Compounds for antiobesity and fat loss

Abstract

Disclosed are pyrazolo[4,3-c]quinoline compounds that inhibit, in some cases selectively, class-IA phosphoinositide 3-kinase (PI3K) p110α isoform, pharmaceutical compositions comprising the compounds, and methods of treatment of various diseases and conditions using compositions comprising the compounds. In particular, disclosed are pyrazolo[4,3- c]quinoline compounds of the formula (I) and their use in the treatment of various diseases and conditions, such as those related to excess action of the p110α isoform of PI3K, including obesity.

Description

[0001] COMPOUNDS FOR ANTIOBESITY AND FAT LOSS

[0002] 1. FIELD OF THE INVENTION

[0003] The present invention relates to pyrazolo[4,3-c]quinoline compounds that inhibit, in some embodiments selectively, class-IA phosphoinositide 3-kinase (PI3K) p110a isoform. The compounds may have application in the treatment of conditions which are related to excess action of the p110a isoform of PI3K, including obesity.

[0004] 2. BACKGROUND TO THE INVENTION

[0005] One of the most important health problems in human and veterinary medicine today is the epidemic of obesity. Chronic consumption of excess calories leads to weight gain and obesity in both humans and companion animals, and to the many health problems that follow.

[0006] In the case of humans, a combination of the modern environment and genetics leads to imbalances in homeostatic mechanisms that lead to excess adiposity and obesity.

[0007] In the case of companion animals, food is an important way in which owners bond with and train their pets. Many owners overfeed their pets as a sign of affection.

[0008] Current weight loss drugs like glucagon-like peptide-1 (GLP-1) agonists cause weight loss by suppressing appetite, sometimes with side effects such as nausea. GLP-1 agonists also cause loss of muscle and weight rebound after ceasing treatment. This leads to low drug compliance in humans. In the case of pets, reduced enthusiasm for food can negatively impact the relationship between animal and owner. There is therefore a need for a weight loss treatment without the disadvantages of current commercial options.

[0009] It is an object of the present invention to go at least some way to meeting this need and / or at least provide the public with a useful choice.

[0010] In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art. 3. SUMMARY OF THE INVENTION

[0011] Accordingly, in a first aspect the invention provides a compound of Formula I R1p 7 R3

[0012] Y'R2 K » '

[0013] Z'V 'N-N <?' N

[0014] II I

[0015] X0^

[0016] -W^

[0017]

[0018] N

[0019] wherein:

[0020] R1is selected from H, halogen, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -OH, -OR, -OC(O)H, -OC(O)R, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR;

[0021] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR,

[0022] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, or a saturated or a partially saturated 3- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0023] R4and R5are each independently selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -C1 haloalkyl; or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated or a fully unsaturated 5 to 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R; V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is CR6or N, and where a maximum of three of Z, Y, X, W and V is N; R6, R7, R8, R9and R10are each independently selected from H, halogen, -Ci-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -Ci-4 haloalkyl, -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR, -CN, -OH, -OR, -O(C1 haloalkyl), -NH2, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 3- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 3- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R, when W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R; wherein each R is independently selected from halogen, optionally substituted C1-6 alkyl group, optionally substituted C2-6 alkenyl group, optionally substituted C2-6 alkynyl group, optionally substituted aryl group, -C1 haloalkyl, -NH₂, -OH, -SH, -NH(C1-6 alkyl), -O(C1-6 alkyl), -S(C1-6 alkyl), -NHPh, -OPh, -SPh, -N(C1-6 alkyl group)2and -NPh2; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from a C1-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group and an aryl group;

[0024] wherein R' is selected from H, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted -C3-8 cycloalkyl group, an optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2- 6 alkenyl and -C2-6 alkynyl.

[0025] In various embodiments:

[0026] R1is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, and -CH2F;

[0027] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, -CH2F;

[0028] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R; R4and R5are each independently selected from H, -Ci-6 alkyl, and -C3-8 cycloalkyl, or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated 5 to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;

[0029] V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of three of Z, Y, X, W and V is N;

[0030] R6, R7, R8, R9and R10are each independently selected from H, halogen, -C1-6 alkyl group, C1-2 haloalkyl, -CN, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 5- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R or

[0031] W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O and N, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0032] each R is independently an optionally substituted C1-6 alkyl group; wherein the one or more optional substituents are each independently selected from a C1-6 alkyl, a C2- 6 alkenyl group, a C2-6 alkynyl group and an aryl group; and

[0033] R' is an optionally substituted C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2- 6 alkenyl and -C2-6 alkynyl.

[0034] In a second aspect the invention provides a compound of Formula I

[0035]

[0036] wherein: R1is selected from H, halogen, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -OH, -OR, -OC(O)H, -OC(O)R, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR;

[0037] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR,

[0038] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, or a saturated or a partially saturated 3- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0039] R4and R5are each independently selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -C1 haloalkyl; or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated or a fully unsaturated 5 to 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R; V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is CR6or N, and where a maximum of three of Z, Y, X, W and V is N;

[0040] R6, R7, R8, R9and R10are each independently selected from H, halogen, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -Ci-4 haloalkyl, -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR, -OH, -OR, -O(C1 haloalkyl), -NH₂, -NHR, -NRR, -NHSO2R', -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 3- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 3- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R,

[0041] when W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0042] wherein each R is independently selected from halogen, optionally substituted Ci-6 alkyl group, optionally substituted C2-6 alkenyl group, optionally substituted C2-6 alkynyl group, optionally substituted aryl group, -C₁ haloalkyl, -NH₂, -OH, -SH, -NH(C1-6 alkyl), -O(C1-6 alkyl), -S(C1-6 alkyl), -NHPh, -OPh, -SPh, -N(C1-6 alkyl group)2and -NPh2; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from a C1-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group and an aryl group;

[0043] wherein R' is selected from H, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted -C3-8 cycloalkyl group, an optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2-6 alkenyl and -C2-6 alkynyl.

[0044] In various embodiments:

[0045] R1is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, and -CH2F;

[0046] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, -CH2F;

[0047] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;

[0048] R4and R5are each independently selected from H, -C1-6 alkyl, and -C3-8 cycloalkyl, or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated 5 to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;

[0049] V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of three of Z, Y, X, W and V is N;

[0050] R6, R7, R8, R9and R10are each independently selected from H, halogen, -C1-6 alkyl group, C1-2 haloalkyl, -CN, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 5- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R or

[0051] W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O and N, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0052] each R is independently an optionally substituted C1-6 alkyl group; wherein the one or more optional substituents are each independently selected from a C1-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group and an aryl group; and

[0053] R' is an optionally substituted C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2-6 alkenyl and -C2-6 alkynyl.

[0054] In various embodiments:

[0055] R1is selected from H and C1-3 alkyl;

[0056] R2and R3are each independently selected from H, -C1-6 alkyl,

[0057] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 5- to 6-membered carbocyclic ring;

[0058] R4and R5are each independently selected from H, -C1-6 alkyl;

[0059] V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of two of Z, Y, X, W and V is N;

[0060] R6, R7, R8, R9and R10are each independently selected from H, Me, Et, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHMe, -NMe2, -NHEt, -NEt2, -NHSO2R', -NO2, and a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 N atoms;

[0061] each R is a C1-6 alkyl group; and

[0062] R' is a C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently a halogen.

[0063] In various embodiments: R1is selected from H and C1-3 alkyl;

[0064] R2and R3are each independently selected from H, -C1-6 alkyl,

[0065] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 5- to 6-membered carbocyclic ring;

[0066] R4and R5are each independently selected from H, -C1-6 alkyl;

[0067] V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of two of Z, Y, X, W and V is N;

[0068] R6, R7, R8, R9and R10are each independently selected from H, Me, t-butyl, -CF3, -C(CF3)Me2, F, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHMe, -NMe2, -NHEt, -NEt2, -NHSO2R', and a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 N atoms; each R is a C1-6 alkyl group; and

[0069] R' is a C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently a halogen.

[0070] In various embodiments:

[0071] R1is Me;

[0072] one of R2and R3is H and one of R2and R3is Me;

[0073] one of R4and R5is H and one of R4and R5is Me;

[0074] V is CR10, W is CR9, X is CR8, Y is CR7, Z is N;

[0075] R7, R8, R9and R10are each independently selected from H, Me, Et, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OMe, -NMe2, -NHSO2Me, -NHSO2(2,4-F-Ph), -NO2, and tetrazine;

[0076] each R is Me; and

[0077] R' is a Me or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently fluorine.

[0078] In various embodiments:

[0079] R1is Me;

[0080] one of R2and R3is H and one of R2and R3is Me;

[0081] one of R4and R5is H and one of R4and R5is Me;

[0082] V is CR10, W is CR9, X is CR8, Y is CR7, Z is N;

[0083] R7, R8, R9and R10are each independently selected from H, Me, t-butyl, -CF3, -C(CF3)Me2, F, -OH, -OMe, -NHSO2Me, -NHSO2(2,4-F-Ph), -NO2, and tetrazine; each R is Me; and

[0084] R' is a Me or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently fluorine.

[0085] In a third aspect the invention provides a pharmaceutical composition comprising a compound according to the first aspect and at least one pharmaceutically acceptable carrier.

[0086] In a fourth aspect the invention provides a method treating or preventing a disease or condition mediated by class I PI3K, preferably class I PI3K 110α, the method comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect, or a pharmaceutical composition according to the second aspect. In a fifth aspect the invention provides a of inducing weight loss in a subject the method comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect, or a pharmaceutical composition according to the second aspect.

[0087] In a sixth aspect the invention provides a method of treating or preventing obesity or an obesity-associated condition in a subject, the method comprising administering to the subject, a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect.

[0088] In various embodiments the therapeutically effective amount is about 0.001 mg / kg to about 500 mg / kg of bodyweight.

[0089] In various embodiments the subject is a human or companion animal, preferably a dog or a cat.

[0090] In various embodiments the companion animal is a dog. In various embodiments the companion animal is a cat.

[0091] In various embodiments the subject is a healthy human and the compound of Formula I is administered for cosmetic use.

[0092] The invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of application, individually or collectively, in any or all combinations of two or more of said parts, elements or features, and where specific integers are mentioned herein that have known equivalents in the art to which the invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth. 4. BRIEF DESCRIPTION OF THE FIGURES

[0093] The invention will now be described by way of example only and with reference to the figures in which:

[0094] Figure 1 shows representative images (A) and graph (B) of the inhibition of phosphorylation of protein kinase B (pAkt) and phosphorylation of S6 ribosomal protein (pS6RbP) by select compounds in SKOV3 cells treated with insulin, as described in Example 3.

[0095] Figure 2 shows representative images (A) and graph (B) of the inhibition of pAkt and pS6RbP by select compounds in SKOV3 cells treated with EGF, as described in Example 3.

[0096] Figure 3A shows representative images of the inhibition of pAkt (top row) and S6RbP (second row down) by 8c at increasing concentrations in SKOV3 cells (starting at 0.013μM on the left-hand side and increasing to 0.041, 0.123, 0.37, 1.11, 3.33 and finally 10 μM on the left-hand side of the image) treated with insulin, as described in Example 3. This figure also shows that Total S6RbP (S235) and B Actin are unaffected at different concentrations, showing that 8c-induced reduction in phosphorylation is not a result of protein degradation and is likely due to inhibition of upstream PI3K activity. Figure 3B is a graph of the inhibition of pAkt by 8c (8c) at increasing concentrations (as shown on the x axis) in SKOV3 cells (as described above for Figure 3A) treated with insulin, as described in Example 3, with % of positive control shown on the y axis.

[0097] Figure 4A shows representative images of the inhibition of pAkt (top row) and pS6RbP (second row down) by 8c (8c) at increasing concentrations in SKOV3 cells (starting at 0.013μM on the left-hand side and increasing to 0.041, 0.123, 0.37, 1.11, 3.33 and finally 10 μM on the left-hand side of the image) treated with EGF, as described in Example 3. This figure also shows that Total S6RbP (S235) and B Actin are unaffected at different concentrations showing that 8c-induced reduction in phosphorylation is not a result of protein degradation and is likely due to inhibition of upstream PI3K activity. Figure 3B is a graph of the inhibition of pAkt by 8c at increasing concentrations (as shown on the x axis) in SKOV3 cells (as described above for Figure 3A) treated with EGF, as described in Example 3, with % of positive control shown on the y axis.

[0098] Figure 5A shows the plasma drug concentration (μM) of neutral (black circle) and salt (white circle) forms of 8c as a function of time on the x axis (min), in vivo in mice, as described in Example 4; Figure 5B Plasma insulin concentration (ng / mL) as a function of time on the x axis (min); Figure 5C whole blood glucose concentration (mmol / L) as a function of time on the x axis (min). All parameters determined in drug-naïve adult male C57BI6 / J mice administer 8c / 8c-HCl 200μM / kg. N=3 mice per time point, data displayed as mean ± SEM.

[0099] Figure 6A is a graph showing the change in body weight from baseline (g) on the y axis in diet-induced obese mice (N=6 mice per time point, data displayed as mean ± SEM) treated twice-daily by oral gavage with 8c (black circle) or vehicle (DMSO) (white circle) diluted 10%(v / v) in PBS as a function of days post treatment as shown on the y axis, as described in Example 5.

[0100] Figure 6B is a graph showing the change in fat mass (g) on the y axis for the mice treated as described for Figure 6A as measured by EchoMRI at baseline (black circle) and after 30 days treatment (white circle). Statistical significance determined by 2-way repeated measured ANOVA with Fisher's LSD and the results show a statistically insignificant increase in fat mass between the baseline measurements and those taken after 1 month (taken to be 30 days) for the vehicle (left-hand results) treated group, and a statistically significant decrease in fat mass between the baseline measurements and those taken after 1 month (taken to be 30 days) for 8c (right-hand results) treated group.

[0101] Figure 6C is a graph showing the change in lean mass (g) on the y axis for the mice treated as described for Figure 6A as measured by EchoMRI at baseline (black circle) and after 30 days treatment (white circle). Statistical significance was determined by 2-way repeated measured ANOVA with Fisher's LSD and the results show no statistical difference in lean mass between the baseline measurements and those taken after 1 month (taken to be 30 days) for either the vehicle (left-hand results) or 8c (right-hand results).

[0102] Figure 7 shows graphs of 8c (50 mg / kg) induced weight, fat mass and lean mass loss in diet induced obese mice, when treated twice daily by oral gavage, as described in Example 5. All treatments administered in PBS with 10%(v / v) DMSO. For Figure 7 a-b data points correspond to the mean (SEM) change, and for Figure 7c-d data points represent individual mice. Specifically, Figure 7A shows the change in % starting weight across treatment time course expressed in terms of days of treatment on the x axis in vehicle (white circle) and 8c (black circle) treated mice (N= 10 per group, data displayed as mean ± SEM), Figure 7B shows the change in absolute body mass (change in grams) across treatment time course expressed in terms of days of treatment on the x axis in vehicle (white circle) and 8c (black circle) treated mice (N= 10 per group, data displayed as mean ± SEM); Figure 7C shows the change in fat mass (g) on the y axis after 4 weeks treatment. Statistical significance was determined by 2-way repeated measured ANOVA with Fisher's LSD. The results show that there was a statistically significant difference between the baseline measurements (black circle) and those taken after 4 weeks (white circles) for both the vehicle treatment group (left-hand results) and the 8c treatment group (right-hand results), with fat loss being greater in 8c treatment group compared to vehicle treatment group; Figure 7D shows the change in lean mass (g) on the y axis after 4 weeks treatment. Statistical significance was determined by 2-way repeated measured ANOVA with Fisher's LSD. The results showed that there was a statistically significant difference between the baseline measurements (black circle) and those taken after 4 weeks (white circles) for both the vehicle treatment group (left hand results) and the 8c treatment group (right hand results).

[0103] Figure 8 shows graphs of 8c (50 mg / kg) induced weight, fat mass and lean mass loss in diet induced obese male mice when treated once daily by oral gavage, as described in Example 5. All treatments administered in PBS with 10%(v / v) DMSO. For Figure 8a-b N = 11 mice per time point, data displayed as mean ± SEM, and for Figure 8c-d data points represent individual mice. Specifically, Figure 8A shows the change in % starting weight across treatment time course expressed in terms of days of treatment on the x axis in vehicle (white circle) and 8c (black circle) treated mice; Figure 8B shows the change in absolute body mass (change in grams) across treatment time course expressed in terms of days of treatment on the x axis in vehicle (white circle) and 8c (black circle) treated mice; Figure 8C shows the change in lean mass (g) on the y axis after 35 days treatment. Statistical significance was determined by 2-way repeated measured ANOVA with Fisher's LSD. The results showing that there was a statistically significant decrease between the baseline measurements (black circle) and those taken after 35 days (white circles) for only the 8c treatment group (right hand results) and no statistically significant results for the vehicle treatment group (left hand results); Figure 8D shows the change in fat mass (g) on the y axis after 35 days treatment. Statistical significance was determined by 2-way repeated measured ANOVA with Fisher's LSD. The results showing that there was a statistically significant increase between the baseline measurements (black circle) and those taken after 35 days (white circles) for the vehicle treatment group (left hand results) and a statistically significant decrease between the baseline measurements (black circle) and those taken after 35 days (white circles) for the 8c treatment group (right hand results).

[0104] Figure 9 shows graphs of 8c induced weight, fat mass and lean mass loss in diet induced obese female mice when treated once daily by oral gavage, as described in Example 5. Mice were treated once daily by oral gavage with 8c (50mg / kg, increased to 100mg / kg on day 21) or vehicle (DMSO) diluted 10%(v / v) in PBS. For Figures 9a-b, N = 11 mice per time point, data displayed as mean ± SEM, and for Figure 9c-d data points represent individual mice. Specifically, Figure 9A shows the change in % starting weight across treatment time course expressed in terms of days of treatment on the x axis in vehicle (white circle) and 8c (black circle) treated mice; Figure 9B shows the change in absolute body mass (change in grams) across treatment time course expressed in terms of days of treatment on the x axis in vehicle (white circle) and 8c (black circle) treated mice; Figure 9C shows the change in lean mass (g) on the y axis after 35 days treatment. Statistical significance was determined by 2-way repeated measured ANOVA with Fisher's LSD. The results showing that there was a statistically significant decrease between the baseline measurements (black circle) and those taken after 35 days (white circles) for both the 8c treatment group (right hand results) and the vehicle treatment group (left hand results); Figure 9D shows the change in fat mass (g) on the y axis after 35 days treatment. Statistical significance was determined by 2-way repeated measured ANOVA with Fisher's LSD. The results showing that there was a statistically significant decrease between the baseline measurements (black circle) and those taken after 35 days (white circles) for the 8c treatment group (right hand results) and a statistically significant increase between the baseline measurements (black circle) and those taken after 35 days (white circles) for the vehicle treatment group (left hand results).

[0105] Figure 10A and B show 8c induced acute, transient hyperglycaemia in diet-induced obese male mice, as described in Example 6. Acute blood glucose response, measured up to four hours post-oral gavage with 8c (black circles) or vehicle (DMSO) (white circles) diluted 10% (v / v) in PBS. N=6 mice per time point, data displayed as mean ± SEM A) Dose administered 35 mg / kg after 14-days treatment. B) Dose administered 52.5 mg / kg after 35-days treatment.

[0106] Figure 11 shows graphs of Transient hyperglycaemia induced by 8c in diet-induced obese mice, as described in Example 7. Mice were treated with vehicle (DMSO) (white circles) and 8c (50mg / kg) (black circles). All treatments administered in PBS with 10%(v / v) DMSO. All data displayed as mean ± SEM, N = 10 per group. Acute blood glucose response, measured up to two hours post-oral gavage with on day 0: B) Acute blood glucose response, measured up to two hours post-oral gavage with on day 21. C) No persistent change in glycaemia is noted when random fed blood glucose is measured prior to morning dose (> 12 hours post-dose).

[0107] Figure 12 shows the plasma drug concentration (ng / ml) of the dihydrochloride (2HCI) salt form of 8c (black circle) as a function of time (hours, h), delivered via oral gavage in water to male beagle dogs, as described in Example 8. N=3 dogs, data displayed as mean ± SEM.

[0108] Figure 13 shows that oral dosing of dogs with 8c induces acute, transient increases in plasma insulin (Figure 13A) and plasma glucose (Figure 13B) as a function of time (hours, h), as described in Example 8. N=3 dogs, data displayed as mean ± SEM. Figure 14 shows the plasma drug concentration (ng / ml) of the dihydrochloride (2HCI) salt form of 8c (black circle) as a function of time (hours, h), delivered via oral gavage in water to male cats, as described in Example 8. N=6 cats, data displayed as mean ± SEM.

[0109] Figure 15 shows that oral dosing of cats with 8c induces acute, transient increases in plasma glucose (mmol / L) as a function of time (hours, h), as described in Example 8. N=6 cats, data displayed as mean ± SEM.

[0110] Figure 16A shows the change in body weight from baseline (grams) in diet-induced obese mice (N=8 mice per time point, data displayed as mean ± SEM) treated once-daily by oral gavage with 26a (white diamonds), 26b (black diamonds), 26c (black circle), or 10% v / v "vehicle" (DMSO, white circle) in PBS as a function of days post-treatment, as described in Example 9.

[0111] Figure 16B shows the change in body weight from baseline (% w / w) in diet-induced obese mice (N=8 mice per time point, data displayed as mean ± SEM) treated once-daily by oral gavage with 26a (white diamonds), 26b (black diamonds), 26c (black circle), or 10% v / v "vehicle" (DMSO, white circle) in PBS as a function of days post-treatment, as described in Example 9.

[0112] Figure 17 shows induced acute, transient hyperglycaemia in diet-induced chow fed male mice, as described in Example 10. Acute blood glucose response, measured up to four hours post-oral gavage with 26a (white diamonds), 26b (black diamonds), 26c (black square), or 10% v / v "vehicle" (DMSO, white circle) in PBS. N=6 mice per time point, data displayed as mean ± SEM.

[0113] Figure 18 shows that oral dosing of dogs with 26c induces acute, transient increases in plasma glucose as a function of time (hours, h), as described in Example 11. N = 5 dogs, data displayed as mean ± SEM.

[0114] 5. DETAILED DESCRIPTION OF THE INVENTION

[0115] Definitions

[0116] As used herein the term "comprising" means "consisting at least in part of". When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner. The term "about" as used herein means a reasonable amount of deviation of the modified term such that the end result is not significantly changed. For example, when applied to a value, the term should be construed as including a deviation of+ / - 5% of the value. As used herein the term "and / or" means "and" or "or", or both. As used herein "(s)" following a noun means the plural and / or singular forms of the noun.

[0117] The term "selectively" as used herein refers to a compound that is more potent against one isoform of a class of enzyme over at least one or more other isoforms, preferably a compound will be more potent against one isoform over all other isoforms of the class of enzyme.

[0118] The term "therapeutically effective amount" as used herein is a suitable dose as may be determined by a person of skill in the art based on a number of known factors. Such a dose can be administered as part of a dosage regimen that may be determined by an attending medical practitioner based on a number of known clinical factors. Such factors will include the size of a subject, their weight, age, body surface area, sex, time and route of administration, other drugs being administered to the subject at the time and the subject's general health (but not limited to). The therapeutically effective amount will be an amount that is sufficient to provide a treatment for the disease or condition to be treated. In some embodiments the disease or condition to be treated is obesity or obesity-associated conditions. In some embodiments the disease or condition to be treated is obesity.

[0119] The term "treatment" as used herein refers to obtaining, generally, a preferred or desired result, typically a preferred or desired pharmacological, physiological and / or cosmetic response or effect. The term "treatment" can refer to a beneficial therapeutic outcome in terms of preventing, or partially or completely curing a disease and / or adverse effect and / or symptoms attributed to the disease. A beneficial therapeutic outcome in the treatment of obesity is weight loss, in particular, loss of fat mass. The term "treatment" can also refer to a beneficial cosmetic outcome in a healthy subject, such as weight loss, in particular, loss of fat mass for aesthetic purposes.

[0120] The term "companion animal" as used herein refers to any domesticated animal and includes, without being limited to, cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, horses, cows, goats, sheep, donkeys, pigs and the like.

[0121] Stereocenters, also known as stereogenic centers, may exist in the compounds described herein. The stereocenters may be designated as ( / ?) or (S), depending on the configuration of substituents in three-dimensional space at the chiral carbon atom. All stereochemical isomeric forms of the compounds, including diastereomeric, enantiomeric, and epimeric forms, as well as D-isomers and L-isomers, and mixtures thereof, including enantiomerically enriched and diastereomerically enriched mixtures of stereochemical isomers, are within the scope of the invention, unless otherwise specified. Individual enantiomers can be prepared synthetically from commercially available enantiopure starting materials or by preparing enantiomeric mixtures and resolving the mixture into individual enantiomers. Resolution methods include conversion of the enantiomeric mixture into a mixture of diastereomers and separation of the diastereomers by, for example, recrystallization or chromatography, and any other appropriate methods known in the art. Starting materials of defined stereochemistry may be commercially available or made and, if necessary, resolved by techniques well known in the art.

[0122] The compounds described herein may also exist as conformational or geometric isomers, including cis, trans, syn, anti, entgegen (5), and zusammen (Z) isomers. All such isomers and any mixtures thereof are within the scope of the invention.

[0123] Also within the scope of the invention are any tautomeric isomers or mixtures thereof of the compounds described. As would be appreciated by those skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism. Examples include, but are not limited to, keto / enol, imine / enamine, and thioketone / enethiol tautomerism.

[0124] The term "compound" as used herein, is also intended to include salts, prodrugs, and prodrug salts of a compound of formulae herein. The term also includes any solvates, hydrates, and polymorphs of any of the foregoing. The specific recitation of "prodrug", "prodrug salt," "solvate, "hydrate or "polymorph" in certain aspects of the invention should not be interpreted as an intended omission of these forms in other aspects of the invention where the term "compound" is used without recitation of these other forms. Also within the scope of the invention are salts of the compounds described herein, including pharmaceutically acceptable salts. A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

[0125] Such salts include acid addition salts and base addition salts. Acid addition salts can be prepared by reacting compounds, in free base form, with inorganic or organic acids. Examples of inorganic acids include, but are not limited to, hydrochloric, hydrobromic, nitric, sulfuric, and phosphoric acid. Examples of organic acids include, but are not limited to, acetic, trifluoroacetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, stearic, salicylic, methanesulfonic, benzenesulfonic, isethionic, sulfanilic, adipic, butyric, and pivalic. Base addition salts can be prepared by reacting compounds, in free acid form, with inorganic or organic bases. Examples of inorganic base addition salts include alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal salts, for example, aluminium, calcium, lithium, magnesium, potassium, sodium, or zinc salts. Examples of organic base addition salts include amine salts, for example, salts of trimethylamine, diethylamine, ethanolamine, diethanolamine, and ethylenediamine.

[0126] The compounds described herein may form or exist as solvates with various solvents. If the solvent is water, the solvate may be referred to as a hydrate, for example, a monohydrate, a di-hydrate, or a tri-hydrate. All solvated forms and unsolvated forms of the compounds described herein are within the scope of the invention.

[0127] As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyse, oxidize, or otherwise react under biological conditions ( / n vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogues or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as amides, esters, carbamates, carbonates, and phosphate analogues. Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed); see also Goodman and Gilmans. The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, " Biotransformation of Drugs'. As used herein the term "biohydrolyzable moiety' means a functional group (e.g., amide, ester, carbamate, carbonate, or phosphate) analogue, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound.

[0128] The compounds described herein may also exist as isotopologues and isotopomers, wherein one or more atoms in the compounds are replaced with different isotopes.

[0129] Suitable isotopes include, for example,1H,2H (D),3H (T),12C,13C,14C,16O, and18O. Procedures for incorporating such isotopes into the compounds described herein will be apparent to those skilled in the art. Isotopologues and isotopomers of the compounds described herein are also within the scope of the invention.

[0130] The term "pharmaceutically acceptable." as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a compound of this invention.

[0131] The general chemical terms used herein have their usual meanings.

[0132] The term "alkyl" as used herein refers to a straight-chain or branched saturated acyclic hydrocarbon group having up to 30 carbon atoms and includes any C1-C26, C1-C22, C1-C18, C1-C10, or C1-C7 alkyl group. In some embodiments, alkyl groups have from 1 to 6, from 1 to 4, from 2 to 6, from 2 to 4, from 1 to 3, or 2 or 3 carbon atoms. Such groups may be referred to herein as Ci-ealkyl, Ci-4alkyl, C2-ealkyl, C2-4alkyl, Ci-salkyl, or C2-salkyl groups. Examples of alkyl groups include but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl, n-hexyl, and the like. The abbreviation " Me" means methyl or -CH₃.

[0133] The term "alkenyl" as used herein refers to a straight-chain or branched unsaturated acyclic hydrocarbon group having one or more carbon-carbon double bonds. In some embodiments, alkenyl groups have from 2 to 6, from 2 to 4, or 2 or 3 carbon atoms. Such groups may be referred to herein as C2-ealkenyl, C2-salkenyl, C2-4alkenyl, or C2-salkenyl groups, or shown as -CH=CHR, -CH=CRR, CR=CHR, -CR=CRR. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0134] The term "alkynyl" as used herein refers to a straight-chain or branched unsaturated acyclic hydrocarbon group having one or more carbon-carbon triple bonds. In some embodiments, alkynyl groups have from 2 to 6, from 2 to 4, or 2 or 3 carbon atoms. Such groups may be referred to herein as C2-ealkynyl, C2-salkynyl, C2-4alkynyl, or C2-salkynyl groups, or shown as -C=CR. Examples of alkynyl groups include but are not limited to ethynyl, propyn-l-yl, propyn-2-yl, and the like.

[0135] The term "aryl" as used herein alone or in combination with other terms, unless indicated otherwise, refers to a radical of a cyclic aromatic hydrocarbon group. Aryl groups include monocyclic and bicyclic ring systems. Aryl groups also include aromaticcycloalkyl and aromatic-cycloalkenyl fused ring systems. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, azulenyl, pentalenyl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl, and the like. In some embodiments, aryl groups have from 6 to 10 ring carbon atoms. Such groups may be referred to herein as 6 to 10-membered aryl groups. In some embodiments, aryl groups are phenyl groups. The term "cycloalkyl" as used herein alone refers to a saturated monocyclic, bicyclic, spirocyclic or bridged carbocyclic ring, having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0136] The term "halogen" as used herein, unless stated otherwise, refers to fluorine, chlorine, bromine, iodine, astatine. In various embodiments, the term "halogen" is shortened to "halo" and compounds containing a halogen can be referred to as a "halide". Preferably, a halogen is fluorine, chlorine, bromine, iodine. More preferably, a halogen is fluorine, chlorine, bromine. More preferably, a halogen is fluorine, chlorine. Most preferably, a halogen is fluorine.

[0137] The term "haloalkyl" as used herein alone refers to an alkyl group comprising one or more halogen atoms substituted for hydrogen atoms.

[0138] In some embodiments, the functional groups described above are substituted with other groups. As used herein, the term "substituted" is intended to mean that one or more hydrogen atoms in the group indicated is replaced with one or more independently selected suitable substituents, provided that the normal valency of each atom to which the substituent / s are attached is not exceeded, and that the substitution results in a stable compound. The term "stable" as used herein, unless indicated otherwise, refers to compounds which possess stability sufficient to allow manufacture and which maintain their integrity for a period of time sufficient to be useful for the purposes described herein. In various embodiments the substituents are selected from halogen, optionally substituted Ci-6 alkyl group, optionally substituted C2-6 alkenyl group, optionally substituted C2-6 alkynyl group, optionally substituted aryl group, -C₁ haloalkyl, -NH₂, -OH, -SH, -NH(CI-6 alkyl), -O(Ci-6alkyl), -S(Ci-6alkyl), -NHPh, -OPh, -SPh, -N(CI-6alkyl group)2 and -NPh2; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from a C1-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group and an aryl group.

[0139] It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are hereby expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

[0140] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure.

[0141] In the disclosure and the claims, "and / or" means additionally or alternatively.

[0142] Any use of a term in the singular also encompasses plural forms.

[0143] Compounds

[0144] The pyrazolo[4,3-c]quinoline compounds of the invention are PI3K inhibitors. The PI3K family of enzymes comprises three classes (I, II and III) of lipid kinases that control the synthesis of second messengers that regulate diverse physiological processes including cell growth, differentiation, and metabolism. The class-I PI3Ks play a key role in regulating growth and metabolism meaning they are often associated with pathologies such as cancer and other overgrowth diseases.

[0145] Class-la PI3Ks consist of a regulatory subunit, and one of three 110 kDa catalytic subunits (pllOo, P and 6). The pllOo isoform is responsible for the majority of the metabolic effects of insulin in vivo (Smith, 2013).

[0146] Insulin is a peptide hormone, responsible for energy deposition, metabolism and growth. Increased glucose levels in the circulation stimulate insulin release. Binding of insulin to its receptor triggers a cascade of reactions leading to the activation of the PI3K / AKT signalling pathways which have many downstream effects on different organs such as the liver and adipose tissue.

[0147] In adipocytes and skeletal muscle, insulin binding stimulates glucose uptake, protein synthesis through the activation of PI3K / AKT signalling. This enhances the glucose uptake by the glucose transporter 4 (GLUT4) membrane translocation. In adipocytes, insulin binding also stimulates lipogenesis decreases lipid degradation.

[0148] In the liver, insulin-mediated activation of the PI3K / AKT pathway restrains gluconeogenesis, glycogenolysis, and export of lipoproteins while it stimulates lipogenesis and glycogen synthesis.

[0149] It is thought that inhibition of all class I PI3K isoforms could lead to reduction of insulin sensitivity in adipose tissue, the liver and skeletal muscles (Savova, 2023). However, both genetic and pharmacological experiments support the specific targeting of pllOo for weight loss. Genetic deletion of pllOo impairs the ability of fibroblasts to differentiate into adipocytes in cell culture (Zhao, 2006) and inhibiting pllOo, but not other PI3-kinases, also blocks adipocyte differentiation (Kim, 2009). Young mice that have a genetic deletion of pllOo specifically (Nelson, 2014) in their adipose tissue or express only one active allele of pllOo (Foukas, 2006) have increased adipose tissue, while aging mice with only one active allele of pllOo are leaner. The latter observation is consistent with a different adipose-specific knockout of pllOo mouse model also being resistant to age-associated obesity (Araiz, 2019).

[0150] Furthermore, genetically activated pllOo in adipocytes of humans and mice leads to adipose tissues overgrowths (Lindhurst, 2012; Ladraa, 2022).

[0151] This data indicates that the pllOo isoform of PI3K can independently regulate the recruitment of new adipocytes and / or adipose tissue growth.

[0152] Pharmacological studies where mice were treated for 1 month with a range of isoformspecific class-I PI3K inhibitors found that only pllOo inhibitors reduce fat accumulation (Smith, 2013).

[0153] Others have shown pllOo specific inhibitors reduce body mass with aging (Hedges, 2023).

[0154] Further, a dual pllOo / pllOd inhibitor has been shown to attenuate diet induced weight gain and induce weight and fat loss in obese mice and reduce markers of adiposity in overweight rhesus monkeys (Ortega-Molina, 2015; Lopez-Guadamillas, 2016).

[0155] Subsequent studies provided evidence that the effect of the dual pllOo / pllOd inhibitor was likely largely driven by inhibition of pllOo, with the pllOo isoform specific inhibitor BYL-719 having similar effects in fat and weight loss in obese ob / ob leptin deficient mice. (Lopez-Guadamillas, 2016).

[0156] Accordingly, the inventors sought to prepare a class of compounds that would inhibit the pllOo isoform of PI3K, and in some cases selectively inhibit the p110α isoform of PI3K, and which therefore could have application as weight loss tools.

[0157] A range of pyrazolo[4,3-c]quinoline compounds were made using standard techniques in the art and their activity tested was against the PllOo, PllOP, P1106 and PlOOy isoforms of Class la PI3K using the methods described in.

[0158] The inventors surprisingly found that a select group of compounds bearing carboxamide groups at the 3-position of the pyrazolo[4,3-c]quinoline showed good activity against the pllOo isoform of PI3K.

[0159] Accordingly, in one aspect the invention broadly consists of a compound of Formula I

[0160] R' R2 RM

[0161] Y'Z'V V N

[0162] ii I

[0163] xw" O

[0164]

[0165] wherein: R1is selected from H, halogen, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -OH, -OR, -OC(O)H, -OC(O)R, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, and -C(O)NRR;

[0166] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)N HR, and -C(O)NRR,

[0167] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, or a saturated or a partially saturated heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0168] R4and R5are each independently selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, and -C₁ haloalkyl;

[0169] or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated or a fully unsaturated 5 to 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0170] V is CR10or N,

[0171] W is CR9or N,

[0172] X is CR8or N,

[0173] Y is CR7or N,

[0174] Z is CR6or N,

[0175] and where a maximum of three of Z, Y, X, W and V is N;

[0176] R6, R7, R8, R9and R10are independently selected from H, halogen, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -C1-2 haloalkyl, -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR, -CN, -OH, -OR, -O(C1haloalkyl), -NH2, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 3- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 3- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R,

[0177] when W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0178] wherein each R is independently selected from halogen, optionally substituted Ci-6 alkyl group, optionally substituted C2-6 alkenyl group, optionally substituted C2-6 alkynyl group, optionally substituted aryl group, -C₁ haloalkyl, -NH₂, -OH, -SH, -NH(C1-6 alkyl), -O(C1-6 alkyl), -S(C1-6 alkyl), -NHPh, -OPh, -SPh, -N(C1-6 alkyl group)2and -NPh2; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from a C1-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group and an aryl group;

[0179] wherein R' is selected from H, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted -C3-8 cycloalkyl group, an optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2-6 alkenyl and -C2-6 alkynyl.

[0180] In another aspect the invention broadly consists of a compound of Formula I

[0181]

[0182] wherein:

[0183] R1is selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -OH, -OR, -OC(O)H, -OC(O)R, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, and -C(O)NRR;

[0184] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)N HR, and -C(O)NRR,

[0185] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, or a saturated or a partially saturated heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R; R4and R5are each independently selected from H, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, and -C₁ haloalkyl;

[0186] or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated or a fully unsaturated 5 to 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0187] V is CR10or N,

[0188] W is CR9or N,

[0189] X is CR8or N,

[0190] Y is CR7or N,

[0191] Z is CR6or N,

[0192] and where a maximum of three of Z, Y, X, W and V is N;

[0193] R6, R7, R8, R9and R10are independently selected from H, halogen, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -C1-2 haloalkyl, -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR, -OH, -OR, -O(C1 haloalkyl), -NH₂, -NHR, -NRR, -NHSO2R', -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 3- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 3- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R,

[0194] when W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0195] wherein each R is independently selected from halogen, optionally substituted C1-6 alkyl group, optionally substituted C2-6 alkenyl group, optionally substituted C2-6 alkynyl group, optionally substituted aryl group, -C₁ haloalkyl, -NH₂, -OH, -SH, -NH(C1-6 alkyl), -O(C1-6 alkyl), -S(C1-6 alkyl), -NHPh, -OPh, -SPh, -N(C1-6 alkyl group)2and -NPh2; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from a C1-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group and an aryl group; wherein R' is selected from H, an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted -C3-8 cycloalkyl group, an optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2-6 alkenyl and -C2-6 alkynyl.

[0196] In various embodiments, R1is selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2- 6 alkynyl, -C3-8 cycloalkyl, -OH, -OR, -OC(O)H, -OC(O)R, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, and -C(O)NRR;

[0197] In various embodiments, R1is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, and -CH2F.

[0198] In various embodiments, R1is selected from H and C1-6 alkyl.

[0199] In various embodiments, R1is selected from H and C1-3 alkyl.

[0200] In various embodiments, R1is selected from H, Me and Et.

[0201] In various embodiments, R1is selected from Me and Et.

[0202] In various embodiments, R1is Me.

[0203] In various embodiments, R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, -CH2F;

[0204] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R.

[0205] In various embodiments, R2and R3are each independently selected from H, -C1-6 alkyl, or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 5- to 6-membered carbocyclic ring.

[0206] In various embodiments, R2and R3are each independently selected from H, Me, or R2and R3taken together with the carbon atom to which they are attached, can form a saturated 5-membered carbocyclic ring.

[0207] In various embodiments, R2and R3are each independently selected from H and Me. In various embodiments, one of R2and R3is H and one of R2and R3is Me.

[0208] In various embodiments, R2is H and R3is Me.

[0209] In various embodiments R2is Me and R3is H.

[0210] In various embodiments, R2and R3are both H. In various embodiments R2and R3are both Me.

[0211] In various embodiments, R4and R5are each independently selected from H, -Ci-6 alkyl, and -C3-8 cycloalkyl,

[0212] or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated 5 to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R.

[0213] In various embodiments, R4and R5are each independently selected from H and -C1-6 alkyl,

[0214] or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated 5 to 6-membered carbocyclic ring.

[0215] In various embodiments, R4and R5are each independently selected from H, -C1-6 alkyl. In various embodiments, R4and R5are both H.

[0216] In various embodiments, R4and R5are both Me.

[0217] In various embodiments, one of R4and R5is H and one of R4and R5is Me.

[0218] In various embodiments, V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of three of Z, Y, X, W and V is N.

[0219] In various embodiments, V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of two of Z, Y, X, W and V is N.

[0220] In various embodiments, V is CR10, W is CR9, X is CR8, Y is CR7, Z is N.

[0221] In various embodiments, V is CR10, W is CR9, X is CR8, Y is N, Z is CR6.

[0222] In various embodiments, V is CR10, W is CR9, X is N, Y is CR7, Z is CR6.

[0223] In various embodiments, V is CR10, W is N, X is CR8, Y is CR7, Z is CR6.

[0224] In various embodiments, V is N, W is CR9, X is CR8, Y is CR7, Z is CR6.

[0225] In various embodiments, V is CR10, W is CR9, X is CR8, Y is CR7, Z is CR6.

[0226] In various embodiments, V is N, W is CR9, X is CR8, Y is N, Z is CR6.

[0227] In various embodiments, V is CR10, W is N, X is CR8, Y is N, Z is CR6.

[0228] In various embodiments, V is N, W is N, X is CR8, Y is N, Z is CR6.

[0229] In various embodiments, V is N, W is CR9, X is CR8, Y is N, Z is N.

[0230] In various embodiments, V is CR10, W is CR9, X is N, Y is N, Z is N.

[0231] In various embodiments, V is CR10, W is CR9, X is N, Y is CR7, Z is N. In various embodiments, R6, R7, R8, R9and R10are each independently selected from H, halogen, -Ci-6 alkyl group, C1-2 haloalkyl, -CN, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 5- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R.

[0232] In various embodiments, R6, R7, R8, R9and R10are each independently selected from H, halogen, -C1-6 alkyl group, C1-2 haloalkyl, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHR, -NRR, -NHSO2R', -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 5- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R.

[0233] In various embodiments, R6, R7, R8, R9and R10are each independently selected from H, Me, Et, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHMe, -NMe2, -NHEt, -NEt2, -NHSO2R', -NO2, and a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 N atoms.

[0234] In various embodiments, R6, R7, R8, R9and R10are each independently selected from H, Me, t-butyl, -CF3, -C(CF3)Me2, F, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHMe, -NMe2, -NHEt, -NEt2, -NHSO2R', and a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 N atoms.

[0235] In various embodiments, R6, R7, R8, R9and R10are each independently selected from H, Me, Et, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OMe, -NMe2, -NHSO2Me, -NHSO2(2,4-F-Ph), -NO2 and tetrazine.

[0236] In various embodiments, R6, R7, R8, R9and R10are each independently selected from H, Me, t-butyl, -CF3, -C(CF3)Me2, F, -OH, -OMe, -NHSO2Me, -NHSO2(2,4-F-Ph) and tetrazine.

[0237] In various embodiments, when W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O and N, and the rings are optionally substituted independently with 1 to 4 substituents selected from R. In various embodiments, when W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from O and N, and the rings are optionally substituted independently with 1 substituent selected from R.

[0238] In various embodiments, each R is independently an optionally substituted Ci-6 alkyl group; wherein the one or more optional substituents are each independently selected from a Ci-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group and an aryl group.

[0239] In various embodiments, each R is independently C1-6 alkyl group.

[0240] In various embodiments, each R is Me.

[0241] In various embodiments, R' is an optionally substituted C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2-6 alkenyl and -C2-6 alkynyl.

[0242] In various embodiments, R' is a C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently a halogen.

[0243] In various embodiments, R' is a Me or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently fluorine.

[0244] In various embodiments:

[0245] R1is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, and -CH2F;

[0246] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, -CH2F;

[0247] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;

[0248] R4and R5are each independently selected from H, -C1-6 alkyl, and -C3-8 cycloalkyl, or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated 5 to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R; V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of three of Z, Y, X, W and V is N;

[0249] R6, R7, R8, R9and R10are each independently selected from H, halogen, -Ci-6 alkyl group, Ci-2 haloalkyl, -CN, -OH, -OR, -O(Ci haloalkyl), -NH2, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 5- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R or

[0250] W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O and N, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0251] each R is independently an optionally substituted C1-6 alkyl group; wherein the one or more optional substituents are each independently selected from a C1-6 alkyl, a C2- 6 alkenyl group, a C2-6 alkynyl group and an aryl group; and

[0252] R' is an optionally substituted C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2- 6 alkenyl and -C2-6 alkynyl.

[0253] In various embodiments:

[0254] R1is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, and -CH2F;

[0255] R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, -CH2F;

[0256] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;

[0257] R4and R5are each independently selected from H, -C1-6 alkyl, and -C3-8 cycloalkyl, or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated 5 to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R; V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of three of Z, Y, X, W and V is N;

[0258] R6, R7, R8, R9and R10are each independently selected from H, halogen, -Ci-6 alkyl group, Ci-2 haloalkyl, -OH, -OR, -O(Ci haloalkyl), -NH2, -NHR, -NRR, -NHSO2R', -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 5- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R or

[0259] W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O and N, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;

[0260] each R is independently an optionally substituted C1-6 alkyl group; wherein the one or more optional substituents are each independently selected from a C1-6 alkyl, a C2- 6 alkenyl group, a C2-6 alkynyl group and an aryl group; and

[0261] R' is an optionally substituted C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2- 6 alkenyl and -C2-6 alkynyl.

[0262] In various embodiments:

[0263] R1is selected from H and C1-3 alkyl;

[0264] R2and R3are each independently selected from H, -C1-6 alkyl,

[0265] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 5- to 6-membered carbocyclic ring;

[0266] R4and R5are each independently selected from H, -C1-6 alkyl;

[0267] V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of two of Z, Y, X, W and V is N;

[0268] R6, R7, R8, R9and R10are each independently selected from H, Me, Et, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHMe, -NMe2, -NHEt, -NEt2, - NHSO2R', -NO2, and a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 N atoms;

[0269] each R is a C1-6 alkyl group; and

[0270] R' is a C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently a halogen.

[0271] In various embodiments:

[0272] R1is selected from H and C1-3 alkyl;

[0273] R2and R3are each independently selected from H, -C1-6 alkyl,

[0274] or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 5- to 6-membered carbocyclic ring;

[0275] R4and R5are each independently selected from H, -C1-6 alkyl;

[0276] V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of two of Z, Y, X, W and V is N;

[0277] R6, R7, R8, R9and R10are each independently selected from H, Me, t-butyl, -CF3, -C(CF3)Me2, F, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHMe, -NMe2, -NHEt, -NEt2, -NHSO2R', and a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 N atoms; each R is a C1-6 alkyl group; and

[0278] R' is a C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently a halogen.

[0279] In various embodiments:

[0280] R1is Me;

[0281] one of R2and R3is H and one of R2and R3is Me;

[0282] one of R4and R5is H and one of R4and R5is Me;

[0283] V is CR10, W is CR9, X is CR8, Y is CR7, Z is N;

[0284] R7, R8, R9and R10are each independently selected from H, Me, Et, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OMe, -NMe2, -NHSO2Me, -NHSO2(2,4-F-Ph), -NO2, and tetrazine.

[0285] each R is Me; and

[0286] R' is a Me or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently fluorine.

[0287] In various embodiments: R1is Me;

[0288] one of R2and R3is H and one of R2and R3is Me;

[0289] one of R4and R5is H and one of R4and R5is Me;

[0290] V is CR10, W is CR9, X is CR8, Y is CR7, Z is N;

[0291] R7, R8, R9and R10are each independently selected from H, Me, t-butyl, -CF3, -C(CF3)Me2, F, -OH, -OMe, -NHSO2Me, -NHSO2(2,4-F-Ph), and tetrazine.

[0292] each R is Me; and

[0293] R' is a Me or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently fluorine.

[0294] In various embodiments, the compound of Formula I is selected from:

[0295] 2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0296] (7? -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; S -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; 2-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0297] 1-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)cyclopentane-l-carboxamide;

[0298] N-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; N, N-Dimethyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0299] 2-((8-(5-(2,4-Difluorophenyl-sulfonamido)-6-methoxy-pyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0300] (7? -2-((8-(5-(2,4-Difluoro-phenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0301] S -2-((8-(5-(2,4-Difluoro-phenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0302] 2-((8-(5-(2,4-Difluorophenyl-sulfonamido)-6-methoxy-pyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide;

[0303] 2-((l-Methyl-8-(5-(methyl-sulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0304] (7? -2-((l-Methyl-8-(5-(methyl-sulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; S -2-((l-Methyl-8-(5-(methyl-sulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0305] 2-Methyl-2-((l-methyl-8-(5-(methylsulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0306] 2-((8-(5-Hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; / ? -2-((8-(5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propan-amide;

[0307] S -2-((8-(5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propan-amide;

[0308] 2-((8-(5-Hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methyl-propanamide;

[0309] 2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0310] f / ? -2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0311] fS -2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0312] 2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide;

[0313] 2-((8-(5-(lH-Tetrazol-5-yl)-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0314] f / ? -2-((8-(5-(lH-tetrazol-5-yl)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0315] S -2-((8-(5-(lH-tetrazol-5-yl)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0316] 2-((8-(5-(lH-Tetrazol-5-yl)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide;

[0317] S -2-((8-(5-methyl-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0318] S -2-((8-(5-ethyl-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0319] fS -2-((8-(5-trifluoromethyl-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; S -2-((8-(5-fluoro-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0320] S -2-((8-(5-chloro-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0321] S -N-Methyl-2-(l-methyl-(8-pyridin-3-yl))-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0322] S -N, N-Dimethyl-2-(l-methyl-(8-pyridin-3-yl))- lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0323] 2-((8-(l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide;

[0324] 1-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)cyclopropane-l-carboxamide;

[0325] fS -2-((8-(6-dimethylamino-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0326] fS -2-((8-(4-methoxyphenyl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0327] fS -2-((8-(2-trifluoromethyl-pyridin-4-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0328] fS -2-((8-(2-methyl-pyridin-4-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide.

[0329] In various embodiments, the compound of Formula I is selected from:

[0330] 2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0331] (7? -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; S -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; 2-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0332] l-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)cyclopentane-l-carboxamide;

[0333] N-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; N, N-Dimethyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; 2-((8-(5-(2,4-Difluorophenyl-sulfonamido)-6-methoxy-pyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0334] / ? -2-((8-(5-(2,4-Difluoro-phenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0335] S -2-((8-(5-(2,4-Difluoro-phenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0336] 2-((8-(5-(2,4-Difluorophenyl-sulfonamido)-6-methoxy-pyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide;

[0337] 2-((l-Methyl-8-(5-(methyl-sulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0338] f / ? -2-((l-Methyl-8-(5-(methyl-sulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0339] fS -2-((l-Methyl-8-(5-(methyl-sulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0340] 2-Methyl-2-((l-methyl-8-(5-(methylsulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0341] 2-((8-(5-Hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; f / ? -2-((8-(5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0342] S -2-((8-(5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0343] 2-((8-(5-Hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methyl-propanamide;

[0344] 2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0345] f / ? -2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0346] fS -2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0347] 2-((8-(6-Fluoro-5-hydroxy-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide;

[0348] 2-((8-(5-(lH-Tetrazol-5-yl)-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; f / ? -2-((8-(5-(lH-tetrazol-5-yl)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0349] S -2-((8-(5-(lH-tetrazol-5-yl)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0350] 2-((8-(5-(lH-Tetrazol-5-yl)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide.

[0351] In various embodiments, the compound of Formula I is selected from:

[0352] 2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0353] (7? -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; S -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; 2-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0354] 1-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)cyclopentane-l-carboxamide;

[0355] N-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; N, N-Dimethyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0356] S -2-((8-(5-trifluoromethyl-pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide.

[0357] In various embodiments, the compound of Formula I is selected from:

[0358] 2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide;

[0359] (7? -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; S -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide; 2-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide;

[0360] l-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)cyclopentane-l-carboxamide;

[0361] N-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide; N, N-Dimethyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide.

[0362] In various embodiments, the compound of Formula I is: fS -2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide. In various embodiments, the compound of Formula I is selected from:

[0363]

[0364] 10

[0365]

[0366]

[0367]

[0368] 5 In various embodiments, the compound of Formula I is selected from:

[0369]

[0370] 5

[0371]

[0372] In various embodiments, the compound of Formula I is selected from:

[0373]

[0374] 10 In various embodiments, the compound of Formula I is selected from:

[0375]

[0376] In various embodiments, the compound of Formula I is:

[0377]

[0378] Pharmaceutical compositions and uses

[0379] In another aspect the invention provides a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.

[0380] Pharmaceutical compositions of the present disclosure may comprise a therapeutically effective amount of a compound of the invention (an "active ingredient"), optionally with one or more additional therapeutic agents, dissolved or dispersed in at least one pharmaceutically acceptable carrier.

[0381] The term "pharmaceutically acceptable carrier" refers to a carrier (e.g. adjuvant or vehicle) that may be administered to a subject together with the compound of the Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is generally safe, non-toxic, and neither biologically nor otherwise undesirable, including carriers suitable veterinary as well as human pharmaceutical use.

[0382] The actual amount of a composition disclosed herein administered to an animal or human patient can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. In certain embodiments, pharmaceutical compositions may comprise, for example, at least about 0.1% of an active compound. In other embodiments, an active compound may comprise between about 2% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and ranges derivable therein. The amount of active compound / s) in each therapeutically useful composition may be prepared is such a way that a suitable dosage will be obtained in a given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.

[0383] The compositions are formulated to allow for administration to a subject by any chosen route, including but not limited to oral or parenteral (including topical, subcutaneous, intramuscular and intravenous) administration. For example, the compositions may be formulated with an appropriate pharmaceutically acceptable carrier (including excipients, diluents, auxiliaries, and combinations thereof) selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compositions may be administered orally as a powder, liquid, tablet or capsule, or topically as an ointment, cream or lotion. Suitable formulations may contain additional agents as required, including emulsifying, antioxidant, flavouring or colouring agents, and may be adapted for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release.

[0384] In certain embodiments, a composition herein and / or additional agent is formulated to be administered via an alimentary route. Alimentary routes include all possible routes of administration in which the composition is in direct contact with the alimentary tract. Specifically, the pharmaceutical compositions disclosed herein may be administered orally, buccally, rectally, or sublingually.

[0385] In certain embodiments the pharmaceutical composition is formulated for oral administration. Accordingly, in such embodiments the method disclosed herein comprises administering orally to a subject a therapeutically effective amount of a compound of Formula I.

[0386] As such, these compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft- shell gelatine capsules, they may be compressed into tablets, or they may be incorporated directly with the food of the diet.

[0387] In various embodiments the pharmaceutical composition formulated for oral delivery is formulated as a tablet. Tablets can be formulated in accordance with conventional procedures by compressing mixtures of the active ingredients with a solid carrier and a lubricant.

[0388] In various embodiments the pharmaceutical composition formulated for oral delivery is formulated as a capsule. Capsules can contain any standard pharmaceutically acceptable carrier such as gelatin or cellulose.

[0389] In various embodiments the pharmaceutical composition formulated for oral delivery is formulated as a chew.

[0390] In various embodiments the compositions may be formulated for administration via alternate routes known to a skilled worker, for example, topical (i.e., transdermal) administration.

[0391] Pharmaceutical compositions for topical administration may include the compositions formulated for a medicated application such as an ointment, patch, spray, gel, paste, cream, or powder. Ointments include all oleaginous, adsorption, emulsion, and water-soluble based compositions for topical application, while creams and lotions are those compositions that include an emulsion base only.

[0392] Topically administered medications may contain a penetration enhancer to facilitate adsorption of the active ingredients through the skin. Suitable penetration enhancers include glycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones, and luarocapram.

[0393] Possible bases for compositions for topical application include polyethylene glycol, lanolin, cold cream, and petrolatum, as well as other suitable absorption, emulsion, or water-soluble ointment base.

[0394] Topical preparations may also include emulsifiers, gelling agents, and antimicrobial preservatives as necessary to preserve the composition and provide for a homogenous mixture. Transdermal administration of the compositions may also comprise the use of a "patch." For example, the patch may supply one or more compositions at a predetermined rate and in a continuous manner over a fixed period of time.

[0395] The compounds of the invention are class-IA PI3K inhibitors that, in some embodiments, selectively inhibit the p110α isoform and therefore may cause weight loss.

[0396] The oral availability of the compounds of the invention is demonstrated in Example 3. Example 4 shows that, at an oral therapeutic dose, the compound of the invention induces fat loss in obese mice.

[0397] Oral administration of the compounds of the invention to mice, decreases the effects of insulin, such as fatty acid synthesis and glucose uptake. Consequently, the animal stores less excess energy as fat, and instead clears the glucose through its urine. Without being bound by theory, it is expected that administration of the compounds of the invention to an animal in need thereof should not affect the animal's appetite. For a companion animal, this means that the owner / pet bond may be reinforced with food, without the detrimental effects of over feeding.

[0398] In various embodiments the pharmaceutical composition is formulated to deliver the compound of Formula I in a therapeutically effective amount as described herein.

[0399] The present invention also relates to methods of inhibiting class I PI3K enzymes and treating or preventing diseases and conditions mediated by class I PI3K, preferably class I PI3K 110α. The present invention also relates to methods of inhibiting class I PI3K enzymes and treating diseases and conditions mediated by class I PI3K, preferably class I PI3K 110α. Examples of diseases and conditions mediated by class I PI3K include, but are not limited to, obesity, cancers, PI 3-kinase related overgrowth syndrome (PROS), bone overgrowth syndromes, hypoglycaemia, allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome. Cancer mediated by class I PI3K include, but are not limited to, endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma. Preferably, the cancer would be associated with hyperactive PI3K signalling.

[0400] In some embodiments, the disease or condition mediated by class I PI3K is a cell proliferative disease including, but not limited to, PI 3-kinase related overgrowth syndrome (PROS), one or more leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma), or a combination thereof. In some embodiments, the disease or condition mediated by class I PI3K is a neurodegenerative disease including, but not limited to, brain trauma, spinal cord trauma, trauma to the peripheral nervous system, Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease / spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffman disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia, age-related dementia, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica or frontal lobe dementia, neurodegenerative disorders resulting from cerebral ischemia or infraction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type, intracranial and intravertebral lesions, hereditary cerebral angiopathy, hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic-related amyloidosis, cardiac-related amyloidosis, chronic hemodialysis arthropathy, Finnish amyloidosis, Iowa amyloidosis, or a combination thereof.

[0401] In some embodiments, the disease or condition mediated by class I PI3K is an inflammatory condition including, but not limited to, Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, obesity, and macular edema, ileitis, ulcerative colitis, Barrett's syndrome, Crohn's disease, or a combination thereof.

[0402] In some embodiments, the disease or condition mediated by class I PI3K is a metabolic disease including, but not limited, Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, obesity, macular edema, or a combination thereof. The present invention also relates to compounds for use in inhibiting class I PI3K enzymes and treating or preventing diseases and conditions mediated by class I PI3K, preferably class I PI3K 110α. The present invention also relates to compounds for use in inhibiting class I PI3K enzymes and treating diseases and conditions mediated by class I PI3K, preferably class I PI3K 110α.

[0403] The present invention also relates to uses of the compounds of formula (I) in the manufacture of medicaments for inhibiting class I PI3K enzymes and treating or preventing diseases and conditions mediated by class I PI3K, preferably class I PI3K 110α. The present invention also relates to uses of the compounds of formula (I) in the manufacture of medicaments for inhibiting class I PI3K enzymes and treating diseases and conditions mediated by class I PI3K, preferably class I PI3K 110α.

[0404] In one aspect the invention provides a method of inducing weight loss in a subject in need thereof the method comprising administering to the subject, a therapeutically effective amount of a compound of Formula I.

[0405] In one aspect the invention provides a method of treating or preventing obesity or obesity-associated conditions in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a compound of Formula I. In one aspect the invention provides a method of treating or preventing obesity in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a compound of Formula I. In one aspect the invention provides a method of treating obesity or obesity-associated conditions in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a compound of Formula I. In one aspect the invention provides a method of treating obesity in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a compound of Formula I. In various embodiments, the subject in need thereof in a human. In other embodiments, the subject in need thereof is a non-human animal. In other embodiments, the subject in need thereof is a companion animal.

[0406] Obesity-associated conditions include, but are not limited to, type 2 diabetes / insulin resistance, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, dislipidemia, hypertension, chronic kidney disease, polycystic ovary syndrome (PCOS), sleep apnea, pancreatitis, gout, osteoarthritis, and cancers such as liver, gallbladder, thyroid, breast, stomach, bowel, pancreas, meningioma, esophagus Adenocarcinoma, kidney, ovary, and endometrium cancer.

[0407] In one aspect, the invention provides use of a compound of Formula I in the manufacture of a medicament for the treatment or prevention of obesity or obesity- associated conditions in a subject. In one aspect, the invention provides use of a compound of Formula I in the manufacture of a medicament for the treatment or prevention of obesity in a subject. In one aspect, the invention provides use of a compound of Formula I in the manufacture of a medicament for the treatment of obesity or obesity-associated conditions in a subject. In one aspect, the invention provides use of a compound of Formula I in the manufacture of a medicament for the treatment of obesity in a subject.

[0408] In one aspect, the invention provides the compound of Formula I for use in the treatment or prevention of obesity or obesity-associated conditions in a subject. In one aspect, the invention provides the compound of Formula I for use in the treatment or prevention of obesity in a subject. In one aspect, the invention provides the compound of Formula I for use in the treatment of obesity or obesity-associated conditions in a subject. In one aspect, the invention provides the compound of Formula I for use in the treatment of obesity in a subject.

[0409] In various embodiments the therapeutically effective amount is about 0.001, 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg / kg of bodyweight and suitable ranges may be selected from any of these values, for example about 0.001 to about 500, about 0.1 to about 500, about 1 to about 500, about 10 to about 500, about 100 to about 500, about 150 to about 500, about 200 to about 500, about 250 to about 500 about 300 to about 500, about 350 to about 500, about 400 to about 500, about 450 to about 500, about 1 to about 400, about 10 to about 400, about 100 to about 400, about 150 to about 400, about 200 to about 400, about 250 to about 400 about 300 to about 400, about 350 to about 400, about 1 to about 350, about 10 to about 350, about 100 to about 350, about 150 to about 350, about 200 to about 350, about 250 to about 350 about 300 to about 350, about 1 to about 300, about 10 to about 300, about 100 to about 300, about 150 to about 300, about 200 to about 300, about 250 to about 300, about 1 to about 250, about 10 to about 250, about 100 to about 250, about 150 to about 250, about 200 to about 250, about 1 to about 200, about 10 to about 200, about 100 to about 200, about 150 to about 200, about 1 to about 150, about 10 to about 150, about 100 to about 150, about 0.1 to about 100, about 1 to about 100, about 10 to about 100, about 50 to about 100, about 0.1 to about 75 mg, about 1 to about 75, about 5 to about 75, about 10 to about 75, about 25 to about 75, about 0.1 to about 50, about 1 to about 50, about 5 to about 50, about 10 to about 50, about 1 to about 25, or about 5 to about 25, or about 10 to about 25 mg / kg of bodyweight.

[0410] In one embodiment the therapeutically effective amount is in the range of about 1 mg / kg of bodyweight to about 500 mg / kg of bodyweight. In one embodiment the therapeutically effective amount is in the range of about 1 mg / kg of bodyweight to about 250 mg / kg of bodyweight.

[0411] In one embodiment the therapeutically effective amount is in the range of about 1 mg / kg of bodyweight to about 100 mg / kg of bodyweight.

[0412] In one embodiment the therapeutically effective amount is in the range of about 1 mg / kg of bodyweight to about 75 mg / kg of bodyweight.

[0413] In one embodiment the therapeutically effective amount is in the range of about 1 mg / kg of bodyweight to about 50 mg / kg of bodyweight.

[0414] In one embodiment the therapeutically effective amount is in the range of about 1 mg / kg of bodyweight to about 25 mg / kg of bodyweight.

[0415] In one embodiment the therapeutically effective amount is in the range of about 10 mg / kg of bodyweight to about 50 mg / kg of bodyweight.

[0416] In one embodiment the therapeutically effective amount is in the range of about 25 mg / kg of bodyweight to about 50 mg / kg of bodyweight.

[0417] In various embodiments the subject in need thereof is a human or companion animal. In various embodiments the subject in need thereof is a human with a body mass index (BMI) of 25 or above.

[0418] In various embodiments the subject in need thereof is a companion animal with a body condition score (BCS) of 6 or above, when using a 1-9 scale for BCS. In various embodiments the subject in need thereof is a companion animal with a body condition score (BCS) of 4 or above, when using a 1-5 scale for BCS.

[0419] The subject in need thereof may be a human or a non-human animal, preferably a companion animal. In one embodiment the companion animal is a dog. In one embodiment the companion animal is a cat.

[0420] The compound of Formula I may be administered orally, for example in a capsule.

[0421] The compound of Formula I may be administered once daily. For example, the compound of Formula I or a pharmaceutical composition comprising the compound of Formula I may be administered at a therapeutically effective amount as described herein once daily.

[0422] The compound of Formula I may be administered twice daily. For example, the compound of Formula I or a pharmaceutical composition comprising the compound of Formula I may be administered twice daily, with each administration delivering the compound of Formula I in a therapeutically effective amount as described herein.

[0423] In various embodiments the method induces weight loss without decreasing appetite. In various embodiments the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I once daily.

[0424] In various embodiments the method comprises administering to the subject a therapeutically effective amount of a compound of Formula I twice daily.

[0425] In various embodiments the subject is a healthy human, wherein the compound of Formula I is administered for cosmetic use. There may be instances where subjects who are not considered overweight, or do not have high BMI or BCS desire weight loss, for example for aesthetic purposes.

[0426] The present invention also provides a kit comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and optionally instructions for use. The present invention also provides a kit comprising a compound of the Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; one or more additional therapeutic agents; and optionally instructions for use.

[0427] The instructions for use may describe the method(s) of treatment in which the compounds are administered. In various embodiments, the instructions for use describe methods of treating the diseases and conditions indicated herein.

[0428] The container may be any vessel or other sealed or sealable apparatus that can hold the pharmaceutical composition. Examples include bottles, ampules, divided or multichambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form and is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag, or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed typically depends on the dosage form involved. More than one container can be used together in a single package for a single dosage form.

[0429] The kits may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. The device may include, for example, an inhaler if the composition is an inhalable composition; a syringe and needle if the composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if the composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.

[0430] In various embodiments, the kits may comprise, for example in a separate vessel or container, one or more additional therapeutic agent, typically in the form of a pharmaceutical composition comprising the additional therapeutic agent and a pharmaceutically acceptable carrier. The additional therapeutic agent may be selected from any of those indicated herein for co-administration with a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0431] The compound of Formula I can be administered as the sole therapeutic agent or in combination with one or more other additional therapeutic agents.

[0432] The compound of Formula I may be administered simultaneously, sequentially, or separately with the one or more additional therapeutic agents. The compound of Formula I and one or more additional therapeutic agents may be administered as single formulation or as separate formulations.

[0433] In various embodiments, the additional therapeutic agent is selected from one or more of a CDK4 and 6 inhibitors; a selective estrogen receptor degrader (SERD); an aromatase inhibitor; a taxane; an mTOR inhibitor; a tyrosine kinase inhibitor; a platinum agent; an anthracycline; an immune checkpoint inhibitor; an antiandrogen; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor; an MEK inhibitor; an ERK inhibitor; a topoisomerase inhibitor; a SERM; or a PARP inhibitor; Metformin; an SGLT2 inhibitor; a GLP1R inhibitor; a GLP1 / GIP inhibitor; a Myostatin inhibitor; an Activin receptor II inhibitor; drugs that suppress food intake known to a skilled worker; or a combination thereof.

[0434] The invention will now be illustrated in a non-limiting way by reference to the following examples.

[0435] 6. EXAMPLES

[0436] General Experimental Methods

[0437] Enzyme activity assays

[0438] The following methods were used to obtain the data reported in Table 2 of Example 2. Phosphoinositide 3-kinase (PI3K) activity was determined using a homogenous time-resolved fluorescence (HTRF) assay kit purchased from Merck Millipore (catalogue #33-017) according to the manufacturer's instructions.

[0439] HTRF assays were performed to determine the half-maximal inhibitory concentration (IC50) of the potential inhibitors. Inhibitors were dissolved in 100% dimethyl sulfoxide (DMSO) vehicle and the vehicle was used at a final concentration in the assay of 2.5% v / v. The enzymes were used at 65% of maximal effective concentration determined from enzyme activity experiments using different amounts of the enzyme (EC65 concentration) and made up with the substrate phosphoinositol-4,5-bisphosphate (PIP2) then 15 μL was added to each well. Inhibitors in 100% DMSO were added to each well in a volume of 0.5 μL, in the enzyme only and no enzyme control conditions only 0.5 μL of 100% DMSO was added. The final concentration of PIP2 in the assay was 10 pM.

[0440] The plate was then pre-incubated for 10 minutes at room temperature, after which adenosine triphosphate (ATP) substrate was added to achieve a final concentration of 10 μM. The plate was then centrifuged at 400 rpm at room temperature for 30 seconds, and then incubated for 45 minutes at room temperature. The reaction was stopped by the addition of the STOP solution Merck Millipore (catalogue #33-017) and the plate centrifuged at 400 rpm at room temperature for 30 seconds.

[0441] Detection

[0442] The detection mix supplied in the HTRF Kit catalogue #33-017 was made up following the manufacturer's instructions and added to each well. The plate was centrifuged at 400 rpm at room temperature for 30 seconds, and then incubated at room temperature between 3 and 20 hours in the dark. The plate was read using a BioTek Synergy 2 multimode reader equipped with the following filters and settings: Excitation: 330-80 nm (Filter: 360 / 40); Emission: 665 and 620 nm (Filter: 665 / 7 and 620 / 40); Counting delay: 50 μsec; Integration window: 400 μsec. The HTRF ratio was determined by: (EM 665nm / EM 620nm) x 10000. Data was expressed as the percentage of control activity as determined by:

[0443] % of uninhibited Control = Sample - no enzyme control) / enzyme — no enzyme) X 100 IC50 were then calculated using a nonlinear regression model of:

[0444] log(inhibitor) vs. response - Variable slope (four parameters) with constraints set at 0 (bottom) and 100 (top) as implemented in GraphPad Prism 6.

[0445] Pharmacokinetic and pharmacodynamic studies

[0446] The following methods are used in Example 4.

[0447] Adult male mice from C57Bl6 / J strain were fasted overnight and killed before 15, 30, 60, 120 or 360 min following administration of 200μM / kg of 8c / 8c-HCI via oral gavage. Mice were killed by CO2 inhalation and blood samples were collected via cardiac puncture and plasma was recovered by centrifuging blood samples at 6000 rpm for 5 min.

[0448] Plasma samples (10 μL) were processed by adding four volumes (40 μL) of ice-cold acetonitrile, containing 0.1 μM ketoconazole as an internal standard, vortexed for 1 min, and centrifuged at 13,000 rpm for 5 min. The resulting supernatants were transferred to HPLC inserts and mixed 1:1 with ultrapure water (MilliQ) containing 0.1% formic acid. A 8c standard curve was generated by the addition of a 5 mM stock solution of 8c in DMSO to drug-free mouse plasma, and then serially diluted to achieve concentrations from 30 μM to 3 nM, processed as described. Quality control samples (10, 1 and 0.1 pM) were made from a separately prepared 5 mM 8c stock solution. 8c concentration was determined using an LC-MS / MS equipped with Jet Stream (Agilent 6460) following chromatographic separation in a Zorbax SB-C18 column (2.1 mm x 50 mm, 5 pm; Agilent Technologies). The mobile phase was a gradient constructed using (A) acetonitrile containing 0.1% formic acid and (B) ultrapure water containing 0.1% formic acid. The gradient profile was: 0-0.5 min, 10% A; then, this was increased to 95% by 1.5 min and maintained for 1 min, returned to 10% A over 0.5 min and held for 2 min before the next sample injection. The flow rate was maintained at 0.5 mL / min throughout the gradient condition. Injection volume was 10 pL. Column oven temperature and autosampler temperature was set to 35 °C and 4 °C, respectively. The quantitation was achieved with MS / MS detection in electrospray ionization (ESI) in positive ion mode. The instrument source parameters were set to gas temperature 300 °C; gas flow 7 L / min; nebulizer 45 psi, sheath gas temperature 300 °C, sheath gas flow 10 L / min. The ion spray voltage was set at 3000 V.

[0449] Detection of the ions was carried out in multiple-reaction monitoring mode (MRM) by monitoring the transitions of m / z Quadrupoles QI and Q3 were set on unit resolution. To generate pharmacokinetic parameters (maximum plasma concentration, time to maximum plasma concentration, half-life, and elimination rate constant), plasma concentration versus time data were analyzed by non-compartmental analysis using Phoenix WinNonlin (Certara, Princeton, NJ, USA).

[0450] Obesity studies

[0451] The following methods are used in Examples 5-7.

[0452] Adult male and female C57BI6 / J mice were fed a commercial high fat diet for 6-10 weeks to induce obesity, before being treated with 8c or vehicle (DMSO) diluted 10%(v / v) in PBS via oral gavage once or twice daily for the indicated amounts and durations. Body composition (lean and fat mass) was assessed at the indicated timepoints. The amounts fed to each mouse are as defined in the Brief Description of Figures section.

[0453] Blood glucose and plasma insulin

[0454] The following methods are used in Examples 6-7.

[0455] Tail blood glucose was measured using a hand-held glucose monitor (Accu-chek performa; Roche, Basel, Switzerland) at the time points indicated in non-fasted mice. Insulin was measured with an ultra-sensitivity mouse insulin ELISA kit (Crystal Chem, IL, U. S. A.) from plasma recovered from blood samples collected from a tail vein in nonfasted mice.

[0456] Cell culture studies

[0457] The following methods are used in Example 3. SKOV3 cells were grown in alpha-modified minimal essential growth medium (oMEM) supplemented with 5% (v / v) foetal bovine serum (Invitrogen), 100 units / ml penicillin and 100 pg / ml streptomycin at 37°C with 5% CO2.

[0458] Twelve-well tissue-culture plates were seeded at 500000 cells per well. Cells were left to recover for at least 12 h and then serum-starved overnight. Cells were then treated with compounds (at a final concentration of either 13nM, 41 nM, 50 nM, 123 nM, 370 nM, 500 nM, 1110 nM, 3330 nM, 5000 nM or 10000 nM) for 60 min and stimulated with 500 nM insulin or 5 nM Epidermal Growth Factor (EGF) for 15 min, followed by washing with cold phosphate-buffered saline [140 mM NaCI, 8 mM Na2HPO4and 2 mM NaH2PO4(pH 7.4)], before the addition of lysis buffer (50 mM (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid) (HEPES)), 150 mM NaCI, 10 mM ethylenediaminetetraacetic acid (EDTA) (pH 8.0), 10 mM Na2P2O7, 2 mM vanadate, 100 mM NaF, 1% (v / v) Nonidet P40, 10 pM leupeptin, 15 pM pepstatin A, 1 mM 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), 0.6 pM aprotinin, 30 pM ALLN (Inhibitor of calpain I, calpain II, cathepsin B and cathepsin L) and 1 mM dithiothreitol (DTT) (pH 7.4).

[0459] Lysates were kept on ice before supernatants were collected after centrifugation at 14000xg for 15 min at 4°C. A Pierce BCA Protein Assay Kit (Thermo Scientific, Waltham, MA, U. S. A.) was used to determine the lysate protein concentration. The lysates were then stored at -80°C for future use.

[0460] Proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) using a 4-15% gradient gel (Bio-Rad, CA, U. S. A.) and transferred onto polyvinylidene difluoride membranes (Pall Corporation, NY, U. S. A.). The membranes were incubated for 1 h in tris-buffered saline with Tween® 20 Detergent (TBS-T) (50 mM Tris, 275 mM NaCI, 5 mM KCI and 0.1% Tween) containing 3% w / v bovine serum albumin (BSA) at room temperature and overnight at 4°C in the same solution containing primary rabbit antibodies (Cell Signalling Technology, Beverly, MA, U. S. A.). Immunoreactive proteins were detected using a horseradish peroxidase-conjugated antirabbit goat Immunoglobulin G (IgG) (Dako and Agilent Technologies, Santa Clara, CA, U. S. A.) and enhanced chemiluminescence (ECL®, GE Healthcare). Signals were detected using Fuji LAS4000 and analyzed with the Fuji Image Gauge software.

[0461] Synthetic chemistry methods

[0462] The synthesis of compounds of the formulae herein can be readily effected by synthetic chemists of ordinary skill. Relevant procedures and intermediates are disclosed, for instance, herein. Other approaches to synthesizing compounds of the invention can readily be adapted from references cited herein. Variations of these procedures and their optimization are within the skill of the ordinary practitioner. The specific approaches and compounds shown in the Examples are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name or not. The suitability of a chemical group in a compound structure for use in synthesis of another compound structure is within the knowledge of one of ordinary skill in the art. Additional methods of synthesizing compounds of the invention and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. The methods described herein may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds herein. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Trans formations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The synthetic methods described herein may also additionally include steps, either before or after any of the steps described in any scheme, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds of the formulae described herein. Intermediates can be used with or without purification (e.g., filtration, distillation, Sublimation, crystallization, trituration, solid phase extraction, and chromatography). Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

[0463] Example 1: Synthesis of compounds of Formula I and related pyrazolo[4,3-c]quinolines

[0464] Overview

[0465] The inventors have synthesised compounds 8a-e, 8h-i, 12a-d, 17a-d, 18a-d, 19a-d, 25a-d, 26a-e, 27a-b, 28a-b and 29a-b, shown in Table 1 below. TaWe 1

[0466] Compound IUPAC name Structure

[0467] CN

[0468] X

[0469] 8a 2-((l-Methyl-8-(pyridin-3-yl)- v° lH-pyrazolo[4,3-c]quinolin-3- LA,.^ A WI o yl)oxy)acetamide

[0470] " vu

[0471] \ / ®

[0472] 8b (7<)-2-((l-Methyl-8-(pyridin-3- yl)-lH-pyrazolo[4,3-c]quinolin- os

[0473] 3-yl)oxy)propanamide ' / \" / II \' \< O \ - -="'A °

[0474] / ) O zw U--——

[0475] / / I II o>

[0476] o 2 ' — '

[0477] 8c (S9-2-((l-Methyl-8-(pyridin-3- yl)-lH-pyrazolo[4,3-c]quinolin- A. %-N \

[0478] A,i. AAA

[0479] 3-yl)oxy)propanamide 11 I 1 °

[0480] ' N-'

[0481] 8d 2-Methyl-2-((l-methyl-8- * • Ms •., Ms (pyridin-3-yl)-lH-pyrazolo[4,3- c]quinolin-3-yl)oxy)propanamide

[0482] 8e l-((l-Methyl-8-(pyridin-3-yl)- lH-pyrazolo[4,3-c]quinolin-3-.-A A 0 NH, yl)oxy)cyclopentane-l- carboxamide 'JT',"' "

[0483] 8h / V-Methyl-2-((l-methyl-8- M fate H (pyridin-3-yl)-lH-pyrazolo[4,3- A 1 c]quinolin-3-yl)oxy)acetamide

[0484] 8i / V, / V-Dimethyl-2-((l-methyl-8- (pyridin-3-yl)-lH-pyrazolo[4,3- c]quinolin-3-yl)oxy)acetamide

[0485] N"

[0486] 12a 2-((8-(5-(2,4-Difluorophenyl- sulfonamido)-6-methoxy- pyridin-3-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- yl)oxy)acetamide

[0487]

[0488] b (R)-2-((8-(5-(2,4-Difluoro- Meo NM%_NM%NHsphenylsulfonamido)-6- methoxypyridin-3-yl)-l-methyl- o=s1=o

[0489] lH-pyrazolo[4,3-c]quinolin-3- yl)oxy)propanamide

[0490] F X CM

[0491] c (S)-2-((8-(5-(2,4-Difluoro- v°

[0492] phenylsulfonamido)-6- 2 O methoxypyridin-3-yl)-l-methyl- \ Z^

[0493] < >z^

[0494] lH-pyrazolo[4,3-c]quinolin-3- \ / ® yl)oxy)propanamide o5

[0495] zH u_

[0496] d 2-((8-(5-(2,4-Difluorophenyl- \ / o \.=

[0497] MeO / \ / \ ii

[0498] ( NM%_N MeMe

[0499] V 7 I II ®\ / ) O ZOT u.-——

[0500] sulfonamido)-6-methoxy- o s ' -f

[0501] HN'"'^;::Af<^fXY^00 pyridin-3-yl)-l-methyl-l / 7- 0=S1=0

[0502] pyrazolo[4,3-c]quinolin-3- yl)oxy)-2-methylpropanamide

[0503] F

[0504] a 2-((l-Methyl-8-(5-(methyl- ^, N.

[0505] „

[0506] x0 if N-N _ sulfonamido)p Me / / / \\ / n,NH2 yridin-3-yl)-l / 7- / / u' oI pyrazolo[4,3-c]quinolin-3-0 HL J

[0507] yl)oxy)acetamide

[0508] b (R)-2-((l-Methyl-8-(5-(methyl- N Me Me.1LJO if % N-N '2,NH2 sulfonamido)pyridin-3-yl)-l / 7- / / 0pyrazolo[4,3-c]quinolin-3- °HII JI J

[0509] yl)oxy)propanamide

[0510] c (S)-2-((l-Methyl-8-(5-(methyl- Me, Me Mex0 if ^1 N / -N \V V / NH2 sulfonamido)pyridin-3-yl)-l / 7- / / ° pyrazolo[4,3-c]quinolin-3- °HA J

[0511] yl)oxy)propanamide

[0512] d 2-Methyl-2-((l-methyl-8-(5- N Me,uMe O if % N-NMesJ NH2(methylsulfonamido)pyridin-3- Mex / / / \\ / yl)-lH-pyrazolo[4,3-c]quinolin-0 Hll X J

[0513] 3-yl)oxy)propanamide

[0514] a 2-((8-(5-Hydroxypyridin-3-yl)-l- “%-N _NH methyl-lH-pyrazolo[4,3-2c]quinolin-3-yl)oxy)acetamide

[0515] b (R)-2-((8-(5-hydroxypyridin-3- yl)-l-methyl-lH-pyrazolo[4,3- r^S “VN 'NHJc]quinolin-3-yl)oxy)propan- amide

[0516]

[0517] c (S)-2-((8-(5-hydroxypyridin-3- yl)-l-methyl-lH-pyrazolo[4,3- c]quinolin-3-yl)oxy)propan- amide

[0518] d 2-((8-(5-Hydroxypyridin-3-yl)-l- CM CMM C methyl-lH-pyrazolo[4,3-MVN NH2c]quinolin-3-yl)oxy)-2-methyl- V propanamide p s

[0519] A z

[0520] > Jz^

[0521] a 2-((8-(6-Fluoro-5-hydroxy- < >z \ / o^

[0522] \ / \ / ® 0)

[0523] pyridin-3-yl)-l-methyl-l / 7- ospyrazolo[4,3-c]quinolin-3- o o25yl)oxy)acetamide Q z

[0524] o \ X

[0525] b (R)-2-((8-(6-Fluoro-5-hydroxy- O O L / L /

[0526] pyridin-3-yl)-l-methyl-l / 7- X X

[0527] pyrazolo[4,3-c]quinolin-3- X X

[0528] yl)oxy)propanamide o ° 7

[0529] Az

[0530] c (S)-2-((8-(6-Fluoro-5-hydroxy- o

[0531] pyridin-3-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- / \ / \ (D (D yl)oxy)propanamide

[0532] A' v*

[0533] d 2-((8-(6-Fluoro-5-hydroxy- FyN Me^ Me^NH2pyridin-3-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- X o I

[0534] yl)oxy)-2-methylpropanamide X N> a 2-((8-(5-(lH-Tetrazol-5-yl)- pyridin-3-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- yl)oxy)acetamide

[0535] b (R)-2-((8-(5-(lH-tetrazol-5-.. Me < N-N -•,NH2 yl)pyridin-3-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- N T II 1 1

[0536] 'N'NH

[0537] yl)oxy)propanamide

[0538] c (S)-2-((8-(5-(lH-tetrazol-5- yl)pyridin-3-yl)-l-methyl-l / 7- “VNMei NH’ pyrazolo[4,3-c]quinolin-3- N T T j 1

[0539] yl)oxy)propanamide

[0540] d 2-((8-(5-(lH-Tetrazol-5- %MVN yl)pyridin-3-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- N K, TyU 1zU1 X1 l yl)oxy)-2-methylpropanamide

[0541]

[0542] a (S9-2-((8-(5-methyl-pyridin-3- yl)-l-methyl-lH-pyrazolo[4,3- c]quinolin-3-yl)oxy)propanamide

[0543] b (S;-2-((8-(5-ethyl-pyridin-3-yl)- X l-methyl-l / 7-pyrazolo[4,3- s o c]quinolin p S X v v°°

[0544] -3-yl)oxy)propanamide p s v°

[0545] p\ z s O s S O

[0546] ^

[0547] \ z\^ z^ c (8-(5-trifluoromethyl- >>z\ z^

[0548] (S9-2-( \ / ® ^

[0549] >>z s ) < > Xz \ / —^ ®^ —

[0550] \ / ® s > < > J —^

[0551] pyridin-3-yl)-l-methyl-l / 7- s ) ( — s > < —

[0552] / \5—

[0553] pyrazolo[4,3-c]quinolin-3- yl)oxy)propanamide

[0554] Q o O

[0555] d (S9-2-((8-(5-fluoro-pyridin-3- Q o

[0556] o 2z

[0557] yl)-l-methyl-lH-pyrazolo[4,3- c]quinolin-3-yl)oxy)propanamide

[0558] e (S9-2-((8-(5-chloro-pyridin-3- yl)-l-methyl-lH-pyrazolo[4,3- c]quinolin-3- yl)oxy)propanamide;

[0559] ^

[0560] a fS9-N-Methyl-2-(l-methyl-(8- z pyridin-3-yl))-lH-pyrazolo[4,3- c]quinolin-3-yl)oxy)propanamide

[0561] b fS9-N, N-Dimethyl-2-(l-methyl-,,

[0562] N MesMe

[0563] Me '

[0564] (8-pyridin-3-yl))- 1H- < 7| N-N V,N~Me pyrazolo[4,3-c]quinolin-3- yl)oxy)propanamide

[0565] a (S9-2-((8-(6-dimethylamino- Me2N. _N. Me

[0566] N-NH2 pyridin-3-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- yl)oxy)propanamide

[0567] b (S9-2-((8-(4-methoxyphenyl)-l- “%_NM\ NH2methyl-lH-pyrazolo[4,3- c]quinolin-3- W iV-4yl)oxy)propanamide;

[0568] a (S9-2-((8-(2-trifluoromethyl- pyridin-4-yl)-l-methyl-l / 7- pyrazolo[4,3-c]quinolin-3- yl)oxy)propanamide

[0569]

[0570] (S9-2-((8-(2-methyl-pyridin-4- yl)-l-methyl-lH-pyrazolo[4,3- c]quinolin-3-yl)oxy)propanamide

[0571]

[0572] Compounds 8a-d, 8h-i, 12a-d, 17a-d, 18a-d, 19a-d, 25a-d, 26a-e, 27a-b, 28a-b and 29a-b in Table 1 were prepared in accordance with Scheme 1.

[0573] 8a-c, f 7a R = CH2CONH28a R = CH2CONH27b R = (R)-CHMeCONH28b R = (R)-CHMeCONH27c R = (S)-CHMeCONH28c R = (S)-CHMeCONH27e R = 1-cyclopentyl-1-CONH28e R = 1-cyclopentyl-1-CONH27f R = CH2CO2Et 8f R = CH2CO2Et

[0574] e (to make 8g) or (3) f (to make 8h) 8g R = OH 8h R = NHMe 8i R = NMe2

[0575] 12a X = CH212b X = (R)-CHMe 12c X = (S)-CHMe 12d X = CMe2

[0576]

[0577] 17a-d a, 16a, 17a X = CH2; 7b, 16b, 17b X = (R)-CHMe; 7c, 16c, 17c X = (S)-CHMe; 7d, 16d, 17d X = CMe2

[0578] 7a-d +

[0579]

[0580] 18a-d 7a, 18a X = CH2; 7b, 18b X = (R)-CHMe; 7c, 18c X = (S)-CHMe; 7d, 18d X = CMe2

[0581] 7a, 19a X = CH2; 7b, 19b X = (R)-CHMe; 7c, 19c X = (S)-CHMe; 7d, 19d X = CMe2

[0582] 7a, 24a, 25a X = CH2; 7b, 24b, 25b X = (R)-CHMe; 7c, 24c, 25c X = (S)-CHMe; 7d, 24d, 25d X = CMe2

[0583] 26a R = Me 26b R = Et 26c R = CF326d R = F

[0584]

[0585] 26e R = Cl 7c 28a X = N, R = NMe2

[0586] 28b X = CH, R= OMe

[0587] 29a R = CF3

[0588]

[0589] 29b R = Me Scheme 1

[0590] Scheme 1. Reagents: a. alcohol, DIAD, PPh3, THF; b. 1-cyclohexyl-l-carboxamide, DBU, DMF; c. 3-pyridineboronic acid (5), PdCl₂(dppf), aq. K₂CO₃, DMF; d. 2-bromo-2- methylpropanamide, NaOH, DMF; e. aq. LiOH, THF; f. MeNH2, EtOH, CH2Cl2; g. SOCl2then Me2NH, THF, CH2Cl2; h. PdCl2(dppf), aq. K2CO3, DMF; i. TFA; j. 5-substituted pyridine-3-boronic acid, PdCl2(dppf), aq. Na2CO3, DMF; k. NaH, DMF then MeI; l. 6M HCl; m. 4-dimethylaminopyridine-3-boronic acid (for 28a) or 4-methoxyphenylboronic acid (for 28b), PdCl2(dppf), aq. Na2CO3, DMF; n. 3-substituted pyridine-4-boronic acid, PdCl2(dppf), aq. Na2CO3, DMF.

[0591] Compound 4 was prepared by the published procedure (Black, 2018). Compounds 7a-c and f bearing an alkoxy substituent at the 3-position of the pyrazolo[4,3-c]pyridine ring were made by a Mitsunobu reaction of compound 4 with an appropriately substituted alcohol (Scheme 1, equation 1). An acidic workup at the end of the Mitsunobu reaction was necessary when the alcohol contained a primary carboxamide, to cleave the iminophosphorane that had formed during the reaction. Compound 7e was prepared by alkylation of 4 with 1-bromo-l-cyclopentylcarboxamide. A Suzuki coupling then introduced the pyridine ring of 8a-c, e and f. Compound 8d was made from compound 6 by reaction with 2-bromo-2-methylpropanamide (equation 2). Ester 8f could undergo hydrolysis to make carboxylic acid 8g, or direct substitution with methylamine to afford 8h (equation 3). Acid 8g was further converted to tertiary carboxamide 8i via the acid chloride.

[0592] Carboxamides 12a-d, 18a-d and 19a-d were made by the Suzuki coupling of bromides 7a-d with the appropriate boronic esters 9a, 9c and 9d (equations 4, 6 and 7).

[0593] Methanesulfonamides 16a-d were brought through with a p-methoxybenzyl protecting group by the Pd-catalysed coupling with boronic ester 9b and then the protecting group was removed by heating in neat TFA to afford 17a-d (equation 5). Tetrazoles 24a-d were also brought through with the same p-methoxybenzyl protecting group by Suzuki coupling of 9e with 7a-d (equation 8). The final compounds 25a-d were then made by heating in neat TFA.

[0594] Synthesis and characterisation information for the compounds of Formula I is provided below.

[0595] 2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (8a)

[0596] 47a

[0597]

[0598] 8a

[0599] Scheme 2

[0600] DIAD (2 eq.) was added to a suspension of 4 (140 mg, 0.50 mmol), glycolamide (1.2 eq.) and PPh3(2 eq.) in dry THF (10 mL), and stirred for 4 h at room temperature (method B). The solvent was then removed in vacuo, and the product was purified by chromatography (CH2CI2: MeOH gradient) to give 2-((8-bromo-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (7a) as an off-white solid (75 mg, 44%):XH NMR (DMSO-cfe) <59.35 (s, 1H), 8.64 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.03 (dd, J = 8.9, 1.9 Hz, 1H), 7.73 (br s, 1H), 7.44 (br s, 1H), 4.80 (s, 2H), 4.35 (s, 3H); LCMS (APCI+) 335 / 337 (MH+, 100%).

[0601] A person skilled in the art can amend the above method, varying the amide reactant used, to make compounds 7b-f.

[0602] A mixture of 7a (75 mg, 0.22 mmol), pyridine-3-boronic acid (1.2 eq.) in 2M aqueous K₂CO₃ (2 mL) and DMF (4 mL) was deoxygenated by bubbling N2through it. PdCl₂(dppf) (5 mol%) was added, and the reaction mixture was heated at 80-100 °C under a balloon of N2 until the reaction was complete by TLC analysis (method A). After cooling to room temperature, the solvents were removed in vacuo, and the resulting product was purified by chromatography (CH2CI2: 10% c. NH3 in MeOH gradient) to give 2-((l-methyl-8-(pyridin-3-yl)-l / 7-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (8a) as a white solid (41 mg, 55%):XH NMR (DMSO-de) 69.15 - 9.18 (m, 2H), 8.69 (d, J = 2.0 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.34 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.16 (dd, J = 8.7, 2.0 Hz, 1H), 7.72 (br s, 1H), 7.58 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.41 (br s, 1H), 4.78 (s, 2H), 4.43 (s, 3H); LCMS (APCI+) 334 (MH+, 100%). Anal. Calcd for C₁₈H₁₅N₅O₂.0.33H₂O: C, 63.72; H, 4.65; N, 20.64. Found C, 63.37; H, 4.49; N, 20.34.

[0603] A person skilled in the art can amend the above method, varying the bromide used, to make compounds 8b-f.

[0604] ( / ?)-2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (8b)

[0605] 4 7b

[0606]

[0607] 8b

[0608] Scheme 3

[0609] Reaction of 4 (100 mg, 0.36 mmol) with S-lactamide as for 7a by method B gave (R)-2-((8-bromo-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (7b) as a white solid (88 mg, 70%):XH NMR (DMSO- e) <59.12 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.93 (dd, J = 8.9, 2.1 Hz, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 5.13 (q, J = 6.8 Hz, 1H), 4.30 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 349 / 351 (MH+, 100%).

[0610] Reaction of 7b (87 mg, 0.25 mmol) as for 8a by method A gave the title compound as a white solid (43 mg, 49%):XH NMR (DMSO- e) <59.15 (dd, J = 2.4, 0.7 Hz, 1H), 9.12 (s, 1H), 8.69 (d, J = 1.9 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (ddd, J= 8.0, 2.4, 1.6 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.16 (dd, J = 8.7, 1.9 Hz, 1H), 7.66 (br s, 1H), 7.57 (dd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.25 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.41 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 348 (MH+, 100%). Anal. Calcd for C₁₉H₁₇N₅O₂.0.25H₂O: C, 64.85; H, 5.01; N, 19.90. Found C, 64.77; H, 4.89; N, 19.87. (S)-2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (8c)

[0611]

[0612] Scheme 4

[0613] Reaction of 4 (100 mg, 0.36 mmol) with R-lactamide as for 7a gave (S)-2-((8-bromo-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (7c) as a white solid (61 mg, 48%):XH NMR (DMSO- e) 69.12 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.94 (dd, J = 8.9, 2.1 Hz, 1H), 7.65 (br s, 1H), 7.24 (br s, 1H), 5.13 (q, J = 6.8 Hz, 1H), 4.30 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 349 / 351 (MH+, 100%).

[0614] Alternative synthesis of compound 7c

[0615] Under nitrogen, THF (20 reaction volume (RV) mL / g) was charged to the reactor followed by a mixture of solids - compound 4 (1.0 eq.), triphenylphosphine (3.0 eq.), (R)-lactamide (1.2 eq.). Further THF (20 RV), with some being used to aid the transfer of the solids into the reactor. The mixture was stirred at 40 °C for 2 hours and then cooled to 0 °C. The resulting slurry was charged with diisopropyl

[0616] azodicarboxylate (DIAD, 3.0 eq.) solution in THF (10 RV) by pressure-equalising dropping funnel over 1-2 hours. The resulting mixture was warmed to 20 °C and held at this temperature for 4-16 hours. To the resulting amber solution, 4 M aqueous hydrochloric acid (3.0 eq.) was added by pressure-equalising dropping funnel over 10-20 minutes. Simultaneously, the mixture was seeded with a sample of the reaction product 7c. The resulting slurry was cooled to 15 °C and stirred for 1-4 days.

[0617] The resulting mixture was decanted into Schott bottles, using additional THF to aid the transfer. The dense solid was allowed to settle. The supernatant was filtered under reduced pressure, followed by the solid, deliquoring the filter cake to surface. Two lots of THF (2 RV) was used to wash the filter cake, deliquoring to surface. Two lots of 2-methyl tetra hydrofuran (2 RV) was used to wash the filter cake, deliquoring to surface. Two lots of MTBE (methyl tert-butyl ether, 2 RV) was used to wash the filter cake, deliquoring to surface. The filter cake was washed once more with MTBE (2 RV) and fully deliquored. The filter cake was air dried for 2-5 hours and then placed under high vacuum for 1-4 days.

[0618] A colourless solid 7c was afforded in 93-96% yield and 97-98 area% purity by UV-HPLC. The chiral purity is 94-96%. The single largest impurity was the carboxylic acid derivative of 7c.

[0619] Reaction of 7b (61 mg, 0.17 mmol) as for 8a, followed by trituration with MeOH gave the title compound as a white solid (32 mg, 52%):XH NMR (DMSO- e) <59.15 (dd, J = 2.4, 0.7 Hz, 1H), 9.11 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.15 (dd, J = 8.7, 1.9 Hz, 1H), 7.66 (br s, 1H), 7.57 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.25 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.41 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 348 (MH+, 100%). Anal. Calcd for C₁₉H₁₇N₅O₂.0.5H₂O: C, 64.03; H, 5.09; N, 19.65. Found C, 63.69; H, 4.83; N, 19.47.

[0620] Alternative synthesis of compound 8c

[0621] A mixture of 22.3 g 7c, pyridine-3-boronic acid (1.5 eq.), Pd(dppf)Cl₂ (2 mol%), and Na₂CO₃ (4.7 eq.) in n-BuOH / water (2:1, 35 RV) was heated at 85 °C under an atmosphere of nitrogen for 1.5 h. The organic layer was washed 3 times with a 1: 1 mixture of cysteine and aqueous sodium hydroxide (25 eq. wrt 2 mol% Pd), during which the palladium could visually be observed transferring from the product-containing organic phase to the aqueous phase. The organic phase is diluted with methanol and stirred with 2-3 %w / w charcoal (with respect to input compound 7c) overnight. The mixture is then filtered through a pad comprised of: top to bottom sand, silica, Celite, sand, filter paper. Extra n-butanol is used to wash residual product from the pad. This removes the charcoal, and any accumulated fine particles present in compound 3 and picked up during processing. The filtrate is concentrated to 10 mL / g (wrt input compound 5) at 50-60 °C under vacuum. At ~28 mL / g the product begins to crystallise. The mixture is stirred as a slurry at 50 °C and then allowed to cool overnight. The mixture is re-heated to 50 °C and heptane (20 mL / g) is added slowly at this temperature. Addition of heptane as an anti-solvent causes more 8c to crystallise from solution to increase yield. The mixture is allowed to cool overnight and filtered. The product is washed with heptane / n-butanol (3:1) and then MTBE and is held under vacuum at 40 °C overnight to purge residual solvent. 8c is obtained in 67% yield with 99.1 area% purity.

[0622] Crystallisation procedure for 8c

[0623] To 8c was added a solution of MeOH (3 RV) and 6 M aqueous HCI (1.0 eq.). The mixture was stirred at 60 °C and sonicated until dissolution. The mixture was held for 15 minutes, by which point it may or may not become turbid. To the resulting mixture was added EtOAc (3.5 RV) by pressure-equalising dropping funnel to afford a thick slurry. The mixture was stirred aggressively for 30 minutes and then allowed to cool to ambient temperature. The resulting mixture was held for 1 hour and then re-heated to 60 °C. To the mixture was added EtOAc (3.5 eq.) by pressure-equalising dropping funnel, becoming an even thicker, immobile slurry. The mixture was then rotated on the rotary evaporator for 1 hour at 60 °C. The mixture was returned to the stirrer-hotplate at 60 °C. 6 M aqueous HCI (1.0 eq.) was added to the mixture in a single portion. The mixture rapidly became a thin, mobile slurry. The solid was dense and rapidly sunk when stirring was stopped. The mixture was allowed to cool to ambient temperature and stirred for 16 hours.

[0624] The mixture was filtered under reduced pressure, deliquoring to surface. EtOAc (2 RV) was used to wash the filter cake, deliquoring to surface (x3 washes). MTBE (2 RV) was used to wash the filter cake, deliquoring to surface (x2 washes). The filter cake was washed once more with MTBE (2 RV) and fully deliquored. The filter cake was air dried for 2-5 hours and then placed under high vacuum for 1-4 days.

[0625] A colourless to off-white solid was afforded in 85-98% yield and 98-99 area% purity by UV-HPLC. The chiral purity was 94-96%. The single largest impurity was 8j, the carboxylic acid derivative of 8c

[0626] 2-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (8d)

[0627]

[0628] Scheme 5

[0629] Reaction of 8-bromo-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-ol (4) (83 mg, 0.30 mmol) with pyridine-3-boronic acid (5) as for 7a, followed by trituration with MeOH gave 1-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-ol (6) (as a yellow powder (45 mg, 55%):XH NMR (DMSO- e) <5 11.31 (br s, 1H), 9.14 (dd, J = 2.4, 0.8 Hz, 1H), 9.04 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.32 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.12 (dd, J = 8.6, 2.0 Hz, 1H), 7.57 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.37 (s, 3H); LCMS (APCI+) 277 (MH+, 100%). Anal. Calcd for C₁₆H₁₂N₄O.H₂O: C, 65.18; H, 4.81; N, 19.00. Found C, 65.50; H, 4.56; N, 18.61.

[0630] A suspension of 6 (80 mg, 0.29 mmol) and NaOH (35 mg, 0.88 mmol) in DMF (2 mL) was stirred at room temperature for 1 h before 2-bromo-2-methylpropanamide (144 mg, 0.87 mmol,) was added, then stirring continued for a further 2 weeks. The solvent was removed in vacuo. Chromatography (CH2CI2: MeOH: c. NH398:2:0.2 to 97:3:0.3 to 96:4:0.4) gave the title compound as a white solid (47 mg, 45%):XH NMR (DMSO- e) <5 9.15 (dd, J = 2.4, 0.8 Hz, 1H), 9.13 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.15 (dd, J = 8.6, 2.0 Hz, 1H), 7.55 - 7.60 (m, 2H), 7.22 (s, 1H), 4.42 (s, 3H), 1.69 (s, 6H); LCMS (APCI+) 362 (MH+, 100%). Anal. Calcd for C₂₀H₁₉N₅O₂: C, 66.47; H, 5.30; N, 19.38. Found C, 66.19; H, 5.33; N, 19.27.

[0631] l-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)cyclopentane-l-carboxamide (8e)

[0632] 5

[0633]

[0634] Scheme 6

[0635] A solution of 1-bromocyclopentane-l-carbonitrile (Ros, 1988) (1.48 g, 8.5 mmol) in cone. H2SO4 (5 mL) was stirred at room temperature overnight and poured onto ice. The mixture was extracted with CH2CI2 and washed with water. The organic layer was dried and reduced to give 1-bromocyclopentane-l-carboxamide as a white solid (1.305 g, 80%):XH NMR (CDCI3) <56.64 (br s, 1H), 5.56 (br s, 1H), 2.49 - 2.39 (m, 2H), 2.32-2.24 (m, 2H), 2.06-1.94 (m, 2H), 1.93-1.83 (m, 2H); LCMS (APCI+) 112.2 (M+-Br, 100%).

[0636] A mixture of 4 (150 mg (0.54 mmol), 1-bromocyclopentane-l-carboxamide (207 mg, 1.08 mmol) and DBU (0.16 mL, 1.07 mmol) in DMF (5 mL) was stirred at room temperature for 6 days. Further 1-bromocyclopentane-l-carboxamide (103 mg, 0.55 mmol) was added and the mixture was heated at 60 “Covernight. Further 1-bromocyclopentane-l-carboxamide (103 mg, 0.55 mmol) and DBU (0.16 mL, 1.07 mmol) was added, and the mixture was heated at 60 °C overnight. The solvent was removed under vacuum and the residue was chromatographed on silica twice, firstly with CHzCIz-MeOH-conc. aq. NH3 (98:2.0:0.2) and secondly with EtOAc-MeOH (99.7:0.3) to give a mixture of l-((8-bromo-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)cyclopentane-l-carboxamide (7e) and 1-cyclopentene-l-carboxamide as a white solid (257 mg). 7e:XH NMR (DMSO-de) <59.03 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 8.8, 2.0 Hz, 1H), 7.43 (br s, 1H), 7.08 (br s, 1H), 6.46 (m, 1H), 2.24 (m, 4H), 1.74 (m, 4H). 1-Cyclopentene-l-carboxamide:XH NMR (DMSO-df, 57.26 (br s, 1H), 6.88 (br s, 1H), 6.46 (m, 1H), 2.41 (br t, J = 7.5 Hz, 4H), 1.84 (pentet, J = 7.6 Hz, 2H).

[0637] The crude mixture of 7e and 1-cyclopentene-l-carboxamide was combined with pyridine-3-boronic acid (5) (17 mg, 0.14 mmol), Pd(dppf)Cl₂ (5.7 mg, 7 mL) and 2M K₂CO₃ (1 mL) in DMF (2 mL) and reacted as for 7a according to Method A.

[0638] Chromatography on silica, eluting with CH2Cl2-MeOH-conc. aq. NH3 (95:5:0.5) gave a crude product which was triturated with methanol to give the title compound (23 mg, 11% over two steps):XH NMR (DMSO-de) <59.15 (d, J = 1.9 Hz, 1H), 9.04 (s, 1H), 8.68 (d, J = 0.8 Hz, 1H), 8.65 (dd, J = 4.7, 1.2 Hz, 1H), 8.34 (br d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.15 (dd, J = 8.7, 1.8 Hz, 1H), 7.58 (dd, J = 7.8, 4.9 Hz, 1H), 7.45 (br s, 1H), 7.08 (br s, 1H), 4.40 (s, 3H), 2.25 (m, 4H), 1.75 (m, 4H); LCMS (APCI+) 388.2 (MH+, 100%). Anal. Calcd for C₂₂H₂₁N₅O₂·0.67H₂O: C, 66.15; H, 5.64: N, 17.53. Found: C, 66.23; H, 5.42; N, 17.29.

[0639] Ethyl 2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetate (8f)

[0640]

[0641] Scheme 7

[0642] Reaction of 4 (600 mg, 2.16 mmol) with ethyl glycolate as for 7a by method B, followed by trituration with 'PrzO gave ethyl 2-((8-bromo-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetate (7f) as a white solid (786 mg, 100%):XH NMR (CDCI3) <59.13 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.81 (dd, J = 8.9, 2.1 Hz, 1H), 4.98 (s, 2H), 4.27 - 4.34 (m, 5H), 1.32 (t, J = 7.1 Hz, 3H); LCMS (APCI+) 364 / 366 (MH+, 100%).

[0643] Reaction of 7f (786 mg, 2.16 mmol) as for 8a by method A gave a crude product which was heated with c. H2SO4 (1 mL) in EtOH (20 mL) for 1 h. The reaction mixture was diluted with CH2CI2 and water, and then solid KHCO3 was added until the aqueous phase reached pH 8. The layers were separated, the aqueous layer extracted with CH2CI2, the combined organic layers were dried (Na2SO4) and the solvents removed in vacuo.

[0644] Chromatography (CH2CI2: MeOH: c. NH3) gave the title compound as a pale brown solid (584 mg, 75%):XH NMR (CDCI3) <59.16 (s, 1H), 8.99 (d, J = 2.3, 0.6 Hz, 1H), 8.68 (dd, J = 4.8, 1.6 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.01 (ddd, J = 7.9, 2.3, 1.6 Hz, 1H), 7.95 (dd, J = 8.6, 2.0 Hz, 1H), 7.46 (ddd, J = 7.9, 4.8, 0.6 Hz, 1H), 5.00 (s, 2H), 4.37 (s, 3H), 4.31 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); LCMS (APCI+) 363 (MH+, 100%). Anal. Calcd for C₂₀H₁₈N₄O₃.0.5H₂O: C, 64.68; H, 5.16; N, 15.09. Found C, 64.43; H, 4.74; N, 14.98.

[0645] 2-((l-Methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetic acid (8g)

[0646]

[0647] 8f8S

[0648] Scheme 8

[0649] A suspension of 8f (150 mg, 0.41 mmol) and LiOH.H₂O (21 mg, 0.50 mmol) in THF (10 mL) and H2O (1 mL) was refluxed for 2 h. The precipitated solid was filtered off, then taken up in H2O and acidified to pH 7 with IM aqueous HCI. The precipitated solid was filtered off and dried to leave the title compound as a white solid (21 mg, 15%):XH NMR (DMSO- e) <59.15 (dd, J = 2.4, 0.7 Hz, 1H), 9.02 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.14 (dd, J = 8.7, 2.0 Hz, 1H), 7.57 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 4.59 (s, 2H), 4.39 (s, 2H); LCMS (APCI+) 335 (MH+, 60%), 277 (M-CH2CO2H, 100%).

[0650] / V-Methyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (8h)

[0651]

[0652] 8f8h

[0653] Scheme 9 Ester 8f (100 mg, 0.28 mmol) was stirred in MeNHz (3 mL, 33% in EtOH) and CH2CI2 (3 mL) for 18 h. The precipitated solid was filtered off, washed with MeOH and dried to leave the title compound as a white solid (80 mg, 83%):XH NMR (DMSO- e) <59.12 -9.18 (m, 2H), 8.69 (d, J = 1.8 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.14 - 8.22 (m, 2H), 7.58 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.82 (s, 2H), 4.42 (s, 3H), 2.69 (d, J = 4.7 Hz, 3H); LCMS (APCI+) 348 (MH+, 100%). Anal. Calcd for C₁₉H₁₇N₅O₂: C, 65.69; H, 4.93; N, 20.16. Found C, 65.54; H, 4.79; N, 19.92.

[0654] / V, / V-Dimethyl-2-((l-methyl-8-(pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (8i)

[0655]

[0656] Scheme 10

[0657] Carboxylic acid 8g (148 mg, 0.44 mmol) was refluxed in SOCI2 (5 mL) for 2 h. The solvent was removed in vacuo. The residue was taken up in CH2CI2 (10 mL) and added dropwise to a solution of Me₂NH (2.2 mL, 2 M in THF, 4.4 mmol) in CH2CI2 (10 mL) at 0 °C over ca 5 mins. After 30 mins the solvents were removed in vacuo. Chromatography (CH2CI2: MeOH: c. NH399:1:0.1 to 98:2:0.2 to 97:3:0.3) gave the title compound as a white solid (121 mg, 76%):XH NMR (DMSO- e) <59.15 (d, J = 2.4, 0.7 Hz, 1H), 9.05 (s, 1H), 8.69 (d, J= 2.0 Hz, 1H), 8.65 (dd, J = 4.8, 1.6 Hz, 1H), 8.34 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.16 (dd, J = 8.6, 2.0 Hz, 1H), 7.57 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 5.17 (s, 2H), 4.41 (s, 3H), 3.03 (s, 3H), 2.87 (s, 3H); LCMS (APCI+) 362 (MH+, 100%). Anal. Calcd for C₂₀H₁₉N₅O₂.0.5H₂O: C, 64.82; H, 5.45; N, 18.90. Found C, 64.94; H, 5.83; N, 18.90.

[0658] 2-((8-(5-(2,4-Difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (12a)

[0659]

[0660] Scheme 11 Reaction of 7a (50 mg, 0.15 mmol) and 2,4-difluoro- / V-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (9a) (Fan, 2017) (70 mg, 0.16 mmol) as for 8a by method A, followed by trituration with MeOH gave the title compound as a white solid (41 mg, 49%):XH NMR (DMSO- e) <5 10.35 (br s, 1H), 9.13 (s, 1H), 8.48 - 8.59 (m, 2H), 8.20 (d, J = 8.6 Hz, 1H), 7.99 - 8.11 (m, 2H), 7.79 (td, J = 8.5, 6.4 Hz, 1H), 7.72 (br s, 1H), 7.57 (t, J = 9.1 Hz, 1H), 7.41 (br s, 1H), 7.22 (t, J = 8.5 Hz, 1H), 4.78 (s, 2H), 4.39 (s, 3H), 3.69 (s, 3H); LCMS (APCI+) 555 (MH+, 100%). Anal. Calcd for C₂₅H₂₀F₂N₆O₅S.H₂O: C, 52.45; H, 3.87; N, 14.68. Found C, 52.42; H, 3.79; N, 14.59.

[0661] ( / ?)-2-((8-(5-(2,4-Difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (12b)

[0662] 9a - ►

[0663]

[0664] Scheme 12

[0665] Reaction of 7b (50 mg, 0.14 mmol) and 9a (67 mg, 0.16 mmol) as for 8a by method A, followed by trituration with MeOH:H2O (3:1) gave the title compound as a white solid (31 mg, 38%):XH NMR (DMSO-de) <5 10.35 (br s, 1H), 9.10 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 8.7, 2.0 Hz, 1H), 7.79 (td, J = 8.6, 6.3 Hz, 1H), 7.66 (br s, 1H), 7.59 (m, 1H), 7.19 - 7.28 (m, 2H), 5.14 (q, J = 6.8 Hz, 1H), 4.38 (s, 3H), 3.69 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 569 (MH+, 100%). Anal. Calcd for C₂₆H₂₂F₂N₆O₅S.1.5H₂O: C, 52.43; H, 4.23; N, 14.11. Found C, 52.30; H, 4.08; N, 13.89.

[0666] (S)-2-((8-(5-(2,4-Difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (12c)

[0667]

[0668] Scheme 13 Reaction of 7c (50 mg, 0.14 mmol) and 9a (67 mg, 0.16 mmol) as for 8a by method A, followed by trituration with MeOH:H2O (3:1) gave the title compound as a white solid (51 mg, 63%):XH NMR (DMSO- e) <5 10.35 (br s, 1H), 9.10 (s, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 8.04 (dd, J = 8.7, 2.0 Hz, 1H), 7.79 (td, J = 8.6, 6.3 Hz, 1H), 7.66 (br s, 1H), 7.59 (m, 1H), 7.19 - 7.28 (m, 2H), 5.14 (q, J = 6.8 Hz, 1H), 4.38 (s, 3H), 3.69 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 569 (MH+, 100%). Anal. Calcd for C26H22F2N6O5S.0.67H2O: C, 53.78; H, 4.05; N, 14.47. Found C, 53.60; H, 4.00; N, 14.30.

[0669] 2-((8-(5-(2,4-Difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide (12d)

[0670] 9a

[0671]

[0672] Scheme 14

[0673] A suspension of 4 (400 mg, 1.44 mmol), 2-bromo-2-methylpropanamide (478 mg, 2.88 mmol) and DBU (0.22 mL, 1.47 mmol) in DMF (5 mL) was heated at 80 °C for 2 days. More 2-bromo-2-methylpropanamide (478 mg, 2.88 mmol) and DBU (0.22 mL, 1.47 mmol) was then added, and then heating continued at 100 °C for a further 2 days. The solvent was removed in vacuo. Chromatography (CH2CI2: MeOH 99:1 to 98:2) gave 2-((8-bromo-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide (7d) as a white solid (224 mg, 43%):XH NMR (DMSO-de) <59.14 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.93 (dd, J = 8.9, 2.1 Hz, 1H), 7.56 (br s, 1H), 7.22 (br s, 1H), 4.31 (s, 3H), 1.68 (s, 6H); LCMS (APCI+) 363 / 365 (MH+, 100%).

[0674] Reaction of 7d (50 mg, 0.14 mmol) and 9a (65 mg, 0.15 mmol) as for 8a by method A, followed by trituration with MeOH gave the title compound as a white solid (46 mg, 58%):XH NMR (DMSO- e) <5 10.35 (br s, 1H), 9.11 (s, 1H), 8.53 - 8.60 (m, 2H), 8.20 (d, J = 8.66 Hz, 1H), 8.08 (d, J = 2.19 Hz, 1H), 8.03 (dd, J = 8.68, 1.95 Hz, 1H), 7.79 (td, J = 8.5, 6.4 Hz, 1H), 7.54 - 7.63 (m, 2H), 7.19 - 7.26 (m, 2H), 4.40 (s, 3H), 3.69 (s, 3H), 1.69 (s, 6H); LCMS (APCI+) 583 (MH+, 100%). Anal. Calcd for C27H24F2N6O5S.H2O: C, 54.00; H, 4.36; N, 13.99. Found C, 53.89; H, 4.24; N, 13.85.

[0675] 2-((l-Methyl-8-(5-(methylsulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (17a)

[0676]

[0677] 17a Scheme 15

[0678] NaH (359 mg, 60% dispersion in oil, 8.98 mmol) was added to a solution of / V-(5-bromopyridin-3-yl)methanesulfonamide (10) (1.50 g, 5.98 mmol) in dry DMF (20 mL) at 0 °C. After 10 mins the ice bath was removed, and the reaction mixture stirred for a further 2 h. 4-Methoxybenzyl chloride (0.89 mL, 6.56 mmol) was then added and stirred at room temperature for 18 h. The solvent was then removed in vacuo. Chromatography (hexanes: EtOAc 9:1 to 4:1 to 3:1 to 2:1) gave / V-(5-bromopyridin-3-yl)- / V-(4-methoxybenzyl)methanesulfonamide (11) as a yellow solid (1.44 g, 65%):XH NMR (CDC ) <58.56 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.80 (s, 2H), 3.78 (s, 3H), 2.98 (s, 3H); LCMS (APCI+) 371 / 373 (MH+, 100%).

[0679] A mixture of 11 (1.43 g, 3.85 mmol), bis(pinacolato)diboron (1.2 eq.) and KOAc (3 eq.) in DMSO (5 mL) was deoxygenated by bubbling N2through it. PdCl₂(dppf) (5 mol%) was added, and the reaction was heated to 80 °C as the reaction mixture became dark. After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with CH2Cl2. The combined extracts were washed with water and dried (Na2SO4), and the solvent was removed in vacuo to give a brown oil which was purified by chromatography (CH2CI2 to CH2CI2: THF 1:1) to give / V-(4-methoxybenzyl)- / V-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (9b) (1.32 g, 82%):XH NMR (CDCh) <58.81 (d, J = 1.5 Hz, 1H), 8.46 (d, J= 2.7 Hz, 1H), 7.93 (dd, J = 2.7, 1.5 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.80 (s, 2H), 3.76 (s, 3H), 2.97 (s, 3H), 1.34 (s, 12H); LCMS (APCI+) 419 (MH+, 100%). Reaction of 7a (100 mg, 0.30 mmol) and 9b (187 mg, 0.45 mmol) as for 8a, by method A gave 2-((8-(5-( / V-(4-methoxybenzyl)methylsulfonamido)pyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (16a) as a white solid (116 mg, 71%):XH NMR (DMSO- e) <59.16 (s, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.37 (t, J = 2.2 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.12 (dd, J = 8.7, 2.0 Hz, 1H), 7.72 (br s, 1H), 7.42 (br s, 1H), 7.26 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.97 (s, 2H), 4.79 (s, 2H), 4.43 (s, 3H), 3.68 (s, 3H), 3.23 (s, 3H); LCMS (APCI+) 547 (MH+, 100%).

[0680] 16a (115 mg, 0.21 mmol) was heated in TFA (3 mL) at 60 °C for 18 h. After cooling to room temperature, the reaction mixture was dripped slowly onto solid NaHCO3, then diluted with CH2CI2 and MeOH and stirred until gas evolution ceased. The solids were filtered off and washed with CH2CI2 and MeOH, and the solvents removed from the filtrate. Chromatography (CH2CI2: MeOH: c. NH398:2:0.2 to 96:4:0.4 to 94:6:0.6 to 90:10:1 to 85: 15: 1.5) followed by trituration with MeOH gave the title compound as a white solid (55 mg, 61%):XH NMR (DMSO-de) <5 10.17 (br s, 1H), 9.16 (s, 1H), 8.88 (s, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 2.0 Hz, 1H), 8.01 (s, 1H), 7.72 (br s, 1H), 7.42 (br s, 1H), 4.78 (s, 2H), 4.41 (s, 3H), 3.15 (s, 3H); LCMS (APCI+) 427 (MH+, 100%). Anal. Calcd for C19H18N6O4S: C, 53.51; H, 4.25; N, 19.71. Found C, 53.69; H, 4.33; N, 19.61.

[0681] ( / ?)-2-((l-Methyl-8-(5-(methylsulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (17b)

[0682]

[0683] Scheme 16

[0684] Reaction of 7b (100 mg, 0.29 mmol) and 9b (144 mg, 0.34 mmol) as for 8a by method A gave (R)-2-((8-(5-( / V-(4-methoxybenzyl)methylsulfonamido)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (16b) as a pale yellow solid (133 mg, 83%):XH NMR (DMSO- e) <59.12 (s, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.36 (t, J = 2.2 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 1.9 Hz, 1H), 7.66 (br s, 1H), 7.21 - 7.29 (m, 3H), 6.85 (d, J = 8.7 Hz, 2H), 5.15 (q, J = 6.8 Hz, 1H), 4.97 (s, 2H), 4.41 (s, 3H), 3.68 (s, 3H), 3.23 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 561 (MH+, 100%).

[0685] 16b (132 mg, 0.24 mmol) was heated in TFA (2 mL) at 60 °C for 18 h. After cooling to room temperature, the reaction mixture was dripped slowly onto solid NaHCO3, then diluted with CH2CI2 and MeOH and stirred until gas evolution ceased. The solids were filtered off and washed with CH2CI2 and MeOH, and the solvents removed from the filtrate. Chromatography (CH2CI2: MeOH: c. NH3 97:3:0.3 to 95:5:0.5 to 90:10:1) followed by trituration with MeOH, gave the title compound as a white solid (27 mg, 26%):XH NMR (DMSO-de) 6 10.13 (br s, 1H), 9.13 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 8.7, 2.0 Hz, 1H), 8.02 (t, J = 2.2 Hz, 1H), 7.66 br (s, 1H), 7.25 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.40 (s, 3H), 3.16 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 441 (MH+, 100%). Anal. Calcd for C20H20N6O4S.0.25H2O: C, 53.98; H, 4.64; N, 18.89. Found C, 54.01; H, 4.48; N, 18.59.

[0686] (S)-2-((l-Methyl-8-(5-(methylsulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (17c)

[0687]

[0688] Scheme 17

[0689] Reaction of 7c (100 mg, 0.29 mmol) and 9b (144 mg, 0.34 mmol) as for 8a by method A gave (S)-2-((8-(5-( / V-(4-methoxybenzyl)methylsulfonamido)pyridin-3-yl)-l-methyl- lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (16c) as a pale yellow solid (148 mg, 92%):XH NMR (DMSO- e) <59.12 (s, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.36 (t, J = 2.2 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 2.0 Hz, 1H), 7.66 (br s, 1H), 7.22 - 7.30 (m, 3H), 6.85 (d, J = 8.7 Hz, 2H), 5.15 (q, J = 6.8 Hz, 1H), 4.97 (s, 2H), 4.41 (s, 3H), 3.68 (s, 3H), 3.23 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 561 (MH+, 100%). 16c (145 mg, 0.26 mmol) was heated in TFA (2 mL) at 60 °C for 18 h. After cooling to room temperature, the reaction mixture was dripped slowly onto solid NaHCO3, then diluted with CH2CI2 and MeOH and stirred until gas evolution ceased. The solids were filtered off and washed with CH2CI2 and MeOH, and the solvents removed from the filtrate. Chromatography (CH2CI2: MeOH: c. NH3 97:3:0.3 to 95:5:0.5 to 90:10:1) followed by trituration with MeOH, gave the title compound as a white solid (58 mg, 51%):XH NMR (DMSO- e) <5 10.17 (br s, 1H), 9.13 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 2.0 Hz, 1H), 8.02 (t, J = 2.2 Hz, 1H), 7.66 (br s, 1H), 7.26 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.40 (s, 3H), 3.16 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 441 (MH+, 100%). Anal. Calcd for C20H20N6O4S.0.33H2O: C, 53.81; H, 4.66; N, 18.82. Found C, 53.73; H, 4.50; N, 18.55.

[0690] 2-Methyl-2-((l-methyl-8-(5-(methylsulfonamido)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (17d)

[0691]

[0692] 17d Scheme 18

[0693] Reaction of 7d (104 mg, 0.29 mmol) and 9b (143 mg, 0.34 mmol) as for 8a by method A gave 2-((8-(5-( / V-(4-methoxybenzyl)methylsulfonamido)pyridin-3-yl)-l-methyl-l / - / -pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide (16d) as an off-white solid (113 mg, 69%):XH NMR (DMSO- e) <59.14 (s, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.35 (t, J = 2.2 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 8.7, 2.0 Hz, 1H), 7.58 (br s, 1H), 7.26 (d, J = 8.7 Hz, 2H), 7.23 (br s, 1H), 6.85 (d, J = 8.7 Hz, 2H), 4.97 (s, 2H), 4.43 (s, 3H), 3.68 (s, 3H), 3.23 (s, 3H), 1.69 (s, 6H); LCMS (APCI+) 575 (MH+, 100%).

[0694] 16d (113 mg, 0.20 mmol) was heated in TFA (2 mL) at 60 °C for 6 h. After cooling to room temperature, the reaction mixture was dripped slowly onto solid NaHCO3, then diluted with CH2CI2 and MeOH and stirred until gas evolution ceased. The solids were filtered off and washed with CH2CI2 and MeOH, and the solvents removed from the filtrate. Chromatography (CH2CI2: MeOH: c. NH398:2:0.2 to 97:3:0.3 to 95:5:0.5 to 97:3:0.3) followed by trituration with MeOH, gave the title compound as a white solid (61 mg, 69%):XH NMR (DMSO-de) <5 10.07 (br s, 1H), 9.14 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 8.7, 2.0 Hz, 1H), 8.01 (t, J = 2.2 Hz, 1H), 7.58 (br s, 1H), 7.23 br (s, 1H), 4.41 (s, 3H), 3.15 (s, 3H), 1.69 (s, 6H); LCMS (APCI+) 455 (MH+, 100%). Anal. Calcd for C21H22N6O4S.0.5H2O: C, 54.42; H, 5.00; N, 18.13. Found C, 54.35; H, 4.90; N, 17.96.

[0695] 2-((8-(5-Hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (18a)

[0696]

[0697] 18a

[0698] Scheme 19

[0699] Reaction of 7a (75 mg, 0.20 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-ol (9c) (54 mg, 0.24 mmol) as for 8a by method A, followed by trituration with MeOH gave the title compound as a white solid (44 mg, 63%):XH NMR (DMSO- e) <5 10.13 (br s, 1H), 9.14 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.19 -8.24 (m, 2H), 8.09 (dd, J = 8.7, 2.0 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 4.78 (s, 2H), 4.41 (s, 3H); LCMS (APCI+) 350 (MH+, 100%). Anal. Calcd for C18H15N5O3.0.33H2O: C, 60.85; H, 4.44; N, 19.71. Found C, 60.92; H, 4.40; N, 19.59. ( / ?)-2-((8-(5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (18b)

[0700]

[0701] 7b18b

[0702] Scheme 20

[0703] Reaction of 7b (80 mg, 0.23 mmol) and 9c (61 mg, 0.28 mmol) as for 8a by method A, followed by trituration with MeOH:H2O (2:1) gave the title compound as a white solid (58 mg, 70%):XH NMR (DMSO- e) <5 10.14 (s, 1H), 9.11 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.18 - 8.23 (m, 2H), 8.08 (dd, J = 8.7, 2.0 Hz, 1H), 7.66 (br s, 1H), 7.63 (dd, J = 2.4, 2.1 Hz, 1H), 7.25 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.40 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 364 (MH+, 100%). Anal. Calcd for C19H17N5O3.1.5H2O: C, 58.46; H, 5.16; N, 17.94. Found C, 58.65; H, 5.14; N, 17.79. (S)-2-((8-(5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (18c)

[0704] + 9c

[0705]

[0706] Scheme 21

[0707] Reaction of 7c (80 mg, 0.23 mmol) and 9c (61 mg, 0.28 mmol) as for 8a by method A, followed by trituration with MeOH:H2O (2:1) gave the title compound as a white solid (63 mg, 76%):XH NMR (DMSO- e) <5 10.13 (s, 1H), 9.11 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.18 - 8.24 (m, 2H), 8.08 (dd, J = 8.7, 2.0 Hz, 1H), 7.66 (br s, 1H), 7.63 (dd, J = 2.4, 2.1 Hz, 1H), 7.25 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.40 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H). LCMS (APCI+) 364 (MH+, 100%); Anal. Calcd for C19H17N5O3.H2O: C, 59.84; H, 5.02; N, 18.36. Found C, 60.06; H, 5.00; N, 18.19.

[0708] 2-((8-(5-Hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)- 2-methylpropanamide (18d)

[0709]

[0710] 18d Scheme 22

[0711] Reaction of 7d (62 mg, 0.17 mmol) and 9c (45 mg, 0.20 mmol) as for 8a by method A, followed by trituration with MeOH:H2O (1:1) gave the title compound as a white solid (50 mg, 78%):XH NMR (DMSO- e) <5 10.14 (s, 1H), 9.13 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.19 - 8.24 (m, 2H), 8.08 (dd, J = 8.7, 2.0 Hz, 1H), 7.63 (dd, J = 2.4, 2.2 Hz, 1H), 7.57 (br s, 1H), 7.22 (br s, 1H), 4.42 (s, 3H), 1.69 (s, 6H). LCMS (APCI+) 378 (MH+, 100%); Anal. Calcd for C20H19N5O3.H2O: C, 60.75; H, 5.35; N, 17.71. Found C, 61.01; H, 5.27; N, 17.61. 2-((8-(6-Fluoro-5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin- 3-yl)oxy)acetamide (19a)

[0712]

[0713] 19a Scheme 23

[0714] A mixture of 5-bromo-2-fluoropyridin-3-ol (13) (500 mg, 2.60 mmol) with bis(pinacolato)-diboron (1.2 eq.) and KOAc (3 eq.) in DMSO (5 mL) was deoxygenated by bubbling N2through it. PdCl₂(dppf) (5 mol%) was added, and the reaction was heated to 80 °C as the reaction mixture became dark. After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with CH2Cl2. The combined extracts were washed with water and dried (Na2SO4), and the solvent was removed in vacuo to give 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-ol (9d) as a brown solid (1.23 g, approximately 50% purity):XH NMR (CDCI3) <58.09 (m, 1H), 7.70 (dd, J 11.1, 1.2 Hz, 1H), 1.34 (s, 12H); LCMS (APCI+) 240 (MH+, 100%).

[0715] Reaction of 7a (72 mg, 0.19 mmol) and 9d as for 8a by method A, followed by followed by trituration with MeOH gave the title compound as an off-white solid (36 mg, 51%):XH NMR (DMSO- e) <510.67 (d, J = 0.9 Hz, 1H), 9.18 (s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.18 (t, J = 2.0 Hz, 1H), 8.08 (dd, J = 8.7, 1.9 Hz, 1H), 7.86 (dd, J = 10.1, 2.2 Hz, 1H), 7.72 (br s, 1H), 7.42 (br s, 1H), 4.79 (s, 2H), 4.42 (s, 3H); LCMS (APCI+) 368 (MH+, 100%). Anal. Calcd for C18H14FN5O3.2.5H2O: C, 52.43; H, 4.64; N, 16.98. Found C, 52.54; H, 4.49; N, 16.92.

[0716] ( / ?)-2-((8-(6-Fluoro-5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (19b)

[0717]

[0718] 7b 19b

[0719] Scheme 24

[0720] Reaction of 7b (80 mg, 0.23 mmol) and 9d as for 8a by method A, followed by trituration with MeOH gave the title compound as a white solid (49 mg, 56%):XH NMR (DMSO- e) <510.67 (s, 1H), 9.11 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.17 (t, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.7, 2.0 Hz, 1H), 7.85 (dd, J = 10.1, 2.2 Hz, 1H), 7.65 (br s, 1H), 7.25 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.40 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 382 (MH+, 100%). Anal. Calcd for C19H16FN5O3.0.67H2O: C, 58.00; H, 4.44; N, 17.80. Found C, 57.99; H, 4.28; N, 17.82.

[0721] (S)-2-((8-(6-Fluoro-5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (19c)

[0722]

[0723] 19c Scheme 25

[0724] Reaction of 7c (80 mg, 0.23 mmol) and 9d as for 8a by method A, followed by trituration with MeOH gave the title compound as a white solid (43 mg, 49%):XH NMR (DMSO- e) <5 10.69 (s, 1H), 9.11 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.17 (m, 1H), 8.06 (dd, J = 8.7, 2.0 Hz, 1H), 7.84 (dd, J = 10.1, 2.1 Hz, 1H), 7.66 (br s, 1H), 7.25 (br s, 1H), 5.14 (q, J = 6.8 Hz, 1H), 4.39 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 382 (MH+, 100%). Anal. Calcd for C19H16FN5O3.0.5H2O: C, 58.46; H, 4.39; N, 17.94. Found C, 58.47; H, 4.27; N, 17.87.

[0725] 2-((8-(6-Fluoro-5-hydroxypyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin- 3-yl)oxy)-2-methylpropanamide (19d)

[0726]

[0727] 7d 19d

[0728] Scheme 26

[0729] Reaction of 7d (46 mg, 0.13 mmol) and 9d as for 8a by method A, followed by trituration with MeOH gave the title compound as a white solid (35 mg, 70%):XH NMR (DMSO- e) <5 10.66 (d, J = 0.9 Hz, 1H), 9.14 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.18 (t, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.7, 2.0 Hz, 1H), 7.85 (dd, J = 10.1, 2.2 Hz, 1H), 7.57 (br s, 1H), 7.22 (br s, 1H), 4.41 (s, 3H), 1.69 (s, 6H); LCMS (APCI+) 396 (MH+, 100%). Anal. Calcd for C20H18FN5O3.H2O: C, 58.11; H, 4.88; N, 16.94. Found C, 57.79; H, 4.89; N, 16.69. 2-((8-(5-(lH-Tetrazol-5-yl)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin- 3-yl)oxy)acetamide (25a)

[0730] 15 20 9e

[0731] 25a

[0732]

[0733] Scheme 27

[0734] EDCI. HCI (5.69 g, 29.7 mmol) was added to a solution of 5-bromonicotinic acid (14) (4.00 g, 19.8 mmol), 4-methoxybenzylamine (3.10 mL, 23.7 mmol), HOBt.H2O (4.55 g, 29.7 mmol) and NEts (8.28 mL, 59.4 mmol) in CH2CI2 (150 mL) at 0 °C. After 15 mins the ice bath was removed and the reaction mixture stirred for a further 18 h at room temperature. The reaction mixture was then washed with saturated aqueous NaHCO3, then with water acidified to pH 3 with IM aqueous HCI. The acid wash was extracted with CH2CI2, then the combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo. The residue was recrystallized from toluene to give 5-bromo- / V-(4-methoxybenzyl)nicotinamide (15) as an off-white solid (5.58 g, 88%):XH NMR (CDCI3) <5 8.86 (d, J = 1.9 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.27 (t, J = 2.1 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.32 (br s, 1H), 4.59 (d, J = 5.5 Hz, 2H), 3.81 (s, 3H); LCMS (APCI+) 321 / 323 (MH+, 100%).

[0735] (COCI)2 (2.03 mL, 24.0 mmol) was added dropwise to a suspension of 15 (3.843 g, 12.0 mmol) and pyridine (1.94 mL, 24.0 mmol) in CH2CI2 (50 mL) at 0 °C, over ca. 5 mins. After 30 mins the ice bath was removed and the reaction mixture stirred for a further 15 mins at room temperature before the solvents were removed in vacuo. The residue was taken up in CH2CI2 (50 mL), then added dropwise to a solution of NaNs (3.11 g, 47.8 mmol) and Bu4N+Br−(772 mg, 2.4 mmol) in water (10 mL) over ca. 30 mins. After 1 h the layers were separated, the aqueous phase extracted with CH2CI2, the combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo.

[0736] Chromatography (CH2CI2: EtOAc 99:1 to 98:2 to 97:3) gave 3-bromo-5-(l-(4-methoxybenzyl)-lH-tetrazol-5-yl)pyridine (20) as a colourless oil (2.66 g, 64%):XH NMR (CDCl3) δ 8.85 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.06 (t, J = 2.1 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.60 (s, 2H), 3.80 (s, 3H); LCMS (APCI+) 346 / 348 (MH+, 100%).

[0737] A mixture of 20 (3.35 g, 9.68 mmol), bis(pinacolato)diboron (1.2 eq.) and KOAc (3 eq.) in DMSO (5 mL) was deoxygenated by bubbling N2through it. PdCl₂(dppf) (5 mol%) was added, and the reaction was heated to 80 °C as the reaction mixture became dark. After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with CH2Cl2. The combined extracts were washed with water and dried (Na2SO4), and the solvent was removed in vacuo to give 3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9e) as a brown oil (7.51 g, approximately 50% purity):1H NMR (CDCl3) δ 9.08 (d, J = 1.6 Hz, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.33 (dd, J = 2.4, 1.6 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.58 (s, 2H), 3.79 (s, 3H), 1.37 (s, 12H); LCMS (APCI+) 394 (MH+, 100%).

[0738] Reaction of 7a (111 mg, 0.30 mmol) and 9e as for 8a by method A gave 2-((8-(5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)acetamide (24a) as an off-white solid (137 mg, 88%):1H NMR (DMSO-d6) δ 9.38 (d, J = 2.2 Hz, 1H), 9.18 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.58 (t, J = 2.1 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.19 (dd, J = 8.7, 1.9 Hz, 1H), 7.72 (br s, 1H), 7.42 (br s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.83 (s, 2H), 4.79 (s, 2H), 4.40 (s, 3H), 3.66 (s, 3H); LCMS (APCI+) 522 (MH+, 100%).

[0739] 24a (135 mg, 0.26 mmol) was heated in TFA (2 mL) at 70 °C for 18 h. After cooling to room temperature, the solvent was removed in vacuo, then 1M aqueous NaOH and MeOH (1:1) was added to the residue. The insoluble material was filtered off through a plug of celite, then the filtrate was acidified to pH 3 with 1M aqueous HCl. The MeOH was removed in vacuo, then the solid filtered off, washed with water and EtOAc, and dried to leave the title compound (25a) as an off-white solid (76 mg, 73%):1H NMR (DMSO-d6) δ 9.51 (s, 1H), 9.37 (d, J = 2.2 Hz, 1H), 9.31 (d, J = 2.0 Hz, 1H), 8.94 (t, J = 2.1 Hz, 1H), 8.88 (s, 1H), 8.43 - 8.36 (m, 2H), 7.78 (br s, 1H), 7.49 (br s, 1H), 4.84 (s, 2H), 4.52 (s, 3H); LCMS (APCI-) 400 (M-H+, 100%). (R)-2-((8-(5-(1H-tetrazol-5-yl)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (25b)

[0740] 25b

[0741]

[0742] MeO Scheme 28

[0743] Reaction of 7b (100 mg, 0.29 mmol) and 9e as for 8a by method A gave (R)-2-((8-(5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (24b) as a yellow solid (119 mg, 78%):1H NMR (DMSO-d6) δ 9.38 (d, J = 2.2 Hz, 1H), 9.14 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.57 (t, J = 2.1 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.18 (dd, J = 8.7, 2.0 Hz, 1H), 7.66 (br s, 1H), 7.26 (br s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.83 (s, 2H), 5.15 (q, J = 6.8 Hz, 1H), 4.38 (s, 3H), 3.66 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 536 (MH+, 100%).

[0744] 24b (118 mg, 0.22 mmol) was heated in TFA (2 mL) at 70 °C for 18 h. After cooling to room temperature, the solvent was removed in vacuo, then 1M aqueous NaOH and MeOH (1:1) was added to the residue. The insoluble material was filtered off through a plug of celite, then the filtrate was acidified to pH 3 with 1M aqueous HCl. The MeOH was removed in vacuo, then the solid filtered off, washed with water and dried to leave the title compound as a cream-coloured solid (70 mg, 76%):XH NMR (DMSO-cfe) <59.34 (d, J = 2.2 Hz, 1H), 9.27 (d, J = 2.0 Hz, 1H), 9.17 (s, 1H), 8.84 (t, J = 2.1 Hz, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.25 (dd, J = 8.7, 1.9 Hz, 1H), 7.69 (br s, 1H), 7.28 (br s, 1H), 5.15 (q, J = 6.8 Hz, 1H), 4.44 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); LCMS (APCI-) 414 (M-H+, 100%). Anal. Calcd for C20H17N9O2.0.5MeOH.1.5H2O: C, 53.71; H, 4.84; N, 27.50. Found C, 53.67; H, 4.49; N, 27.47. (S)-2-((8-(5-(1H-tetrazol-5-yl)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (25c)

[0745] 25c

[0746]

[0747] MeO Scheme 29

[0748] Reaction of 7c (100 mg, 0.29 mmol) and 9e as for 8a by method A gave (S)-2-((8-(5-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (24c) as a yellow solid (121 mg, 79%):1H NMR (DMSO-d6) δ 9.38 (d, J = 2.2 Hz, 1H), 9.14 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.57 (t, J = 2.1 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.18 (dd, J = 8.7, 2.0 Hz, 1H), 7.66 (br s, 1H), 7.26 (br s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.83 (s, 2H), 5.15 (q, J = 6.8 Hz, 1H), 4.38 (s, 3H), 3.66 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H); LCMS (APCI+) 536 (MH+, 100%).

[0749] 24c (120 mg, 0.22 mmol) was heated in TFA (2 mL) at 70 °C for 18 h. After cooling to room temperature, the solvent was removed in vacuo, then 1M aqueous NaOH and MeOH (1:1) was added to the residue. The insoluble material was filtered off through a plug of celite, then the filtrate was acidified to pH 3 with 1M aqueous HCl. The MeOH was removed in vacuo, then the solid filtered off, washed with water and dried to leave the title compound as a cream-coloured solid (80 mg, 86%):XH NMR (DMSO-cfe) <59.34 (d, J = 2.2 Hz, 1H), 9.27 (d, J = 2.0 Hz, 1H), 9.17 (s, 1H), 8.84 (t, J = 2.1 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.25 (dd, J = 8.7, 1.9 Hz, 1H), 7.67 (br s, 1H), 7.27 (br s, 1H), 5.16 (q, J = 6.8 Hz, 1H), 4.44 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); LCMS (APCI-) 414 (M-H+, 100%); LCMS (APCI+) 416 (MH+, 100%). Anal. Calcd for C20H17N9O2.2H2O: C, 53.21; H, 4.69; N, 27.92. Found C, 53.40; H, 4.50; N, 27.94. 2-((8-(5-(1H-Tetrazol-5-yl)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide (25d)

[0750] 7d

[0751] 25d

[0752]

[0753] Scheme 30

[0754] Reaction of 7d (75 mg, 0.21 mmol) and 9e as for 8a by method A gave 2-((8-(5-(1-(4-methoxy-benzyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)-2-methylpropanamide (24d) as an off-white solid (111 mg, 98%):1H NMR (DMSO-d6) δ 9.38 (d, J = 2.2 Hz, 1H), 9.16 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.57 (t, J = 2.1 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.18 (dd, J = 8.7, 2.0 Hz, 1H), 7.58 (br s, 1H), 7.23 (br s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.83 (s, 2H), 4.40 (s, 3H), 3.66 (s, 3H), 1.69 (s, 6H); LCMS (APCI+) 550 (MH+, 100%).

[0755] 24d (110 mg, 0.20 mmol) was heated in TFA (2 mL) at 70 °C for 18 h. After cooling to room temperature, the solvent was removed in vacuo, then IM aqueous NaOH and MeOH (3:1) was added to the residue. The insoluble material was filtered off through a plug of celite, then the filtrate was acidified to pH 3 with 1M aqueous HCl. The MeOH was removed in vacuo, then the solid filtered off, washed with water and dried to leave the title compound as an off-white solid (57 mg, 66%):XH NMR (DMSO- e) <59.35 (d, J = 2.2 Hz, 1H), 9.27 (d, J = 2.0 Hz, 1H), 9.21 (s, 1H), 8.84 (t, J = 2.1 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.25 (dd, J = 8.7, 1.9 Hz, 1H), 7.59 (br s, 1H), 7.24 (br s, 1H), 4.46 (s, 3H), 1.70 (s, 6H); LCMS (APCI+) 430 (MH+, 100%). Anal. Calcd for C21H19N9O2.2H2O: C, 54.19; H, 4.98; N, 27.08. Found C, 53.97; H, 4.79; N, 27.11. (S)-2-((1-methyl-8-(5-methylpyridin-3-yl)-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (26a)

[0756] MesN–N

[0757] O

[0758]

[0759] Scheme 31

[0760] General Procedure. To a vessel containing starting material 7c, boronic acid (1.4 - 2.0 eq.), and Pd(dppf)Cl₂-CH2Cl2 (5-10 mol%) was added DMF (26 RV) and 1 M aqueous sodium carbonate (13 RV). The mixture was stirred vigorously and heated to 95 °C for 4-16 hours. The mixture was allowed to cool to ambient temperature to afford a black suspension.

[0761] The mixture was diluted with water and extracted into DCM (5x). The extracts were combined, dried over sodium sulfate, filtered, and concentrated. The residue was stripped from water / acetic acid solution x2. The residue was purified by reversed phase flash column chromatography in 10-90% MeOH in water with 0.1% v / v acetic acid modifier. The appropriate fractions were combined and stripped from ethanol and held under high vacuum. An off-white to pale brown solid was afforded in >20% yield and >85 area% purity by UV-HPLC.

[0762] (S)-2-((8-(5-ethylpyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (26b)

[0763] (S)-2-((l-methyl-8-(5-(trifluoromethyl)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (26c)

[0764] (S)-2-((8-(5-fluoropyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (26d)

[0765] (S)-2-((8-(5-chloropyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (26e)

[0766]

[0767] 7c 26b R = Et

[0768] 26c R = CF3

[0769] 26d R = F

[0770] 26e R = Cl

[0771] Scheme 32

[0772] Under nitrogen, to the reactor was charged nBuOH (10 RV) and 1 M aqueous Na2CO3solution (8 RV, 3.0 eq.). The mixture was charged with starting material 7c and the relevant boronic acid (1.2 eq.). Additional nBuOH (9 RV) was added to aid transfer. The mixture was stirred vigorously and heated to 90 °C. When the mixture reached 80-85 °C the catalyst Pd(dppf)Cl₂-CH2Cl2 (0.25 mol%) was added. The mixture was stirred aggressively for 1-4 hours at 90 °C, affording a black biphasic solution.

[0773] To the mixture was added cysteine (0.5 eq.) and the mixture was vigorously stirred at 70 °C for 6-16 hours. The stirring was stopped, and the aqueous phase was removed. To the mixture was added an aqueous solution comprised of cysteine (0.5 eq.) and 0.25 M aqueous Na₂CO₃ solution (8 RV, 0.75 eq.). The mixture was stirred at 70 °C for 6-16 hours. The stirring was stopped, and the aqueous phase was removed. To the mixture was added an aqueous solution comprised of cysteine (0.5 eq.) and 0.25 M aqueous Na₂CO₃ solution (8 RV, 0.75 eq.). The mixture was stirred at 70 °C for 6-16 hours. The stirring was stopped, and the aqueous phase was removed.

[0774] To the resulting amber solution was added an aqueous solution comprised of 0.1 M NaHCOs and 0.1 M NaCI (8 RV). The mixture was stirred vigorously at 70 °C for 1-2 hours. The stirring was stopped, and the aqueous phase was removed. To the mixture was added an aqueous solution comprised of 0.2 M NaCI (8 RV). The mixture was stirred vigorously at 70 °C for 1-2 hours. The stirring was stopped, and the aqueous phase was removed. The organic phase was filtered hot and then allowed to cool to 40-50 °C with stirring. The mixture was seeded with the expected product, and the resulting suspension was stirred and allowed to cool to ambient temperature and held for 1-3 days.

[0775] The slurry was distilled at 30 °C until a significant quantity of water was no longer present in the distillate. The mixture was heated to 40-50 °C and distillation was continued until about 4-8 g / g solvent remained. Additional nBuOH (10 RV) was charged and the mixture was distilled at 50-60 °C to about 4-8 g / g solvent with respect to input starting material. The mixture was allowed to cool to ambient temperature and stirred. MTBE (4-8 RV) was added followed by heptane (4-8 RV). The resulting off-white slurry was stirred at ambient temperature for 2-4 days.

[0776] The mixture was filtered under reduced pressure, deliquoring to surface. MTBE / nBuOH (4:1 v / v, 2 RV) was used to wash the filter cake, deliquoring to surface (x2). MTBE (2 RV) was used to wash the filter cake, deliquoring to surface (x2). The filter cake was washed once more with MTBE (2 RV) and fully deliquored. The filter cake was air dried for 2-5h and then placed under high vacuum for 1-4 days.

[0777] A solid product was afforded in >20% yield and >85 area% purity by UV-HPLC.

[0778] Crystallisation procedure for (S)-2-((l-methyl-8-(5-(trifluoromethyl)pyridin-3-yl)-lH-pyrazolo[4,3-c]quinolin-3-yl )oxy)propanamide (26c)

[0779] To 26c was added a solution comprised of MeOH (8 RV) and AcCI (1.0 eq.). The mixture was stirred at 50 °C and sonicated until dissolution. The mixture was held for 15 minutes and cooled to 45 °C, by which point the mixture became turbid. To the slurry was added MTBE (4 RV) by pressure-equalising dropping funnel. The slurry was then stirred with increasing aggression for 20 minutes to afford a thick, creamy slurry. A solution comprised of MeOH (3 RV) and AcCI (1.0 eq.) was added by pressure-equalising dropping funnel. The mixture immediately became a thin, mobile, pale yellow, slurry. The stirring rate was reduced appropriately. To the mixture was added MTBE (4 RV) by pressure-equalising dropping funnel. This was followed by MTBE / heptane (1:1 v / v, 4 RV), followed by heptane (8 RV). The resulting slurry was stirred for 1 hour at 45 °C and then allowed to cool to ambient temperature and held for 1 day.

[0780] The mixture was filtered under reduced pressure, deliquoring to surface. MTBE (2 RV) was used to wash the filter cake, deliquoring to surface (x4 washes). The filter cake was washed once more with MTBE (2 RV) and fully deliquored. The filter cake was air dried for 2-5 hours and then placed under high vacuum for 1-4 days.

[0781] A bright, pale-yellow solid was afforded in 80-90% yield and 98-99 area% purity by UV-HPLC. The chiral purity was 94-96%. The single largest impurity was the methyl ester derivative of 26c.

[0782] (S)-N-Methyl-2-(1-methyl-(8-pyridin-3-yl))-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (27a)

[0783]

[0784] Scheme 33 Compound 8c (1.0 g) was placed under an atmosphere of nitrogen to which was added DMF (20 RV). The resulting suspension was heated to 80 °C for 10 minutes to afford an amber solution. The mixture was rapidly cooled to 0 °C after which NaH (60% w / w dispersion in mineral oil, 0.5 eq.) was added. The resulting mixture was held for 10 minutes after which Mel (0.5 eq.) was added. The resulting suspension was allowed to reach ambient temperature and stirred overnight.

[0785] The mixture was quenched by addition of TFA (3.0 eq.) and diluted with ethanol / water. The mixture was stripped from water (3x) and the residue was partitioned between nBuOH and aqueous sodium carbonate solution at 50 °C. The aqueous phase was removed and the organic phase was washed with brine at 50 °C. The organic phase was stripped and reconstituted in nBuOH (10 RV) at 50 °C. The slurry was stirred for 1 hour and sequentially was added MTBE (10 RV) and heptane (10 RV). The mixture was stirred for 3 days at ambient temperature. The solid was then filtered under reduced pressure and washed with MTBE.

[0786] A1 / 2 portion of the obtained solid was dissolved in MeOH acidified with formic acid and filtered. The filtrate was stripped. The afforded residue was purified by reversed phase flash column chromatography in 3-30% MeOH in water acidified with 0.1% w / w formic acid modifier. The appropriate fractions were combined and concentrated. The residue was stripped from ethanol (x3).

[0787] A pale brown sticky solid was afforded in 10% yield and >98 area% purity by UV-HPLC.

[0788] (S)-N,N-Dimethyl-2-(8-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (27b)

[0789]

[0790] 27b

[0791] Scheme 34

[0792] Compound 8c (1.0 g) was dissolved in 6 M HCI and stirred at ambient temperature over 3 days. The mixture was stripped from water (5x). The resulting mixture was redissolved in water and DIPEA (5 eq.) was added to the solution. The resulting suspension was stripped from water (2x). The mixture was resuspended in MeCN and stripped (3x) to afford a crude mixture of carboxylic acid (8j) and DIPEA-2HCI.

[0793] Crude 8j was suspended in DCM (20 RV) and DIPEA (1.0 eq.) was added to afford a solution. The solution was cooled to 0 °C and thionyl chloride (2.0 eq.) was added. The mixture was held at 0 °C for 1 hour, to which was added dimethylamine (2 M solution in THF, 10 eq.). The mixture was held for 1 hour.

[0794] The mixture was diluted with nBuOH and washed with aqueous sodium carbonate solution followed by brine (x2). The mixture was concentrated and reconstituted in DCM, dried over sodium sulfate, filtered, and concentrated. The residue was reconstituted in DCM and loaded onto a pad of silica. The mixture was eluted in 0-60% EtOH in DCM and concentrated. The product was stripped from ethanol (3x).

[0795] A pale-brown sticky solid was afforded in 78% yield and >98 area% purity by UV-HPLC.

[0796] (S)-2-((8-(6-(dimethylamino)pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (28a)

[0797]

[0798] 7c 28a

[0799] Scheme 35

[0800] The title compound was prepared according to the General Procedure described for 26a. (S)-2-((8-(4-methoxyphenyl)-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (28b)

[0801]

[0802] 28b Scheme 36

[0803] The title compound was prepared according to the General Procedure described for 26a (Scheme 31).

[0804] (S)-2-((1-methyl-8-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (29a) and (S)-2-((1-methyl-8-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]quinolin-3-yl)oxy)propanamide (29b) 29a R = CF3

[0805]

[0806] 29b R = Me Scheme 37

[0807] The title compounds were prepared according to the General Procedure described for 26a (Scheme 31).

[0808] Other compounds of the invention can also be prepared by varying the Schemes above. For example, Scheme 38 can be used and varied to make compounds of the invention where R1bears an alkyl group.

[0809]

[0810] Scheme 38

[0811] Scheme 39 and variations can be used to make substituted carboxamide compounds of the invention.

[0812] Me, N-N

[0813]

[0814] Scheme 39

[0815] Example 2: Inhibition of Class la PI3K by pyrazolo[4,3-c]quinoline compounds A large range of pyrazolo[4,3-c]quinoline compounds was tested against the P110α, P110β, P110δ and P100γ isoforms of Class Ia PI3K as discussed above. The results are shown, with reference to Formula II, in Table 2 below.

[0816]

[0817] Table 2: IC50values for Class Ia PI3K

[0818] Compound R11R12R13p110α p110β p110δ p110γ

[0819] 8a CH2CONH2 H H B C c C 8b (R)-CHMeCONH2H H B c c C 8c (S)-CHMeCONH2H H B c c c 8d CMe2CONH2H H B c c c 8e 1-cyclopentyl-l- H H B c c c CONH2

[0820] 8h CH2CONHMe H H B c c c 8i CH2CONMe2H H C c c c 12a CH2CONH2 OMe NHSO2(F2-Ph) A A A A 12b (R)-CHMeCONH2OMe NHSO2(F2-Ph) A A A A 12c (S)-CHMeCONH2OMe NHSO2(F2-Ph) A A A A 12d CMe2CONH2OMe NHSO2(F2-Ph) A A A A 17a CH2CONH2 H NHSO2Me A B A A 17b (R)-CHMeCONH2H NHSO2Me A C A A 17c (S)-CHMeCONH2H NHSO2Me A C A A 17d CMe2CONH2H NHSO2Me A C A B 18a CH2CONH2 H OH A B A A 18b (R)-CHMeCONH2H OH A C A B 18c (S)-CHMeCONH2H OH A C A B 18d CMe2CONH2H OH A C B B 19a CH2CONH2 F OH A B A A 19b (R)-CHMeCONH2F OH A B A A 19c (S)-CHMeCONH2F OH A B A A 19d CMe2CONH2F OH A C A B

[0821]

[0822] 25a CH2CONH2 H tetrazole A A A A 25b (R)-CHMeCONH2H tetrazole A A A A 25c (S)-CHMeCONH2H tetrazole A B A A 25d CMe2CONH2H tetrazole A B A A 26a (S)-CHMeCONH2H Me A C C C 26c (S)-CHMeCONH2H CF3A B A A 26d (S)-CHMeCONH2H F B C C C 26e (S)-CHMeCONH2H Cl A C C C

[0823]

[0824] The IC50values in Table 2 are represented by the following indicators:

[0825] • A indicates an IC50 of <100 nM

[0826] • B indicates an IC50 of 100-999 nM

[0827] • C indicates an IC50 of >1000 nM

[0828] Good potency and selectivity towards pllOo was seen for 8a. The o-methyl carboxamide 8b (R-enantiomer) was both less potent, and less selective than 8a, while the S-enantiomer 8c was more potent and more selective. The dimethyl carboxamide 8d had potency and selectivity comparable to 8a. 8e had comparable selectivity to 8a and 8b, but was less selective than 8c. Compounds 8h and 8i also showed modest selectivity for pllOo.

[0829] Example 3: Inhibition of PI3K signalling in cells

[0830] Without wishing to be bound by theory the inventors believe that a PI3K pllOo inhibitor to treat obesity would be able to enter cells and specifically block relevant signalling pathways. Insulin and EGF acting via receptor kinases activate PI3K pllOo which leads to the phosphorylation of Akt and pS6RbP.

[0831] To assess the ability of compounds 8a, 8d and 8c to inhibit insulin and EGF induced activation of pAkt and pS6RbP as a readout of their ability to inhibit PI3K pllOo in cell culture, SKOV3 cells were treated with increasing concentrations (0.05-10uM) of these compounds and then stimulated with insulin or EGF.

[0832] At 5pM all compounds substantially suppressed insulin and EGF-induced Akt and pS6RbP phosphorylation (Figures 1-2) indicating effective inhibition of PI3K pllOo in cells. Of these compounds 8c had the highest potency with suppressions of Akt and EGF induced Akt phosphorylation being evident at concentrations of <10uM (Figures 3-4). Example 4: Oral bioavailability

[0833] Selectively inhibiting PI3K pllOa isoform in vivo requires the uptake of the drug from the gut, which would suppress the ability of insulin to facilitate muscle and fat uptake of glucose from the blood and release of glucose into the blood from the liver. This leads to elevations in blood glucose and a compensatory increase in insulin secretion. Therefore, to assess the oral bioavailability of 8c and its ability to suppress PI3K pllOa isoform activity in vivo, mice were treated with 8c or its salt form (8c-HCI) via oral gavage and blood samples were collected to measure drug, insulin and glucose concentration.

[0834] Drug pharmacokinetic properties were determined via linear trapezoidal method in PK solver 2.0. The maximum blood concentration of 8c and its salt form were 52.3 and 71.8 mM, respectively which was recorded at 15 min for 8c and 30 min for its salt form. 8c (had a half-life of 119.9 min and its salt form 66.3 min. Both forms of 8c led to a significant elevation in blood glucose and insulin, which peaked at 60 min following dosing (Figure 5B-C). Blood glucose and insulin peak occurred following 8c peak in the blood, which was at 15-30 min (Figure 5A).

[0835] This data indicates that 8c is orally bioavailable and induced effects that would be expected of a PI3K pllOa isoform inhibitor (increased blood glucose and insulin) in vivo in mice. Furthermore, the short half-life of 8c (119.9 min, Figure 5A) indicated that its effect on the PI3K pllOa isoform is likely to be transient which is advantageous because it would avoid chronic / prolonged hyperglycaemia. This was confirmed by blood glucose and insulin returning to expected basal levels withing 2-3h.

[0836] Example 5: Weight and fat loss in obesity

[0837] To investigate if oral administration of 8c can induce weight-loss in vivo, male mice were fed a high fat diet to induce obesity (6-8 weeks), then treated twice daily via oral gavage with 8c. Dosing was initiated at 35 mg / kg which resulted in a 1-2% loss of body mass after 15 days, at which point the dose was increased to 52.5 mg / kg for 20 days. By this time 8c treated mice had lost >6% of their body weight while vehicle treated mice had gained ~2% body weight (Figure 6A).

[0838] The weight loss was primarily attributed to loss of fat mass with 30 days treatment with 8c resulting in a significant loss of fat mass with no change in lean mass (Figure 6B).

[0839] During this same time period vehicle-treated mice gained significant body weight.

[0840] The data indicated that treatment with 8c induced weight loss by reducing adipose tissue mass. Consistent with this, treatment of diet-induced obese mice twice daily for 28 days with 8c at 50 mg / kg induced >15% (>5g) weight loss, an effect not seen in vehicle treated mice (Figure 7A-B). This weight loss was primarily due to loss of fat mass, which decreased also by an average of 5g. A small but statistically significant loss of lean mass was also observed in though vehicle and 8c treated group (Figure 7C).

[0841] Weight and fat loss can also be achieved by treating diet induced obese mice once daily with 8c (Figure 8A-C), and this is also observed in diet induced obese female mice (Figure 9A-C). While 50 mg / kg of 8c once daily was sufficient to prevent high fat diet induced weight gain in female mice, higher doses (100 mg / kg) were required to suppresses PI3K pllOo activity to a large enough extent to induce weight loss.

[0842] Example 6: Transient increase in blood glucose

[0843] To determine whether there was a dose-dependent effect of 8c on blood glucose, as a readout of PI3K pllOo isoform inhibition, diet-induced obese male mice were treated with either 35 mg / kg (Figure 1OA) or 52.5 mg / kg (Figure 1OB) of 8c via oral gavage, and blood glucose was measured for up to 240 min after dosing. 60 minutes following dosing blood glucose was higher in mice treated with the higher dose of 8c, indicating dose dependent inhibition of PI3K pllOo isoform inhibition in vivo by 8c.

[0844] Example 7: No adaption to drug treatment

[0845] To understand if diet-induced obese mice adapt to 8c treatment, mice were treated long-term (21 days) with 8c and blood glucose response to a single dosing of 8c was assessed at 0 and 21 days of treatment. Similar elevation in blood glucose following dosing was seen at both time points, indicating the mice were not adapting to the treatment (Figure 11A-B). Furthermore, the effect of 8c treatment on blood glucose remained transient, with blood glucose measured 12+h following dosing throughout the 21 days treatment period being similar in vehicle and 8c-treated mice (Figure 11C). Example 8: Oral bioavailability and suppression of PI3K pl 10a isoform activity To assess the oral bioavailability of 8c and its ability to suppress PI3K pllOo isoform activity in vivo, dogs and cats were treated with 8c salt form (2HCI) via oral gavage and blood samples were collected to measure drug, insulin and glucose concentration. 8c concentration in the blood increased after dosing in dogs (Figure 12) and cats (Figure 14) peaking at 15-30 min at 1500-2000 ng / ml when dosed at 60 mg / kg. 8c was eliminated from blood with 2-4h. 8c led to a significant elevation in blood glucose in cats (Figure 15) at 60 and 30 mg / kg and glucose and insulin in dogs at 60 mg / kg (Figure 13A-B). Blood glucose and insulin peaked at 15-30 min following dosing (Figure 13A-B and Figure 15).

[0846] Examples 9 to 11 relate to the use of compounds 26a-26c. Example 9: Weight loss in obesity

[0847] To understand if oral administration of 26a-c can induce weight loss in vivo, male mice were fed a high fat diet to induce obesity (6-8 weeks), then treated twice daily via oral gavage with 25mg / kg of either 26a, 26b or 26c, or vehicle control, for eight days. By this time mice treated with 26c had lost a statistically significant amount of weight (5% body mass) compared to either 26a (2.5%), 26b (3%) or vehicle (no significant loss). The results of this example are shown in Figure 16A-B.

[0848] Example 10: Blood glucose levels

[0849] Pharmacodynamic properties of 26a-c are consistent with expected inhibition of PI3K (increased blood glucose), indicating these compounds are orally bioavailable and bioactive in vivo in chow-fed mice. Observed blood glucose effects are consistent with greater potency of 26c, with blood glucose levels remaining elevated 2-hours after administration (see Figure 17).

[0850] Example 11: Oral bioavailability and suppression of PI3K pllOa isoform activity To assess the oral bioavailability of 26c and its ability to suppress PI3K pllOa isoform activity in vivo, dogs were treated with 26c 2 salt form (2HCI) via oral gavage and blood samples were collected to measure insulin concentration. 26c led to a significant elevation in insulin glucose in dogs (Figure 18) at 60 mg / kg peaking at 30 min following dosing and remaining elevated for at least 2 h.

[0851] 7. REFERENCES

[0852] Araiz, C. e. (2019). Enhanced beta-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K pllOalpha inactivation in adipose tissue. Nat Commun, 1546. doi:doi: 10.1038 / s41467-019-09514-l

[0853] B. K. Ghotekar, M. G. (2010). Synthesis of new quinoline fused heterocycles such as benzo[h]-l,6-naphthyridines and pyrazolo[4,3-c]quinolones. Monatsh. Chem., 169-175. Foukas, L. C. (2006). Critical role for the pllOalpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature, 366-370. doi:doi: 10.1038 / nature04694 Hedges, C. P. (2023). Dietary supplementation of clinically utilized PI3K pllOalpha inhibitor extends the lifespan of male and female mice. Nat Aging, 162-172. doi:doi: 10.1038 / s43587-022-00349-y

[0854] Kim, J. E. (2009). Investigating the role of class-IA PI 3-kinase isoforms in adipocyte differentiation. Biochem Biophys Res Commun, 830-834.

[0855] doi: doi: 10.1016 / j.bbrc.2008.12.089

[0856] Ladraa, S. e. (2022). PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption. Sci Adv. doi: doi: 10.1126 / sciadv.ade7823

[0857] Lindhurst, M. J. (2012). Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet, 928-933. doi:doi: 10.1038 / ng.2332 Lopez-Guadamillas, E. e. (2016). PI3Kalpha inhibition reduces obesity in mice. Aging (Albany NY), 2747-2753. doi:doi: 10.18632 / aging.101075

[0858] Savova, M. S. (2023). Targeting PI3K / AKT signaling pathway in obesity. Biomedicine & Pharmacotherapy, 114244. doi:doi.org / 10.1016 / j.biopha.2023.114244

[0859] Nelson, V. L. (2014). Adipose tissue insulin resistance due to loss of PI3K pllOalpha leads to decreased energy expenditure and obesity. Am J Physiol Endocrinol Metab, E1205-1216. doi:doi: 10.1152 / ajpendo.00625.2013

[0860] Ortega-Molina, A. e. (2015). Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. Cell Metab, 558-570. doi:doi: 10.1016 / j.cmet.2015.02.017

[0861] Smith, G. C. (2013). Extended treatment with selective phosphatidylinositol 3-kinase and mTOR inhibitors has effects on metabolism, growth, behaviour and bone strength. FEBS J, 5337-5349. doi:doi: 10.1111 / febs.12428

[0862] Zhao, J. J. (2006). The pllOalpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci USA, 16296-16300. doi:doi: 10.1073 / pnas.0607899103

[0863] Black, S. L. (2018). Synthesis and 1H, 13C and 15N NMR characterisation of substituted pyrazolo[4,3-c]quinolines and related compounds. Tetrahedron, 2797-2806. doi:doi.org / 10.1016 / j.tet.2018.04.061

[0864] Ros, F. (1988). Reaction of.alpha. -bromoisobutyronitrile with nitroalkane anions. J. Org. Chem. 2868-2870. doi:doi.org / 10.1021 / jo00247a047

[0865] Fan, Y. H. (2017). Design, synthesis, and biological evaluation of novel 3-substituted imidazo[l,2-a]pyridine and quinazolin-4(3H)-one derivatives as PI3Ko inhibitors. Eur J Med Chem. 2017 Oct 20;139:95-106. doi: 10.1016 / j.ejmech.2017.07.074

Claims

1. WHAT WE CLAIM:

1. A compound of Formula I4. 6.wherein:7.R1is selected from H, halogen, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -OH, -OR, -OC(O)H, -OC(O)R, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)NHR, and -C(O)NRR;8.R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2- 6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -C₁ haloalkyl, -O(Ci haloalkyl), -CO2H, -CO2R, -CHO, -C(O)R, -C(O)NH2, -C(O)N HR, and -C(O)NRR,9.or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, or a saturated or a partially saturated 3- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;10.R4and R5are each independently selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2- 6 alkynyl, -C3-8 cycloalkyl, and -C₁ haloalkyl;11.or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated or a fully unsaturated 5 to 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;12.V is CR10or N,13.W is CR9or N,14.X is CR8or N,15.Y is CR7or N,16.Z is CR6or N,17.and where a maximum of three of Z, Y, X, W and V is N;18.R6, R7, R8, R9and R10are each independently selected from H, halogen, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -Ci-4 haloalkyl, -CO2H, -CO2R, -CHO, - C(O)R, -C(O)NH2, -C(O)NHR, -C(O)NRR, -CN, -OH, -OR, -O(C1 haloalkyl), -NH2, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 3- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 3- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R, when W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring, or a saturated or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;19.wherein each R is independently selected from halogen, optionally substituted Ci-6 alkyl group, optionally substituted C2-6 alkenyl group, optionally substituted C2-6 alkynyl group, optionally substituted aryl group, -C₁ haloalkyl, -NH2, -OH, -SH, -NH(CI-6 alkyl), -O(Ci-6 alkyl), -S(Ci-6 alkyl), -NHPh, -OPh, -SPh, -N(CI-6 alkyl group)2and -NPh2; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from a Ci-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group, and an aryl group;20.wherein R' is selected from H, an optionally substituted Ci-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted -C3-8 cycloalkyl group, an optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl, alkenyl, alkynyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2-6 alkenyl, and -C2-6 alkynyl.

2. The compound of claim 1, wherein22.R1is selected from H, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, and -CH2F;23.R2and R3are each independently selected from H, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-8 cycloalkyl, -CF3, -CHF2, and -CH2F;24.or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 3- to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;25.R4and R5are each independently selected from H, -C1-6 alkyl, and -C3-8 cycloalkyl, or R4and R5taken together with the nitrogen atom to which they are attached, can form a saturated or a partially saturated 5 to 6-membered carbocyclic ring, and the ring is optionally substituted independently with 1 to 4 substituents selected from R;26.V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of three of Z, Y, X, W and V is N;27.R6, R7, R8, R9and R10are each independently selected from H, halogen, -Ci-6 alkyl group, Ci-2 haloalkyl, -CN, -OH, -OR, -O(Ci haloalkyl), -NH2, -NHR, -NRR, -NHSO2R', -NO2, -SH, -SR, -S(O)R, -SO2R, -SO2NH2, -SO2NHR, -SO2NRR, a saturated or a partially saturated or a fully unsaturated 5- to 6-membered carbocyclic ring, and a saturated or a partially saturated or a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 heteroatoms selected from O, N and S, and the rings are optionally substituted with 1 to 4 substituents independently selected from R or28.W is CR9and X is CR8, or when X is CR8and Y is CR7, or when Y is CR7and Z is CR6, or when Z is CR6and V is CR10, W and X taken together, or X and Y taken together, or Y and Z taken together, or Z and V taken together can form a saturated or a partially saturated or a fully unsaturated 5- or 6-membered carbocyclic ring or a partially saturated or a fully unsaturated 5- or 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from O and N, and the rings are optionally substituted independently with 1 to 4 substituents selected from R;29.each R is independently an optionally substituted C1-6 alkyl group; wherein the one or more optional substituents are each independently selected from a C1-6 alkyl, a C2-6 alkenyl group, a C2-6 alkynyl group, and an aryl group; and30.R' is an optionally substituted C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for each of said alkyl and aryl groups are each independently selected from the following groups, halogen and C1-6 alkyl, -C2-6 alkenyl and -C2-6 alkynyl.

3. The compound of claim 1 or claim 2, wherein32.R1is selected from H and C1-3 alkyl;33.R2and R3are each independently selected from H, -C1-6 alkyl,34.or R2and R3taken together with the carbon atom to which they are attached, can form a saturated or a partially saturated 5- to 6-membered carbocyclic ring;35.R4and R5are each independently selected from H, -C1-6 alkyl;36.V is CR10or N, W is CR9or N, X is CR8or N, Y is CR7or N, Z is N, and where a maximum of two of Z, Y, X, W and V is N; R6, R7, R8, R9and R10are each independently selected from H, Me, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OR, -O(Ci haloalkyl), -NH₂, -NHMe, -NMe2, -NHEt, -NEL, -NHSO2R', -NO2, and a fully unsaturated 5- to 6-membered heterocyclic ring comprising 1 to 4 N atoms;37.each R is a C1-6 alkyl group; and38.R' is a C1-6 alkyl group or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently a halogen.

4. The compound of any one of claims 1 to 3, wherein:40.R1is Me;41.one of R2and R3is H and one of R2and R3is Me;42.one of R4and R5is H and one of R4and R5is Me;43.V is CR10, W is CR9, X is CR8, Y is CR7, Z is N;44.R7, R8, R9and R10are each independently selected from H, Me, Et, t-butyl, -CF3, -C(CF3)Me2, -CN, F, Cl, -OH, -OMe, -NMe2, -NHSO2Me, -NHSO2(2,4-F-Ph), -NO2and tetrazine;45.each R is Me; and46.R' is a Me or optionally substituted aryl group; wherein the one or more optional substituents for the aryl group are each independently fluorine.

5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier.

6. A method of treating or preventing a disease or condition mediated by class I PI3K, preferably class I PI3K 110α comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 4 or a pharmaceutical composition of claim 5.

7. A method of inducing weight loss in a subject the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 4 or a pharmaceutical composition of claim 5.

8. A method of treating or preventing obesity or an obesity-associated condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 4 or a pharmaceutical composition of claim 5.

9. The method of any one of claims 6 to 8, wherein the therapeutically effective amount is about 0.001 mg / kg to about 500 mg / kg of bodyweight.

10. The method of any one of claims 6 to 9, wherein the subject is a human or companion animal.

11. The method of claim 10, wherein the companion animal is a dog.

12. The method of claim 10, wherein the companion animal is a cat.

13. The method of any one of claims 6 to 10, wherein the subject is a healthy human and the compound of Formula I is administered for cosmetic use.

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