), 3.93 (s, 3H);13C NMR (101 MHz, DMSO-d6): 5186.0, 160.3, 139.6, 133.3, 125.1, 124.2, 113.8, 106.1, 53.0, 48.8.

[1076] Step 2: 3-(2-chloroethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (6)

[1077] A solution of 2-chloro-1-(5-methoxy-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (5.8 g, 25.8 mmol) in EtsSiH (29 mL) and trifluoroacetic acid (30 mL) was stirred at 70 °C for 16 h. The reaction mixture was poured onto ice (~200 g), diluted with H2O (100 mL), and washed with hexane (3 x 200 mL) which was discarded. The aqueous layer was then slowly neutralised with saturated aq. Na2COs and extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (4.6 g, 85%).1H NMR (400 MHz, CDCI3): 58.08 (s, 1H), 7.56 (d, J = 8.7 Hz, 1 H), 7.21 (d, J = 2.0 Hz, 1 H), 6.61 (d, J = 8.7 Hz, 1 H), 3.99 (s, 3H), 3.95 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H);13C NMR (101 MHz, CDCI3): 5159.9, 141.4, 125.1, 124.8, 122.1, 112.7, 105.5, 53.6, 44.6, 28.4.

[1078] Step 3: 5-methoxy-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S73)

[1079] A solution of 3-(2-chloroethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (1 g, 4.75 mmol) in anhydrous DMF (5 mL) was treated with pyrrolidine (1.0 mL, 11.9 mmol) in a pressure

[1080] 1006352981tube which was then sealed and heated to 80 °C for 6 h. The reaction mixture was cooled, pH adjusted to pH 1-2 with 1 M aq. HCI, and washed with CH2CI2 (2 x 50 mL) which was discarded. The aqueous layer was adjusted to pH 9-10 with saturated aq. Na2COs and 15% aq. NaOH (1 mL) was added. The solution was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0.1 - 8% MeOH / NH3 in CH2CI2) to afford the title compound as a yellow oil (1.1 g, 95%).1H N MR (400 MHz, DMSO-56): 510.80 (s, 1H), 7.62 (d, J = 8.6 Hz, 1 H), 7.28 (d, J = 2.6 Hz, 1 H), 6.49 (d, J = 8.6 Hz, 1 H), 3.85 (s, 3H), 2.89 - 2.80 (m, 2H), 2.76 - 2.64 (m, 2H), 2.53 - 2.45 (m, 4H), 1.77 - 1.59 (m, 4H);13C NMR (101 MHz, DMSO-de): 5158.4, 141.3, 125.2, 124.5, 122.2, 112.6, 104.1, 56.4, 53.6, 52.4, 23.6, 23.2.

[1081] Step 4: 5-methoxy-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S73-fumarate)

[1082] 5-Methoxy-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (1.1 g, 4.48 mmol) was formulated as the fumarate salt according to General Procedure C, to afford a light yellow solid (2:1 amine:fumaric acid, 669 mg, 46%).1H NMR (400 MHz, DMSO-de): 5 11.28 (s, 1 H), 7.88 (dd, J = 8.6, 7.4 Hz, 1 H), 7.56 (d, J = 2.7 Hz, 1 H), 6.79 (dd, J = 8.6, 1.6 Hz, 1H), 6.57 (s, 2H), 3.08 (t, J = 8.8 Hz, 1H), 2.99 -2.83 (m, 5H), 2.18 - 2.06 (m, 1 H), 1.96 - 1.78 (m, 2H), 1.51 - 1.41 (m, 1 H), 0.82 - 0.74 (m, 1 H), 0.22 (dt, J = 8.4, 5.9 Hz, 1H);13C NMR (101 MHz, DMSO-56): 5168.3, 158.5, 141.0, 135.3, 125.5, 124.6, 122.4, 111.0, 104.3, 55.2, 53.1, 52.5, 23.0, 22.2;1H qNMR Purity: 96.8% (ERETIC); LCMS: tR(3.151 min) m / z = 246.15 [M+H]+.

[1083] Synthesis of 3-(2-(azetidin-1-yl)ethyl)-5-methoxy-1H-pyrrolo[3,2-6]pyridine (S77)

[1084]

[1085] 1006352981Step 1: 3-(2-(azetidin-1-yl)ethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (S77)

[1086] A solution of 3-(2-chloroethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (1.0 g, 4.75 mmol) in anhydrous MeCN (5 mL) was treated with azetidine (0.86 mL, 12.8 mmol) and the reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled, pH adjusted to pH 1-2 with 1M aq. HCI, and washed with CH2CI2 (2 x 50 mL) which was discarded. The aqueous layer was pH adjusted to pH 9-10 with saturated aq. Na2COs and 15% aq. NaOH (1 mL) was added. The solution was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (1 - 8% MeOH / NH3 in CH2CI2) to afford the title compound as a yellow oil (400 mg, 40%).1H NMR (400 MHz, MeOD-ck): 57.59 (d, J = 8.7 Hz, 1H), 7.18 (s, 1H), 6.54 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H), 3.33 - 3.28 (m, 4H), 2.99 - 2.71 (m, 4H), 2.25 - 2.00 (m, 2H).

[1087] Step 2: 3-(2-(azetidin-1-yl)ethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine oxalate

[1088] (S77-oxalate)

[1089] 3-(2-(azetidin-1-yl)ethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (105 mg, 0.45 mmol) was formulated as the oxalate salt according to General Procedure C to afford a white solid (1:1 amine:oxalic acid, 106 mg, 73%).1H NMR (400 MHz, DMSO-de): 511.12 (s, 1H), 7.69 (d, J = 8.7 Hz, 1 H), 7.37 (d, J = 2.7 Hz, 1 H), 6.56 (d, J = 8.7 Hz, 1 H), 4.04 (t, J = 8.1 Hz, 4H), 3.90 (s, 3H), 3.47 (t, J = 7.4 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.33 (p, J = 8.1 Hz, 2H);13C NMR (101 MHz, DMSO-de): 5164.6, 158.7, 140.7, 126.0, 124.7, 122.7, 108.7, 104.6, 54.3, 53.7, 52.6, 19.6, 16.0;1H qNMR Purity: 98.0% (ERETIC); LCMS: tR(3.024 min) m / z = 232.15 [M+H]+.

[1090] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine (S81)

[1091]

[1092] 1006352981Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S81 -fumarate)

[1093] A solution of 3-(2-chloroethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (500 mg, 2.37 mmol) in DMAc (5 mL) was treated with racemic cis 2-azabicyclo[3.1.0]hexane hydrochloride (568 mg, 4.75 mmol) and DIPEA (2.07 mL, 11.9 mmol) in a sealed pressure tube and heated to 80 °C for 3 h. The reaction mixture was adjusted to pH 1- 2 with 1 M aq. HCI, and washed with CH2CI2 (2 x 50 mL) which was discarded. The aqueous layer was adjusted to pH 9-10 with saturated aq. Na2COs and 15% aq. NaOH (0.5 mL) was added. The solution was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (1 - 8% MeOH / NH3 in CH2CI2) to afford the title compound as a yellow oil (150 mg) which was then formulated as the fumarate salt according to General Procedure C, to afford a white solid (2:1 amine:fumaric acid, 53 mg, 7%).1H NMR (400 MHz, DMSO-c / e): 510.89 (d, J = 2.7 Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.33 (d, J = 2.7 Hz, 1 H), 6.63 - 6.43 (m, 2H), 3.86 (s, 3H), 3.17 - 3.04 (m, 1 H), 3.03 - 2.83 (m, 5H), 2.21 - 2.04 (m, 1 H), 2.00 - 1.74 (m, 2H), 1.53 - 1.39 (m, 1 H), 0.84 - 0.72 (m, 1 H), 0.28 - 0.13 (m, 1H);13C NMR (101 MHz, DMSO-d6): 5167.3, 158.6, 141.2, 134.8, 125.5, 124.6, 122.4, 111.7, 104.3, 54.2, 52.5, 48.0, 40.2, 26.1, 22.9, 14.8, 1.9;1H qNMR Purity: 97.6% (ERETIC); LCMS: tR(3.263 min) m / z = 258.10 [M+H]+.

[1094] Synthesis of 3-(2-((1 / ?,5S)-2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine (S82)

[1095]

[1096] Step 1: 3-(2-((1R,5S)-2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S82-fumarate)

[1097] A suspension of K2CO3 (656 mg, 4.75 mmol) in DMSO (5 mL) was treated with (1 S,5R)~ 2-azabicyclo[3.1.0]hexane hydrochloride (284 mg, 2.37 mmol), followed by 3-(2- 1006352981chloroethyl)-5-methoxy-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 0.95 mmol) and the reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EtOAc (70 mL), washed with H2O (5 x 5 mL), brine (3 x 5 mL), and dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography (0.1 - 5% MeOH / NH3 in CH2CI2) to afford the title compound as an off-white solid (85 mg) which was then formulated as the fumarate salt according to General Procedure C, to afford an off-white solid (1:1 amine:fumaric acid, 59 mg, 17%).

[1098] 1H NMR (400 MHz, DMSO-56): 510.91 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 2.6 Hz, 1H), 6.56 (s, 2H), 6.52 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.19- 3.10 (m, 1H), 3.10 -2.84 (m, 5H), 2.27 -2.12 (m, 1H), 1.98- 1.77 (m, 2H), 1.54 - 1.39 (m, 1H), 0.85 - 0.73 (m, 1H), 0.31 - 0.18 (m, 1H);13C NMR (101 MHz, DMSO-56): 5166.7, 158.5, 141.1, 134.5, 125.4, 124.6, 122.3, 111.4, 104.2, 54.0, 52.5, 48.0, 40.1, 26.0, 22.7, 14.8, 1.9;1H qNMR Purity: 98.1% (ERETIC).

[1099] Synthesis of 3-(2-(azetidin-1-yl)ethyl)-5-ethoxy-1H-pyrrolo[3,2-6]pyridine (S83)

[1100]

[1101] Step 1: 1,1'-(5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine-1,3-diyl)bis(2-chloroethan-1-one) (9)

[1102] To an ice-cold solution of 5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (4.5 g, 27.7 mmol) in anhydrous CH2CI2 (100 mL) was added added AICI3 (11.1 g, 83.2 mmol) portion wise. Chloroacetyl chloride (3.31 mL, 41.6 mmol) in anhydrous CH2CI2 (50 mL) was added dropwise over 1 h and the resultant mixture was stirred for 6 h at RT. The reaction mixture was poured onto ice (~250 g) and stirred for 48 h. The precipitate was collected by vacuum filtration and dried to a constant weight to afford the title compound as an off-white solid (5.5 g, 63%).1H NMR (400 MHz, DMSO-d6): 58.79 (s, 1H), 8.52 (dd, J = 9.1, 0.6 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 5.28 (s, 2H), 5.25 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H);13C NMR (101 MHz, DMSO-56): 5186.8, 166.3, 161.3, 141.1, 133.4, 127.2, 124.6, 118.4, 108.6, 61.7, 49.4, 43.3, 14.4.

[1103] 1006352981Step 2: 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (10)

[1104] A solution of 1,1'-(5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine-1,3-diyl)bis(2-chloroethan-1-one) (5.5 g, 17.5 mmol) in TFA (20 mL) was stirred at RT for 3 h. Triethylsilane (20 mL) was added and the reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was cooled, poured into water (100 mL), and washed with hexane (3 x 50 mL) which was discarded. The aqueous layer was basified by portion wise addition of solid K2CO3 and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with H2O (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0% - 25%, EtOAc in hexane) to afford the title compound as a white, crystalline solid (1.8 g, 46%).

[1105] 1H NMR (400 MHz, CDCI3): 58.04 (br. s, 1 H), 7.52 (d, J = 8.7 Hz, 1 H), 7.21 - 7.16 (m, 1H), 6.59 (dd, J = 8.7, 0.4 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.94 (t, J = 7.3 Hz, 2H), 3.26 (td, J = 7.3, 0.8 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H);13C NMR (101 MHz, CDCI3): 5 159.6, 141.7, 124.9, 124.7, 121.8, 112.6, 105.8, 61.6, 44.6, 28.4, 14.9.

[1106] Step 3: 3-(2-(azetidin-1-yl)ethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[1107] (S83 -fumarate)

[1108] A mixture of 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (235 mg, 1.05 mmol) and azetidine (0.75 mL, 11.1 mmol) was stirred at RT for 18 h. The resultant solution was added slowly to H2O (15 mL) and extracted with Et20 (50 mL). The organic extract was washed with H2O (10 x 20 mL), brine (2 x 20 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound which was then formulated as the fumarate salt according to General Procedure C, to afford a yellow crystalline solid (1:1 amine:fumaric acid, 169 mg, 45%).1H NMR (400 MHz, DMSO-d6): 511.00 (d, J = 1.9 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 6.55 (s, 2H), 6.52 (dd, J = 8.7, 0.4 Hz, 1 H), 4.35 (q, J = 7.0 Hz, 2H), 3.83 (t, J = 7.9 Hz, 4H), 3.32 - 3.23 (m, 2H), 2.83 (t, J = 7.6 Hz, 2H), 2.25 (p, J = 7.8 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H);13C NMR (101 MHz, DMSO-c / e): 6 167.2, 158.3, 140.9, 134.7, 125.8, 124.6, 122.5, 109.5, 104.7, 60.5, 55.3, 53.5, 20.0, 16.3, 14.7.

[1109] 1006352981Synthesis of 5-ethoxy-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-6]pyridine (S86)

[1110]

[1111] Step 1: 5-ethoxy-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S86)

[1112] To a stirred solution of 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (300 mg, 1.34 mmol) in DMSO (3 mL) was added pyrrolidine (0.44 mL, 5.34 mmol) and the reaction was stirred at RT for 24 h. The reaction mixture was diluted with H2O (50 mL) and extracted with Et20 (3 x 20 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0.1% - 15% MeOH / NH3 in CH2CI2) to afford the title compound as a colourless oil (302 mg, 87%).1H NMR (400 MHz, CDCI3): 5 8.14 (s, 1 H), 7.52 (d, J = 8.7 Hz, 1 H), 7.16 (d, J = 2.6 Hz, 1 H), 6.58 (d, J = 8.7 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2H), 3.15 - 3.07 (m, 2H), 3.07 - 2.98 (m, 2H), 2.82 - 2.75 (m, 4H), 1.97 - 1.84 (m, 4H), 1.44 (t, J = 7.1 Hz, 3H).

[1113] Step 2: 5-ethoxy-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[1114] (S86 -fumarate)

[1115] 5-ethoxy-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (280 mg, 1.08 mmol) was formulated as the fumarate salt according to General Procedure C, to afford a white solid (2:1 amine:fumaric acid, 230 mg, 63%).1H NMR (400 MHz, DMSO-d6): 510.90 (s, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.32 (d, J = 2.7 Hz, 1 H), 6.50 (d, J = 8.7 Hz, 1 H), 6.48 (s, 1 H), 4.33 (q, J = 7.1 Hz, 2H), 3.11 - 2.88 (m, 4H), 2.88 - 2.75 (m, 4H), 1.79 (h, J = 3.1 Hz, 4H), 1.34 (t, J = 7.0 Hz, 3H);13C NMR (101 MHz, DMSO-d6): 5167.7, 158.1, 141.1, 135.1, 125.4, 124.5, 122.3, 111.2, 104.4, 60.4, 55.4, 53.2, 23.0, 22.4, 14.7;1H qNMR Purity: 98.2% (ERETIC).

[1116] 1006352981Synthesis of 5-ethoxy-3-(2-(2-methylpyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S87)

[1117]

[1118] Step 1: 5-ethoxy-3-(2-(2-methylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S87)

[1119] To a stirred solution of 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (220 mg, 0.98 mmol) in DMSO (1 mL) was added 2-methylpyrrolidine (0.5 mL, 4.9 mmol) and the resultant solution was stirred at RT for 24 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0.1% - 15% MeOH / NH3 in CH2CI2) to afford the title compound as a white solid (180 mg, 67%).1H NMR (400 MHz, CDCI3): <58.17 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1 H), 4.44 (q, J = 7.0 Hz, 2H), 3.40 - 3.24 (m, 2H), 3.10 - 2.92 (m, 2H), 2.57 - 2.35 (m, 2H), 2.30 (q, J = 8.9 Hz, 1 H), 2.03 - 1.89 (m, 1 H), 1.88 - 1.79 (m, 1 H), 1.79 - 1.67 (m, 1H), 1.55 - 1.44 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H), 1.17 (d, J = 6.1 Hz, 3H);13C NMR (101 MHz, CDCI3): 5159.2, 141.9, 124.6, 124.0, 121.4, 114.7, 105.4, 61.2, 60.2, 54.3, 53.8, 32.7, 23.5, 21.7, 18.8, 14.9;1H qNMR Purity: 100% (ERETIC).

[1120] Synthesis of 5-ethoxy-3-(2-(2-ethylpyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-6]pyridine (S88)

[1121]

[1122] 1006352981Step 1: 5-ethoxy-3-(2-(2-ethylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S88)

[1123] To a stirred solution of 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (250 mg, 1.11 mmol) in DMSO (2.5 mL) was added 2-ethylpyrrolidine hydrochloride (755 mg, 5.56 mmol) and K2CO3 (770 mg, 5.60 mmol) and the resultant mixture was stirred at RT for 24 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (5 x 25 mL). The combined organic extracts were washed with H2O (3 x 50 mL), brine (2 x 50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0.1% - 15% MeOH / NH3 in CH2CI2) to afford the title compound as a white solid (285 mg, 89%).1H NMR (400 MHz, CDCI3): 58.14 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 3.40 - 3.24 (m, 2H), 3.10 -2.91 (m, 2H), 2.57 - 2.46 (m, 1H), 2.36 -2.19 (m, 2H), 2.01 - 1.90 (m, 1H), 1.88 - 1.65 (m, 3H), 1.58 - 1.45 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H), 1.37 - 1.24 (m, 1H), 0.89 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCI3): 5 159.3, 142.0, 124.8, 124.2, 121.6, 114.6, 105.5, 66.8, 61.4, 54.7, 54.2, 30.1, 26.7, 23.5, 22.1, 15.0, 11.1;1H qNMR Purity: 99.3% (ERETIC).

[1124] Synthesis of (R)-5-ethoxy-3-(2-(2-methylpyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S89)

[1125]

[1126] Step 1: (R)-5-ethoxy-3-(2-(2-methylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S89)

[1127] (R)-5-ethoxy-3-(2-(2-methylpyrrolidin-1 -y l)ethy l)-1 / - / -pyrrolo[3,2-£>]pyrid ine was synthesised in the same manner as S87, using 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (300 mg, 1.34 mmol) and (R)-2-methylpyrrolidine (0.44 mL, 4.27 mmol), to afford the desired product as an off-white solid which was then formulated as the fumarate salt according to General Procedure C, to afford an off-white solid (2:1 amine:fumaric acid, 155 mg, 35%).1H NMR (400 MHz, DMSO-56): 510.90 (s, 1H), 7.63 (d, J = 8.7 Hz, 1 H), 7.32 (d, J = 2.6 Hz, 1 H), 6.54 - 6.41 (m, 2H), 4.33 (q, J = 7.0 Hz, 2H), 3.40 - 3.27 (m, 2H), 3.00 - 2.81 (m, 2H), 2.79 - 2.60 (m, 2H), 2.59 - 2.51 (m, 1 H), 10063529812.05 - 1.87 (m, 1 H), 1.83 - 1.69 (m, 2H), 1.55 - 1.36 (m, 1 H), 1.33 (t, J = 7.0 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H);13C NMR (101 MHz, DMSO-d6): 5167.6, 158.1, 141.1, 135.1, 125.4, 124.5, 122.3, 111.3, 104.4, 60.3, 52.8, 52.7, 31.9, 22.3, 21.2, 17.5, 14.7;1H qNMR Purity: 96.7% (ERETIC).

[1128] Synthesis of ( / ?)-5-ethoxy-3-(2-(2-ethylpyrrolidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S90)

[1129]

[1130] S90

[1131] Step 1: (R)-5-ethoxy-3-(2-(2-ethylpyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S90)

[1132] (R)-5-ethoxy-3-(2-(2-ethylpyrrolidin-1 -y I )ethy l)-1 / - / -py rrolo[3, 2-£>]py ridine was synthesised in the same manner as S88, using 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (250 mg, 1.11 mmol) and (R)-2-ethylpyrrolidine

[1133] hydrochloride (755 mg, 5.56 mmol), to afford a white solid (295 mg, 92%).1H NMR (400 MHz, CDCIs): <58.22 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.42 - 3.26 (m, 2H), 3.10 - 2.92 (m, 2H), 2.60 -2.49 (m, 1 H), 2.38 - 2.21 (m, 2H), 2.09 - 1.90 (m, 1 H), 1.87 - 1.69 (m, 3H), 1.58 - 1.45 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H), 1.37 - 1.25 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCI3): 5159.3, 142.0, 124.8, 124.2, 121.6, 114.6, 105.5, 66.8, 61.4, 54.7, 54.2, 30.1, 26.7, 23.5, 22.1, 15.0, 11.1;1H qNMR Purity: 99.0% (ERETIC).

[1134] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-ethoxy-1H-pyrrolo[3,2-b]pyridine (S91)

[1135]

[1136] 1006352981Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (S91)

[1137] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in the same manner as S88, using 3-(2-chloroethyl)-5-ethoxy-1H-pyrrolo[3,2-b]pyridine (200 mg, 0.89 mmol) and racemic cis 2-azabicyclo[3.1,0]hexane hydrochloride (830 mg, 6.75 mmol), to afford a white solid (114 mg, 31%).1H NMR (400 MHz, CDCh): 58.17 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 2.7 Hz, 1 H), 6.54 (d, J = 8.7 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2H), 3.18 - 2.87 (m, 6H), 2.14 - 1.96 (m, 2H), 1.95 - 1.84 (m, 1H), 1.47 (ddd, J = 8.3, 6.1, 4.2 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H), 0.72 (ddd, J = 6.0, 4.3, 2.6 Hz, 1H), 0.17 (dt, J = 8.2, 5.9 Hz, 1H);13C NMR (101 MHz, CDCh): 5159.4, 142.0, 124.8, 124.4, 121.7, 114.1, 105.5, 61.4, 54.9, 48.7, 40.8, 26.8, 23.8, 15.3, 15.0, 2.1;1H qNMR Purity: 95.1% (ERETIC).

[1138] Synthesis of 3-(2-((1 / ?,5S)-2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-5-ethoxy-1H-pyrrolo[3,2-b]pyridine (S92)

[1139]

[1140] Step 1: 3-(2-((1R,5S)-2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (S92)

[1141] 3-(2-((1 R,5S)-2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in the same manner as S88, using 3-(2-chloroethyl)-5-ethoxy-1 / - / -pyrrolo[3,2-b]pyridine (300 mg, 1.34 mmol) and (1R,5S)-2-azabicyclo[3.1.0]hexane hydrochloride (830 mg, 6.75 mmol), to afford a white solid (127 mg, 35%).1H NMR (400 MHz, CDCh): 58.40 (s, 1 H), 7.43 (d, J = 8.7 Hz, 1 H), 7.09 (d, J = 2.6 Hz, 1 H), 6.52 (d, J = 8.7 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2H), 3.17 - 3.02 (m, 3H), 3.01 - 2.82 (m, 3H), 2.11 -1.92 (m, 2H), 1.92 - 1.80 (m, 1 H), 1.51 - 1.36 (m, 4H), 0.71 (ddd, J = 5.9, 4.3, 2.7 Hz, 1H), 0.14 (dt, J = 8.2, 5.8 Hz, 1H);13C NMR (101 MHz, CDCh): 5159.3, 142.0, 124.9, 124.3, 121.6, 114.4, 105.4, 61.4, 55.0, 48.6, 40.8, 26.9, 24.0, 15.2, 15.0, 1.9;1H qNMR Purity: 98.3% (ERETIC).

[1142] 1006352981Synthesis of 3-(2-(azetidin-1-yl)ethyl)-6-fluoro-1H-pyrrolo[3,2-6]pyridine (S95)

[1143]

[1144] Step 1: 2-chloro-1-(6-fluoro-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (11)

[1145] To an ice-cold solution of 6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (9.0 g, 66.1 mmol) in anhydrous CH2CI2 (250 mL) was added powdered AICI3 (26.4 g, 198 mmol).

[1146] Chloroacetyl chloride (6.4 mL, 79.3 mmol) in anhydrous CH2CI2 (80 mL) was added dropwise over 30 min and the resultant mixture was stirred cold for 30 min. The reaction mixture was poured over ice (~ 300 g) and stirred for 1 h and sonicated for 10 min. The precipitate was collected by vacuum filtration and dried to a constant weight to afford the title compound as a light-brown solid (3.1 g, 22%).1H NMR (400 MHz, DMSO-cfe): 6 12.51 (s, 1 H), 8.55 (dd, J = 2.6, 1.6 Hz, 1 H), 8.48 (d, J = 3.3 Hz, 1 H), 7.86 (dd, J = 9.4, 2.6 Hz, 1H), 5.18 (s, 2H);13C NMR (101 MHz, DMSO-d6): 5185.8, 156.0 (d, J = 245.7 Hz), 139.9, 136.8 (d, J = 2.5 Hz), 133.5 (d, J = 26.8 Hz), 129.1 (d, J = 8.6 Hz), 114.0, 107.1 (d, J = 22.4 Hz), 48.6;19F NMR (376 MHz, DMSO-56): 5 -135.0.

[1147] Step 2: 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (12)

[1148] A mixture of 2-chloro-1-(6-fluoro-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (2.3 g, 10.8 mmol), triethylsilane (13 mL, 81.1 mmol), and TFA (6.2 mL) was stirred at 70 °C for 3 h. TFA (6.2 mL) was added and the reaction mixture stirred for a further 21 h. TFA (6.2 mL) was added and the reaction mixture stirred for a further 6 h. Triethylsilane (13 mL, 81.1 mmol) and TFA (6.2 mL) was added and the reaction mixture stirred for a further 16 h. The reaction mixture was then cooled and poured over ice (~300 g) and the resultant solution was washed with hexane (2 x 100 mL) which was discarded. The aqueous layer was then neutralised with portion wise addition of Na2COs and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with H2O (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was diluted with warm Et20 and an insoluble brown residue was removed by filtration through a plug of anhydrous Na2SO4. The filtrate was concentrated 1006352981under reduced pressure, and the resultant solid was suspended in CH2CI2. The precipitate was collected by vacuum filtration to afford the title compound as an off-white solid (2.1 g, 98%).1H N MR (400 MHz, DMSO-56): 511.23 (s, 1H), 8.31 (dd, J = 2.5, 1.7 Hz, 1 H), 7.64 (dd, J = 9.9, 2.6 Hz, 1 H), 7.56 (d, J = 2.6 Hz, 1 H), 3.93 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H);13C NMR (101 MHz, DMSO-56): 5155.8 (d, J = 242.5 Hz), 142.1, 130.6 (d, J = 26.7 Hz), 128.3 (d, J = 3.8 Hz), 128.2 (d, J = 8.8 Hz), 111.2, 105.1 (d, J = 22.3 Hz), 44.5, 27.7;19F NMR (376 MHz, DMSO-56): 5 -137.6.

[1149] Step 3: 3-(2-(azetidin-1-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[1150] (S95 -fumarate)

[1151] To a suspension of 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) and K2CO3 (420 mg, 3.03 mmol) in anhydrous MeCN (2.5 mL) was added azetidine (0.2 mL, 3.03 mmol) and the resultant mixture was heated to 60 °C and stirred for 24 h. The reaction was cooled and concentrated under a stream of nitrogen gas. The residue was diluted with EtOAc (50 mL), washed with H2O (3 x 5 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (1 - 10% MeOH / NH3 in CH2CI2) to afford the title compound as an off-white resin (99 mg) which was then formulated as the fumarate salt according to General Procedure C, to afford a white, crystalline solid (1:1.4 amine:fumaric acid, 150 mg, 44%).1H NMR (400 MHz, DMSO-56): 511.34 (s, 1H), 8.31 (dd, J = 2.6, 1.6 Hz, 1 H), 7.65 (dd, J = 9.9, 2.6 Hz, 1 H), 7.52 (d, J = 2.2 Hz, 1 H), 6.54 (s, 3H), 3.83 (t, J = 7.8 Hz, 4H), 3.39 - 3.16 (m, 2H), 3.01 - 2.79 (m, 2H), 2.24 (p, J = 7.8 Hz, 2H);13C NMR (101 MHz, DMSO-56): 5167.4, 155.8 (d, J = 242.6 Hz), 142.1, 134.8, 130.5 (d, J = 26.7 Hz), 128.3 (d, J = 8.8 Hz), 128.1, 110.5, 105.1 (d, J = 22.2 Hz), 55.0, 53.4, 19.9, 16.2;19F NMR (376 MHz, DMSO-56): 5-137.5;1H qNMR Purity: 98.8% (ERETIC).

[1152] Synthesis of 6-fluoro-3-(2-(2-methylazetidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-6]pyridine (S96)

[1153]

[1154] 1006352981Step 1: 6-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S96)

[1155] To a solution of 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (500 mg, 2.52 mmol) in anhydrous MeCN (10 mL) was added K2CO3 (3.48 g, 25.2 mmol), sodium iodide (378 mg, 2.52 mmol), and 2-methylazetidine hydrochloride (680 mg, 6.29 mmol) and the resultant suspension was heated to 80 °C and stirred for 20 h. The reaction mixture was cooled and diluted with EtOAc (50 mL), washed with H2O (2 x 15 mL), saturated aq. Na2COs (15 mL), and brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0.1 - 10% MeOH / NH3 in CH2CI2) to afford the title compound as an off-white solid (210 mg, 36%).

[1156] 1H N MR (400 MHz, DMSO-c / e): 511.09 (s, 1H), 8.28 (dd, J = 2.5, 1.7 Hz, 1H), 7.58 (dd, J = 10.0, 2.6 Hz, 1 H), 7.45 (d, J = 2.5 Hz, 1 H), 3.32 - 3.22 (m, 1 H), 3.09 (h, J = 6.3 Hz, 1 H), 2.91 - 2.79 (m, 1 H), 2.78 - 2.61 (m, 3H), 2.61 - 2.52 (m, 1 H), 1.99 (dtd, J = 9.7, 7.6, 2.1 Hz, 1H), 1.74 - 1.57 (m, 1H), 1.12 (d, J = 6.1 Hz, 3H);13C NMR (151 MHz, DMSO-c / e): 5155.7 (d, J = 242.2 Hz), 142.4, 130.2 (d, J = 26.4 Hz), 128.1 (d, J = 8.7 Hz), 127.3 (d, J = 3.6 Hz), 113.3, 104.7 (d, J = 22.2 Hz), 61.9, 58.2, 50.9, 25.2, 22.2, 21.8;19F NMR (376 MHz, DMSO-c / e): 5-138.1;1H qNMR Purity: 95.3% (ERETIC).

[1157] Step 2: 6-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S96 -fumarate)

[1158] 6-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (190 mg, 0.81 mmol) was formulated as the fumarate salt according to General Procedure C to afford a white solid (1:1.5 amine:fumaric acid, 323 mg, 97%).1H NMR (400 MHz, DMSO-c / e): 5 11.34 (s, 1 H), 8.32 (dd, J = 2.5, 1.7 Hz, 1 H), 7.66 (dd, J = 9.9, 2.6 Hz, 1 H), 7.52 (d, J = 2.4 Hz, 1 H), 6.55 (s, 3H), 4.09 (h, J = 6.8 Hz, 1 H), 3.83 (td, J = 8.9, 3.8 Hz, 1 H), 3.52 (q, J = 8.9 Hz, 1H), 3.41 - 3.27 (m, 1H), 3.26 - 3.13 (m, 1H), 2.93 (t, J = 7.8 Hz, 2H), 2.38 - 2.22 (m, 1H), 2.06 - 1.95 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H);13C NMR (101 MHz, DMSO-c / e): 5167.2, 155.8 (d, J = 242.5 Hz), 142.0, 134.7, 130.5 (d, J = 26.8 Hz), 128.3 (d, J = 8.8 Hz), 128.0 (d, J = 3.4 Hz), 110.8, 105.2 (d, J = 22.2 Hz), 63.8, 54.0, 50.1, 24.2, 20.0, 18.8;19F NMR (376 MHz, DMSO-c / e): 5-137.5;1H qNMR Purity: 98.9% (ERETIC).

[1159] 1006352981Synthesis of 6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-6]pyridine (S97)

[1160]

[1161] Step 1: 6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S97)

[1162] To a suspension of 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) and K2CO3 (420 mg, 3.03 mmol) in anhydrous MeCN (2.5 mL) was added pyrrolidine (0.25 mL, 3.03 mmol) and the resultant mixture was heated to 60 °C and stirred for 24 h. The reaction mixture was cooled and concentrated under a stream of nitrogen gas. The residue was diluted with EtOAc (50 mL), washed with H2O (3 x 5 mL), and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated in warm Et20, cooled, and collected by vacuum filtration to afford the title compound as an off-white solid (130 mg, 55%).1H NMR (400 MHz, DMSO-de): 511.09 (s, 1 H), 8.28 (dd, J = 2.5, 1.7 Hz, 1 H), 7.59 (dd, J = 10.0, 2.6 Hz, 1 H), 7.46 (d, J = 2.5 Hz, 1 H), 2.95 - 2.82 (m, 2H), 2.78 - 2.64 (m, 2H), 2.54 - 2.38 (m, 4H), 1.75 - 1.60 (m, 4H);13C NMR (101 MHz, DMSO-d6): 5155.7 (d, J = 242.1 Hz), 142.4, 130.2 (d, J = 26.5 Hz), 128.1 (d, J = 8.7 Hz), 127.2 (d, J = 3.6 Hz), 113.5, 104.7 (d, J = 22.2 Hz), 56.2, 53.5, 23.5, 23.1;19F NMR (376 MHz, DMSO-d6): 5 -138.1.

[1163] Step 2: 6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine fumarate

[1164] (S97 -fumarate)

[1165] 6-fluoro-3-(2-(pyrrolidin-1 -yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (125 mg, 0.54 mmol) was formulated as the fumarate salt according to General Procedure C to afford a white solid (1:1.5 amine:fumaric acid, 187 mg, 86%).1H NMR (400 MHz, DMSO-d6): 511.33 (s, 1 H), 8.37 - 8.23 (m, 1 H), 7.65 (dd, J = 9.9, 2.5 Hz, 1 H), 7.54 (d, J = 2.1 Hz, 1 H), 6.53 (s, 3H), 3.34 - 3.21 (m, 2H), 3.19 - 3.00 (m, 6H), 1.95 - 1.78 (m, 4H);13C NMR (101 MHz, DMSO-c / e): 5167.2, 155.8 (d, J = 242.5 Hz), 142.1, 134.7, 130.5 (d, J = 26.8 Hz), 128.3 (d, J = 8.8 Hz), 128.0, 110.9, 105.1 (d, J = 22.3 Hz), 54.4, 52.9, 22.9, 21.2;19F NMR (376 MHz, DMSO-d6): 5-137.5;1H qNMR Purity: 99.4% (ERETIC).

[1166] 1006352981Synthesis of ( / ?)-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-6]pyridine (S98)

[1167]

[1168] Step 1: (R)-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S98)

[1169] (R)-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in the same manner as S96, using 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (500 mg, 2.52 mmol) and (R)-2-methylpyrrolidine hydrochloride (765 mg, 6.29 mmol), to afford an off-white solid (520 mg, 84%).1H NMR (400 MHz, DMSO-56): 511.08 (s, 1H), 8.28 (dd, J = 2.6, 1.7 Hz, 1H), 7.59 (dd, J = 10.0, 2.6 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 3.23 - 3.03 (m, 2H), 3.00 - 2.87 (m, 1 H), 2.87 - 2.73 (m, 1 H), 2.40 - 2.21 (m, 2H), 2.14 (q, J = 8.7 Hz, 1 H), 1.94 - 1.76 (m, 1 H), 1.75 - 1.54 (m, 2H), 1.39 - 1.20 (m, 1 H), 1.01 (d, J = 6.0 Hz, 3H);13C NMR (151 MHz, DMSO-56): 5155.7 (d, J = 242.1 Hz), 142.5, 130.2 (d, J = 26.5 Hz), 128.1 (d, J = 8.7 Hz), 127.2 (d, J = 3.5 Hz), 113.7, 104.7 (d, J = 22.1 Hz), 59.2, 53.8, 53.2, 32.5, 23.2, 21.4, 19.1;19F NMR (376 MHz, DMSO-56): 5-138.1;1H qNMR Purity: 96.0% (ERETIC).

[1170] Step 2: (R)-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-5]pyridine fumarate (S98 -fumarate)

[1171] (R)-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-5]pyridine (500 mg, 2.02 mmol) was formulated as the fumarate salt according to General Procedure C to afford a white solid (1:1.5 amine:fumaric acid, 816 mg, 96%).1H NMR (400 MHz, DMSO-56): 511.35 (s, 1 H), 8.32 (dd, J = 2.5, 1.7 Hz, 1 H), 7.66 (dd, J = 9.9, 2.6 Hz, 1 H), 7.56 (d, J = 2.4 Hz, 1 H), 6.54 (s, 3H), 3.61 - 3.50 (m, 1 H), 3.50 - 3.38 (m, 1 H), 3.24 - 2.96 (m, 4H), 2.90 (q, J = 8.4 Hz, 1H), 2.15 - 2.01 (m, 1H), 1.95 - 1.79 (m, 2H), 1.64 - 1.49 (m, 1H), 1.25 (d, J = 6.4 Hz, 3H);13C NMR (101 MHz, DMSO-56): 5167.1, 155.8 (d, J = 242.4 Hz), 142.0, 134.7, 130.5 (d, J = 26.8 Hz), 128.3 (d, J = 8.8 Hz), 127.9 (d, J = 3.5 Hz), 111.1, 105.2

[1172] 1006352981(d, J = 22.2 Hz), 61.6, 52.23, 52.12, 31.23, 21.09, 21.06, 16.2;1H qNMR Purity: 98.2% (ERETIC).

[1173] Synthesis of (R)-6-fluoro-3-(2-(2-methylazetidin-1 -y I )ethy I )-1 H-pyrrolo[3,2-b]pyridine (S99)

[1174]

[1175] Step 1: (R)-6-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-b]pyridine (S99)

[1176] (R)-6-fluoro-3-(2-(2-methylazetidin-1 -y l)ethy I )-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in a similar manner as S96, using 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-5]pyridine (500 mg, 2.52 mmol) and (R)-2-methylazetidine hydrochloride (680 mg, 6.29 mmol), to afford an off-white solid (325 mg, 55%).1H NMR (400 MHz, DMSO-d6): 511.09 (s, 1H), 8.28 (dd, J = 2.5, 1.7 Hz, 1H), 7.58 (dd, J = 10.0, 2.6 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 3.32 - 3.23 (m, 1 H), 3.09 (h, J = 6.3 Hz, 1 H), 2.90 - 2.80 (m, 1 H), 2.76 - 2.63 (m, 3H), 2.61 -2.52 (m, 1H), 1.99 (dtd, J = 9.7, 7.6, 2.1 Hz, 1H), 1.71 - 1.56 (m, 1H), 1.12 (d, J = 6.1 Hz, 3H);13C NMR (151 MHz, DMSO-d6): 5155.7 (d, J = 242.2 Hz), 142.4, 130.2 (d, J = 26.4 Hz), 128.1 (d, J = 8.7 Hz), 127.3 (d, J = 3.6 Hz), 113.3, 104.7 (d, J = 22.2 Hz), 61.9, 58.2, 50.9, 25.2, 22.2, 21.8;19F NMR (376 MHz, DMSO-d6): 5-138.1.

[1177] Step 2: (R)-6-fluoro-3-(2-(2-methylazetidin-1 -y l)ethy I )-1 / - / -py rrolo[3,2-£>]py rid ine fumarate (S99 -fumarate)

[1178] (R)-6-fluoro-3-(2-(2-methylazetidin-1-yl)ethyl)-1 / - / -pyrrolo[3,2-5]pyridine (300 mg, 1.29 mmol) was formulated as the fumarate salt according to General Procedure C to afford a white solid (1:1.5 amine:fumaric acid, 482 mg, 92%).1H NMR (400 MHz, DMSO-cfe): 5 11.38 (s, 1 H), 8.32 (dd, J = 2.5, 1.7 Hz, 1 H), 7.66 (dd, J = 9.9, 2.6 Hz, 1 H), 7.53 (d, J = 2.3 Hz, 1 H), 6.55 (s, 3H), 4.17 (h, J = 6.8 Hz, 1 H), 3.88 (td, J = 9.1, 4.0 Hz, 1 H), 3.59 (q, J = 9.1 Hz, 1H), 3.45 - 3.30 (m, 1H), 3.31 - 3.17 (m, 1H), 2.95 (t, J = 7.9 Hz, 2H), 2.32 (dtd, J = 12.2, 8.4, 4.3 Hz, 1 H), 2.12 - 1.96 (m, 1 H), 1.40 (d, J = 6.6 Hz, 3H);13C NMR (101 MHz, DMSO-de): 5167.4, 155.8 (d, J = 242.5 Hz), 142.0, 134.8, 130.5 (d, J = 26.8

[1179] 1006352981Hz), 128.3 (d, J = 8.9 Hz), 128.0 (d, J = 3.4 Hz), 110.6, 105.2 (d, J = 22.3 Hz), 63.9, 53.6, 50.0, 24.1, 19.9, 18.5;19F NMR (376 MHz, DMSO-56): 5-137.5;1H qNMR Purity: 98.7% (ERETIC).

[1180] Synthesis of 3-(2-(2-ethylpyrrolidin-1 -yl)ethyl)-6-fluoro-1 H-pyrrolo[3,2-6]pyridine (S100)

[1181]

[1182] S100

[1183] Step 1: 3-(2-(2-ethylpyrrolidin-1 -yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-£>]pyridine fumarate (S100-fumarate)

[1184] General Procedure A using 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-5]pyridine (200 mg, 1.01 mmol) and 2-ethylpyrrolidine hydrochloride (205 mg, 1.51 mmol), gave the desired product as an off-white solid (65 mg) which was then formulated as the fumarate salt according to General Procedure C, to afford an off-white solid (1:1.5 amine:fumaric acid, 100 mg, 23%).1H N MR (400 MHz, DMSO-56): 511.30 (s, 1H), 8.32 (dd, J = 2.5, 1.7 Hz, 1 H), 7.65 (dd, J = 9.9, 2.6 Hz, 1 H), 7.54 (d, J = 2.5 Hz, 1 H), 6.54 (s, 3H), 3.60 - 3.30 (m, 2H), 3.17 - 2.72 (m, 5H), 2.11 - 1.97 (m, 1H), 1.93 - 1.70 (m, 3H), 1.64 - 1.48 (m, 1 H), 1.48 - 1.32 (m, 1 H), 0.87 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, DMSO-56): 5 166.9, 155.7 (d, J = 242.1 Hz), 142.1, 134.6, 130.4 (d, J = 26.9 Hz), 128.3 (d, J = 8.4 Hz), 127.9 (d, J = 3.2 Hz), 111.4, 105.1 (d, J = 22.4 Hz), 67.2, 53.1, 52.9, 28.8, 24.2, 21.5, 21.4, 10.5;19F NMR (376 MHz, DMSO-56): 5-137.6;1H qNMR Purity: 96.6% (ERETIC).

[1185] 1006352981Synthesis of ( / ?)-3-(2-(2-ethylpyrrolidin-1 -yl)ethyl)-6-fluoro-1 H-pyrrolo[3,2-b]pyridine (S101)

[1186]

[1187] Step 1: (R)-3-(2-(2-ethylpyrrolidin-1-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S101 -fumarate)

[1188] (R)-3-(2-(2-ethy Ipy rrol id in-1 -yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3, 2-£>]py rid ine was synthesised in the same manner as S88, using 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) and (R)-2-ethylpyrrolidine hydrochloride (696 mg, 5.03 mmol), afforded an off-white solid which was then formulated as the fumarate salt according to General Procedure C, to afford a white solid (1:1.5 amine:fumaric acid, 299 mg, 68%).

[1189] 1H N MR (400 MHz, DMSO-d6): 511.29 (s, 1H), 8.31 (dd, J = 2.6, 1.7 Hz, 1H), 7.65 (dd, J = 9.9, 2.6 Hz, 1 H), 7.54 (d, J = 2.5 Hz, 1 H), 6.55 (s, 3H), 3.54 - 3.33 (m, 2H), 3.16 -2.97 (m, 2H), 2.97 - 2.69 (m, 3H), 2.11 - 1.97 (m, 1H), 1.93 - 1.72 (m, 3H), 1.63 - 1.48 (m, 1 H), 1.46 - 1.31 (m, 1 H), 0.86 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, DMSO-d6): 5 166.9, 155.8 (d, J = 242.5 Hz), 142.1, 134.6, 130.4 (d, J = 26.8 Hz), 128.3 (d, J = 8.8 Hz), 127.9 (d, J = 3.7 Hz), 111.5, 105.1 (d, J = 22.4 Hz), 67.1, 53.1, 52.9, 28.8, 24.2, 21.5, 21.4, 10.5;1H qNMR Purity: 99.7% (ERETIC).

[1190] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1H-pyrrolo[3,2-b]pyridine (S102)

[1191]

[1192] 1006352981Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (S102)

[1193] Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in the same manner as S96, using 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (620 mg, 3.12 mmol) and racemic cis 2-azabicyclo[3.1,0]hexane hydrochloride (933 mg, 7.80 mmol), to afford a white solid (439 mg, 57%).1H NMR (600 MHz, DMSO-de): 511.09 (s, 1 H), 8.28 (dd, J = 2.5, 1.6 Hz, 1 H), 7.59 (dd, J = 9.9, 2.6 Hz, 1 H), 7.48 (d, J = 2.5 Hz, 1 H), 3.00 - 2.84 (m, 3H), 2.85 - 2.63 (m, 3H), 1.93 - 1.67 (m, 3H), 1.41 - 1.30 (m, 1 H), 0.63 (ddd, J = 5.2, 4.3, 2.8 Hz, 1 H), 0.02 (dt, J = 8.2, 5.5 Hz, 1H);13C NMR (151 MHz, DMSO-d6): 5155.7 (d, J = 242.1 Hz), 142.5, 130.2 (d, J = 26.4 Hz), 128.1 (d, J = 8.7 Hz), 127.3 (d, J = 3.6 Hz), 113.6, 104.7 (d, J = 22.1 Hz), 54.5, 47.7, 40.3, 26.5, 23.5, 14.4, 1.2;19F NMR (376 MHz, DMSO-56): 5-138.1;1H qNMR Purity: 99.2% (ERETIC).

[1194] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S102-fumarate)

[1195] Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (400 mg, 1.63 mmol) was formulated as the fumarate salt according to General Procedure C to afford a white solid (1:1.5 amine:fumaric acid, 564 mg, 82%).1H NMR (400 MHz, DMSO-de): 511.24 (s, 1 H), 8.30 (dd, J = 2.6, 1.6 Hz, 1 H), 7.63 (dd, J = 9.9, 2.6 Hz, 1 H), 7.53 (d, J = 2.4 Hz, 1 H), 6.57 (s, 3H), 3.30 - 3.16 (m, 1 H), 3.15 - 2.93 (m, 5H), 2.39 - 2.19 (m, 1 H), 2.02 - 1.76 (m, 2H), 1.58 - 1.46 (m, 1 H), 0.87 (ddd, J = 6.6, 4.5, 2.7 Hz, 1H), 0.34 (dt, J = 8.6, 6.3 Hz, 1H);13C NMR (101 MHz, DMSO-56): 5166.7, 155.7 (d, J = 242.3 Hz), 142.2, 134.4, 130.4 (d, J = 26.6 Hz), 128.2 (d, J = 8.9 Hz), 127.7 (d, J = 3.5 Hz), 111.9, 105.0 (d, J = 22.2 Hz), 53.7, 48.0, 39.9, 25.7, 22.1, 15.0, 2.3;1H qNMR Purity: 98.9% (ERETIC).

[1196] 1006352981Synthesis of 3-(2-((1 / ?,5S)-2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1H-pyrrolo[3,2-b]pyridine (S103)

[1197]

[1198] Step 1: 3-(2-((1R,5S)-2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S103-fumarate)

[1199] 3-(2-(( 1 R,5S)-2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3, 2-£>]py rid ine was synthesised in the same manner as S88, using 3-(2-chloroethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) and (1R,5S)-2-azabicyclo[3.1,0]hexane hydrochloride (696 mg, 5.03 mmol), to afford a colourless oil which was then formulated as the fumarate salt according to General Procedure C, to afford a crystalline, white solid (1:1.5 amine:fumaric acid, 302 mg, 73%).1H N MR (400 MHz, DMSO-d6): 511.21 (s, 1 H), 8.30 (dd, J = 2.6, 1.6 Hz, 1 H), 7.62 (dd, J = 9.9, 2.6 Hz, 1 H), 7.52 (d, J = 2.6 Hz, 1H), 6.58 (s, 3H), 3.21 - 3.12 (m, 1H), 3.11 - 2.95 (m, 5H), 2.23 (td, J = 10.7, 7.7 Hz, 1 H), 2.00 - 1.81 (m, 2H), 1.56 - 1.46 (m, 1 H), 0.84 (ddd, J = 6.6, 4.4, 2.2 Hz, 1 H), 0.29 (dt, J = 8.5, 6.1 Hz, 1H);13C NMR (101 MHz, DMSO-d6): 5166.6, 155.7 (d, J = 242.4 Hz), 142.3, 134.4, 130.4 (d, J = 26.6 Hz), 128.2 (d, J = 8.8 Hz), 127.7 (d, J = 3.5 Hz), 112.1, 104.9 (d, J = 22.3 Hz), 53.8, 48.0, 40.0, 25.8, 22.3, 14.9, 2.2;1H qNMR Purity: 98.7% (ERETIC).

[1200] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1-methyl-1 H-pyrrolo[3,2-b]pyridine (S104)

[1201]

[1202] 1006352981Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-methyl-1 / - / -pyrrolo[3,2-b]pyridine (S104)

[1203] A solution of racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (250 mg, 1.0 mmol) in anhydrous DMF (5 mL) at 0 °C was treated with 60% w / w NaH mineral oil dispersion (61 mg, 1.06 mmol) and the mixture was stirred for 30 min. lodomethane (70 pL, 1.12 mmol) was added dropwise at 0 °C and the resultant mixture was warmed to RT and stirred for 2 h. The reaction mixture was quenched with dropwise addition of H2O until gas evolution ceased, and the reaction mixture was diluted with EtOAc (20 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with H2O (2 x 50 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (0 - 5% MeOH / NH3 CH2CI2) to afford the title compound as a colourless oil that solidified upon standing (234 mg, 89%).1H NMR (400 MHz, CDCI3): 5 8.36 (dd, J = 2.5, 1.7 Hz, 1H), 7.28 (dd, J = 9.3, 2.5 Hz, 1H), 7.18 (d, J = 0.9 Hz, 1H), 3.74 (s, 3H), 3.20 - 3.05 (m, 3H), 3.04 - 2.90 (m, 2H), 2.87 (td, J = 5.9, 2.6 Hz, 1 H), 2.15 - 1.96 (m, 2H), 1.96 - 1.85 (m, 1H), 1.47 (ddt, J = 8.5, 6.0, 4.4 Hz, 1H), 0.73 (ddd, J = 6.1, 4.3, 2.7 Hz, 1H), 0.17 (dt, J = 8.3, 5.9 Hz, 1H);13C NMR (101 MHz, CDCI3): 5 156.3 (d, J = 245.8 Hz), 142.6, 131.3 (d, J = 27.0 Hz), 130.3 (d, J = 3.8 Hz), 129.6 (d, J = 8.0 Hz), 114.3, 102.9 (d, J = 22.6 Hz), 54.8, 48.6, 40.8, 33.0, 26.7, 23.4, 15.2, 2.0.

[1204] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-methyl-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S104-fumarate)

[1205] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-methyl-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 0.77 mmol) was formulated as the fumarate salt according to General Procedure C to afford a white solid (1:1.5 amine:fumaric acid, 260 mg, 78%).

[1206] 1H NMR (400 MHz, DMSO-56): 58.32 (dd, J = 2.5, 1.6 Hz, 1H), 7.84 (dd, J = 10.2, 2.6 Hz, 1H), 7.52 (s, 1H), 6.58 (s, 3H), 3.76 (s, 3H), 3.32 - 3.18 (m, 1H), 3.17 -2.94 (m, 5H), 2.32 (td, J = 10.8, 7.8 Hz, 1H), 2.04 - 1.76 (m, 2H), 1.55 (ddd, J = 10.1, 7.0, 4.5 Hz, 1 H), 0.88 (ddd, J = 6.7, 4.5, 2.6 Hz, 1 H), 0.37 (dt, J = 8.7, 6.3 Hz, 1 H);13C NMR (101 MHz, DMSO-de): 5166.8, 155.8 (d, J = 242.9 Hz), 142.1, 134.4, 131.7 (d, J = 3.6 Hz), 130.4 (d, J = 26.8 Hz), 129.2 (d, J = 8.6 Hz), 111.5, 103.9 (d, J = 22.9 Hz), 53.6, 47.9, 39.9, 32.7, 25.7, 21.9, 15.0, 2.4;19F NMR (376 MHz, DMSO-56): 5-137.2;1H qNMR Purity: 97.8% (ERETIC).

[1207] 1006352981Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-1-ethyl-6-fluoro-1 H-pyrrolo[3,2-b]pyridine (S105)

[1208] N N N N

[1209] H

[1210]

[1211] S102 S105

[1212] Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-ethyl-1 / - / -pyrrolo[3,2-b]pyridine (S105)

[1213] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-ethyl-1H-pyrrolo[3,2-b]pyridine was synthesised in the same manner as S104, using racemic 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (250 mg, 1.00 mmol) and iodoethane (90 pL, 1.12 mmol), to afford a yellow oil (224 mg, 80%).1H NMR (400 MHz, CDCh): 58.36 (dd, J = 2.5, 1.6 Hz, 1 H), 7.30 (dd, J = 9.4, 2.6 Hz, 1 H), 7.22 - 7.20 (m, 1 H), 4.09 (q, J = 7.3 Hz, 2H), 3.22 - 3.06 (m, 3H), 3.06 - 2.84 (m, 3H), 2.15 - 1.96 (m, 2H), 1.96 - 1.84 (m, 1H), 1.49 - 1.41 (m, 4H), 0.73 (ddd, J = 6.0, 4.3, 2.7 Hz, 1H), 0.17 (dt, J = 8.3, 5.9 Hz, 1H);13C NMR (101 MHz, CDCh): 5156.2 (d, J = 245.7 Hz), 142.7, 131.3 (d, J = 26.9 Hz), 128.6 (d, J = 7.9 Hz), 128.4 (d, J = 3.8 Hz), 114.3, 102.8 (d, J = 22.7 Hz), 54.8, 48.6, 41.3, 40.8, 26.8, 23.6, 15.3, 15.2, 2.0.

[1214] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-ethyl-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S105-fumarate)

[1215] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-ethyl-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 0.73 mmol) was formulated as the fumarate salt according to General Procedure C to afford an off-white solid (1:1.5 amine:fumaric acid, 172 mg, 53%).1H NMR (400 MHz, DMSO-56): 58.32 (dd, J = 2.5, 1.6 Hz, 1H), 7.90 (dd, J = 10.3, 2.6 Hz, 1H), 7.60 (s, 1H), 6.58 (s, 3H), 4.16 (q, J = 7.2 Hz, 2H), 3.19 (dd, J = 10.3, 8.3 Hz, 1H), 3.12 - 2.94 (m, 5H), 2.25 (td, J = 10.8, 7.6 Hz, 1H), 2.01 - 1.81 (m, 2H), 1.52 (ddd, J = 10.1, 8.6, 4.6 Hz, 1 H), 1.34 (t, J = 7.2 Hz, 3H), 0.85 (ddd, J = 6.7, 4.4, 2.6 Hz, 1H), 0.31 (dt, J = 8.4, 6.1 Hz, 1H);13C NMR (101 MHz, DMSO-56): 5167.1, 156.2 (d, J = 242.7 Hz), 142.6, 134.8, 130.8 (d, J = 26.8 Hz), 130.4 (d, J = 3.6 Hz), 128.7 (d, J

[1216] 1006352981= 8.5 Hz), 112.4, 104.3 (d, J = 22.9 Hz), 54.2, 48.4, 41.1, 40.5, 26.3, 22.7, 15.8, 15.4, 2.6;19F NMR (376 MHz, DMSO-56): 5-137.3;1H qNMR Purity: 95.6% (ERETIC).

[1217] Synthesis of racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1-isopropyl-1 H-pyrrolo[3,2-b]pyridine (S106)

[1218]

[1219] Step 1: Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-b]pyridine (S106)

[1220] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-b]pyridine was synthesised in the same manner as S104, using racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1 / - / -pyrrolo[3,2-b]pyridine (250 mg, 1.0 mmol) and iodopropane (112 pL, 1.12 mmol), to afford a yellow colourless oil (240 mg, 82%).1H N MR (400 MHz, CDCh): 58.36 (dd, J = 2.5, 1.6 Hz, 1H), 7.37 - 7.27 (m, 2H), 4.52 (hept, J = 6.7 Hz, 1 H), 3.24 - 3.06 (m, 3H), 3.05 - 2.85 (m, 3H), 2.16 - 1.97 (m, 2H), 1.96 - 1.85 (m, 1 H), 1.53 (d, J = 6.8 Hz, 6H), 1.48 (ddt, J = 8.5, 6.2, 4.4 Hz, 1H), 0.73 (ddd, J = 6.0, 4.3, 2.7 Hz, 1H), 0.17 (dt, J = 8.3, 5.8 Hz, 1H);13C NMR (101 MHz, CDCh): 5156.1 (d, J = 245.4 Hz), 142.7, 131.3 (d, J = 26.9 Hz), 128.3 (d, J = 7.8 Hz), 125.1 (d, J = 3.8 Hz), 114.3, 103.0 (d, J = 22.8 Hz), 54.8, 48.6, 47.8, 40.8, 26.8, 23.8, 22.6, 15.2, 2.0.

[1221] Step 2: Racemic cis 3-(2-(2-azabicyclo[3.1.0]hexan-2-yl)ethyl)-6-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-b]pyridine fumarate (S106-fumarate)

[1222] Racemic cis 3-(2-(2-azabicyclo[3.1,0]hexan-2-yl)ethyl)-6-fluoro-1-isopropyl-1 / - / -pyrrolo[3,2-b]pyridine (200 mg, 0.73 mmol) was formulated as the fumarate salt according to General Procedure C to afford an off-white solid (1:1.5 amine:fumaric acid, 266 mg, 83%).1H NMR (400 MHz, DMSO-56): 58.32 (dd, J = 2.5, 1.5 Hz, 1 H), 7.93 (dd, J = 10.5, 2.6 Hz, 1H), 7.71 (s, 1H), 6.58 (s, 3H), 4.71 (hept, J = 6.7 Hz, 1H), 3.26 - 3.17 (m, 1H), 3.13 - 2.96 (m, 5H), 2.29 (td, J = 10.8, 7.6 Hz, 1H), 2.02 - 1.82 (m, 2H), 1.54 1006352981(ddd, J = 10.3, 8.6, 4.7 Hz, 1 H), 1.43 (d, J = 6.6 Hz, 6H), 0.87 (ddd, J = 6.6, 4.4, 2.6 Hz, 1H), 0.33 (dt, J = 8.4, 6.2 Hz, 1H);13C NMR (101 MHz, DMSO-56): 5167.2, 156.2 (d, J = 242.5 Hz), 142.5, 134.9, 130.9 (d, J = 26.7 Hz), 128.4 (d, J = 8.5 Hz), 127.3 (d, J = 3.7 Hz), 112.5, 104.4 (d, J = 22.9 Hz), 54.1, 48.4, 47.6, 40.4, 26.2, 22.8, 22.7, 15.4, 2.8;19F NMR (376 MHz, DMSO-56): 5-137.3;1H qNMR Purity: 98.4% (ERETIC).

[1223] Synthesis of 6-chloro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[3,2-6]pyridine (S111)

[1224] 13

[1225]

[1226] Step 1: 2-chloro-1-(6-chloro-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (13)

[1227] To an ice-cold suspension of 6-chloro-1 / - / -pyrrolo[3,2-b]pyridine (5.0 g, 32.8 mmol) in CH2CI2 (250 mL) was added AICI3 (13.1 g, 98.3 mmol) and the resultant mixture was stirred for 30 min. Chloroacetyl chloride (5.73 mL, 72.1 mmol) in CH2CI2 (100 mL) was added dropwise over 1 h and the resultant mixture was stirred at 0 °C for 4 h. The reaction mixture was poured onto crushed ice (250 g) and was stirred vigorously for 2 h. The precipitate was collected by vacuum filtration and washed with H2O (2 x 50 mL) and Et20 (100 mL). The solid was dried under vacuum to afford the title compound (5.7 g, 76%).1H NMR (400 MHz, DMSO-d6): 513.13 (s, 1H), 8.61 (s, 1H), 8.59 - 8.57 (m, 1 H), 8.26 - 8.20 (m, 1 H), 5.16 (s, 2H).

[1228] Step 2: 6-chloro-3-(2-chloroethyl)-1H-pyrrolo[3,2-b]pyridine (14)

[1229] 2-chloro-1-(6-chloro-1 / - / -pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (5.5 g, 24 mmol) was dissolved in TFA (25 mL) and heated to 40 °C for 1 h. Triethylsilane (25 g, 215 mmol) was added and the reaction heated to reflux and stirred for 18 h. The reaction mixture was poured into 6 M aq. HCI (100 mL) and washed with hexane (2 x 50 mL) which was discarded. The aqueous phase was neutralised by portionwise addition of Na2COs. The resultant precipita...

Claims

1. CLAIMS1. A compound of formula (I):(I)whereinA is a 4-14 membered heterocyclyl optionally substituted with one or more substituents selected from: halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(0), SO2 and NR4;each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N and NR5,said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-61006352981cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N and NR5;each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3;R6is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyleneP(O)(OR12)2, C(O)R12, CO2R12, C(O)N(R12)2, S(O)R12and SO2R12, C3-6 cycloalkyl, C6-9 alkylenecycloalkyl, C3-6 heterocyclyl, C6-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-9 alkylenecycloalkyl, C3-6 heterocyclyl, C6-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R12, C(O)N(R12)2, OR12, N(R12)2, NO2, SR12and SO2R12,said C3-6 cycloalkyl, C6-9 alkylenecycloalkyl, C3-6 heterocyclyl, C6-9 alkyleneheterocycloalkyl, C4-7 heterocyclyl, C7-10 alkyneneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being further optionally substituted with a substituent independently selected from (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR12;1006352981each R12is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3;R9is independently selected from H, halogen, CN, OR13, N(R13)2, SR13, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R13, C(O)R13, C(O)N(R13)2, C(O)C(O)N(R13)2, OC(O)R13, OC(O)OR13, OC(O)N(R13)2, OS(O)R13, OS(O)N(R13)2, OSO2R13, OP(O)(OR13)2, OCi-6alkyleneP(O)(OR13)2, S(O)R13, S(O)N(R13)2, SO2R13, N(R13)2, N(R13)C(O)R13, N(R13)C(O)OR13, N(R13)C(O)N(R13)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R13, C(O)N(R13)2, OR13, N(R13)2, NO2, SR13and SO2R13,said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-61006352981alkynyl, C2-6 haloalkynyl, Cs-ecycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR13;each R13is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C-i-ehaloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce-alkyleneheteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3;R10is independently selected from H, halogen, CN, OR14, N(R14)2, SR14, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R14, C(O)R14, C(O)N(R14)2, C(O)C(O)N(R14)2, OC(O)R14, OC(O)OR14, OC(O)N(R14)2, OS(O)R14, OS(O)N(R14)2, OSO2R14, OP(O)(OR14)2, OCi-6alkyleneP(O)(OR14)2, S(O)R14, S(O)N(R14)2, SO2R14, N(R14)2, N(R14)C(O)R14, N(R14)C(O)OR14, N(R14)C(O)N(R14)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R14, C(O)N(R14)2, OR14, N(R14)2, NO2, SR14and SO2R14,1006352981said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR14;each R14is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3;wherein one of R9and R10is H, and the other one of R9and R10is other than H;or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein:R9is independently selected from halogen, CN, OR13, N(R13)2, SR13, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R13, C(O)R13, C(O)N(R13)2, C(O)C(O)N(R13)2, OC(O)R13, OC(O)OR13, OC(O)N(R13)2, OS(O)R13, OS(O)N(R13)2, OSO2R13, OP(O)(OR13)2, OCi-6alkyleneP(O)(OR13)2, S(O)R13, S(O)N(R13)2, SO2R13, N(R13)2, N(R13)C(O)R13, N(R13)C(O)OR13, N(R13)C(O)N(R13)2, NO2, C3-8 cycloalkyl, C3-141006352981alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R13, C(O)N(R13)2, OR13, N(R13)2, NO2, SR13and SO2R13,said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, Cs-ecycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR13;each R13is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N, NH and NCH3;and R10is H.10063529813. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R9is H, andR10is independently selected from H, halogen, CN, OR14, N(R14)2, SR14, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R14, C(O)R14, C(O)N(R14)2, C(O)C(O)N(R14)2, OC(O)R14, OC(O)OR14, OC(O)N(R14)2, OS(O)R14, OS(O)N(R14)2, OSO2R14, OP(O)(OR14)2, OCi-6alkyleneP(O)(OR14)2, S(O)R14, S(O)N(R14)2, SO2R14, N(R14)2, N(R14)C(O)R14, N(R14)C(O)OR14, N(R14)C(O)N(R14)2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12aryl, C7-18 alkylenearyl, C5-10 heteroaryl, C4-16 alkyleneheteroaryl,said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R14, C(O)N(R14)2, OR14, N(R14)2, NO2, SR14and SO2R14,said C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C4-16 alkyleneheteroaryl each being further optionally substituted with a substituent selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoeities selected from O, S, S(O), SO2, N, and NR14;each R14is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16alkyleneheteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and Ce- alkyleneheteroaryl each being1006352981optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(O), SO2, N, NH and NCH3.

4. The compound of any one of claims 1 -3, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein A is a 4-8 membered heterocyclyl.

5. The compound of any one of claims 1 -4, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein A is a monocyclic heterocyclyl.

6. The compound any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein A is substituted.

7. The compound of claim 6, A is substituted by an optionally substituted Ci -ealkyl.

8. The compound of any one of claims 1 -4, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein A is a bicyclic heterocyclyl.

9. The compound of any one of claims 1 -8, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R6is H.

10. The compound of any one of claims 1 -2 and 4-8, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R9is selected from: F, Cl, Br, -CN, optionally substituted C1-ealkoxy, C(O)N(R13)2.

11. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R9is selected from F, Cl and Br.100635298112. The compound of claims 10 or 11, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R9is F.

13. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R9is C(O)N(R13)2and each R13is H.

14. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R9is a C2-ealkoxy.

15. The compound of any one of claims 1 and 3-9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein R10is F.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, wherein A is an optionally substituted 4-14 membered heterocyclyl comprising an optionally substituted 4-, 5- or 6-membered heterocyclyl, optionally as part of a polycyclic ring system.

17. The compound of any one of claims 1 -15, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, provided as a compound of formula (IV)wherein1006352981A1is a covalent bond or C(Rg)(Rh)A2is a covalent bond of C(R')(Rj)Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R' and Rj(if present) are each independently selected from H, halogen, (0), CN, C1-8 alkoxy, C-i-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(O), SO2 and NR4each R4is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl, and C3-7 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, S(O), SO2, N and NR5,said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6alkynyl, C2-6 haloalkynyl, C3-7 cycloalkyl and C3-7 heterocycloalkyl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R5, C(O)N(R5)2, OR5, N(R5)2, NO2, SR5and SO2R5,said C3-C7 cycloalkyl and C3-7 heterocycloalkyl each being further optionally substituted with a substituent independently selected from (0), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-ealkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N and NR5;each R5is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl,said C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C5-10 heterocycloalkyl, C6-12 aryl and C5-10 heteroaryl each being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-61006352981alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, S(0), SO2, N, NH and NCH3;or alternatively one of Raand Rband one of Rband Rctogether form a Ci-salkylene or Ci-sheteroalkylene to form a fused ring system, the other one of Raand Rb, and Rband Rcis independently selected from H, halogen, (0), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R4, C(O)N(R4)2, OR4, N(R4)2, NO2, SR4, SO2R4, C1-6 alkyl, C1-6 haloalkyl, C2-ealkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-8 alkylamino, C1-8 alkylsulfonyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from 0, S, N, S(0), SO2 and NR4.

18. The compound of claim 1, selected from any one of:Compound No. StructureSilHJS12HS13HS14HiS15H1006352981Compound No. StructureS16Txf Hp S17wHS18HS19HS20■ > - I i ' Ho S21■ C i H<\r^ S22■ C if H1006352981Compound No. Structure \ J S23H.a 6cZI<0^ zHS24 Xo LL o o < w\S25T|a.S26V "S37S38S391006352981Compound No. StructureS40HS41' ^"'NHS42CV \NsT5#'"'CN7Hp- / S43 CKHS44 CK N^^ j'H5^'"" / _ J S45Ho hr S46CK -N- J.' x^ ' NH1006352981Compound No. Structure C j S57BlrN'piHS58: BPr^caHS59030 C-^s S60BrxVNV^tH r a, S61' ^■" NHS62HS631006352981Compound No. StructureS64Hf.S65’ " NHo> S66HS72 0 / O'rN'r' H^'JS73 0 ^0^. Nk / HS74 y,"0"0" H^\-'^X S75"oiM / H1006352981Compound No. StructureS76 / \ '0" S77 ^. O 0^N00\ \'•X- N H'0"" S78H( 079 0 J S' / O0N0 / ' X ''NHS80C'0 S81xX-NH<0^ S82 / .0 NU 1 / HS831006352981Compound No. StructureS84cl ziXziXS85 HH zHo o o) ) )0 S86 \ / O. J I X> H(S87 ( ( ( o o o oo o oH IZ ZEZ TZ ZEZ^P S p p P 88S89S90S911006352981Compound No. StructureS92ZI^ 6, S93 zH> zH J m o) HX dw S94mHS95H H ZEZP IZ Z9 p 5^^ S 6 J I T>S97S98S99f ' X'P;" XxSX'N''' w1006352981Compound No. StructureS100 JS101 J X Yy F^^NS102 J £pS103. N. J I X >S104 J I X >^hT^* S105 J x x>F)S106 J I T >S107fk / .. 1 1>1006352981Compound No. StructureS108I X>X-* X S109§s)x> Ci-S110 -N ySill N / X>- NS112 Nx / C:

5. X\, A:: X^yA S113X X XS114S115TT51006352981Compound No. StructureS116 / C(.--S117 N / S118 / T" \\? ’> S119.\ X S120:: J Xxx \sS121 / ifS122<■' < S123 N. / £ " Y"'x1006352981Compound No. Structure 's"1 S124hS125 / O'- 8S126S127S128S129P;S130-AS131 X1006352981Compound No. Structure\ / S132or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

19. A medicament comprising a compound of any one of claims 1 -18 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof.

20. A pharmaceutical composition comprising a compound of any one of claims 1 -18 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, and a pharmaceutically acceptable excipient.

21. A method of any one or more of the following:• treating a disease, disorder or condition by activation of a serotonin receptor, and / or• treating a mental illness; and / or• treating a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition; and / or• treating weight; and / or• increasing neuronal plasticity; and / or• increasing dendritic spine density;the method comprising administering to a subject in need thereof a compound of any one of claims 1-18 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof, the medicament of claim 19 or the pharmaceutical composition of claim 20.100635298122. Use of a compound of any one of claims 1 -18 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph and / or prodrug thereof in the manufacture of a medicament for one or more of:• treating a disease, disorder or condition by activation of a serotonin receptor, and / or• treating a mental illness; and / or• treating a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition; and / or• treating weight; and / or• increasing neuronal plasticity; and / or• increasing dendritic spine density.1006352981

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