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COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR MODULATING SGK ACTIVITY, AND METHODS THEREOF

20210032239 ยท 2021-02-04

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention provides novel chemical compounds useful for treating one or more of autoimmune diseases, cancer, cardiovascular diseases, inflammatory diseases and diabetes, or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.

    Claims

    1. A compound having the structural formula of (I): ##STR00156## wherein, A is an aryl group selected from the group consisting of unsubstituted 5- or 6-membered aryl groups and substituted 5- or 6-membered aryl groups; L is a linking group comprising ##STR00157## Y.sub.1 is CR.sub.1 or N, wherein R.sub.1 is a hydrogen, or a C.sub.1-C.sub.6 alkyl group, OR.sub.h, SR.sub.h, N(R)R.sub.h, wherein R is selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group and R.sub.h is a hydrocarbyl group; Y.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, or a C.sub.1-C.sub.6 alkyl group; Y.sub.3 is CR.sub.3 or N, wherein R.sub.3 is H, or a C.sub.1-C.sub.6 alkyl group; each of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is independently selected from the group consisting of CR and N, wherein R is H or a C.sub.1-C.sub.6 alkyl group; and R.sub.4 is H, a C.sub.1-C.sub.6 alkyl group, N(R)R, N(R)C(O)R, N(R)C(O)NHR, ROR, wherein each of R and R is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group, wherein R.sub.4 and Y.sub.1 optionally may join together to form a 5- to 8-membered ring, or a pharmaceutically acceptable form thereof.

    2. The compound of claim 1, wherein L comprises ##STR00158## wherein R.sub.7 is H or a C.sub.1-C.sub.6 alkyl group.

    3. The compound of claim 1, wherein A is selected from the group consisting of: ##STR00159## wherein X is a halogen atom and R.sub.8 is OR.sub.7, wherein R.sub.7 is H or a C.sub.1-C.sub.6 alkyl group.

    4. The compound of claim 1, wherein Y.sub.1, Y.sub.2 and Y.sub.3 are selected from the group consisting of: Y.sub.1=CR.sub.1, Y.sub.2=CR.sub.2, Y.sub.3=CR.sub.3; Y.sub.1=CR.sub.1, Y.sub.2=N, Y.sub.3=CR.sub.3; Y.sub.1=CR.sub.1, Y.sub.2=CR.sub.2, Y.sub.3=N; Y.sub.1=N, Y.sub.2=N, Y.sub.3=CR.sub.3; and Y.sub.1=N, Y.sub.2=CR.sub.2, Y.sub.3=N.

    5. (canceled)

    6. The compound of claim 1, wherein Z.sub.3 is CR.sub.5 and Z.sub.4 is CR.sub.6, having the structural formula: ##STR00160## R.sub.5 is H or a C.sub.1-C.sub.6 alkyl group; and R.sub.6 is H or a C.sub.1-C.sub.6 alkyl group.

    7. The compound of claim 1, wherein Z.sub.1 and Z.sub.2 are selected from the group consisting of: Z.sub.1=Z.sub.2=CR; Z.sub.1=Z.sub.2=N; Z.sub.1=N, Z.sub.2=CR; and Z.sub.1=CR, Z.sub.2=N, wherein each R is H.

    8. (canceled)

    9. The compound of claim 6, having the structural formula: ##STR00161##

    10. The compound of claim 9, having the structural formula: ##STR00162##

    11. The compound of claim 9, wherein X is F or Cl, R.sub.5=R.sub.6=R.sub.7=H, R.sub.4 is NH.sub.2, R.sub.9 is OR.sub.9, wherein R.sub.9 is a hydrogen or a C.sub.1-C.sub.6 alkyl group.

    12. The compound of claim 9, wherein at least one of Z.sub.1 and Z.sub.2 is N.

    13. The compound of claim 9, wherein at least one of Y.sub.2 and Y.sub.3 is not N.

    14. The compound of claim 10, having the structural formula: ##STR00163##

    15. The compound of claim 14, wherein X is F, R.sub.9 is CH.sub.3, Y.sub.2 is CH, Y.sub.3 is N, and R.sub.1 is a C.sub.1-C.sub.6 alkyl group.

    16. (canceled)

    17. The compound of claim 14, wherein X is F, R.sub.9 is CH.sub.3, Y.sub.2 is N, Y.sub.3 is CH, and R.sub.1 is a C.sub.1-C.sub.6 alkyl group.

    18. (canceled)

    19. The compound of claim 14, wherein X is F, R.sub.9 is CH.sub.3, Y.sub.2 is CH, Y.sub.3 is CH, and R.sub.1 is a C.sub.1-C.sub.6 alkyl group.

    20. (canceled)

    21. The compound of claim 1, wherein R.sub.4 and Y.sub.1 join together to form a 5- to 8-membered ring Q, having the structural formula: ##STR00164##

    22. (canceled)

    23. (canceled)

    24. A pharmaceutical composition comprising an amount of a compound having the structural formula of (I): ##STR00165## wherein, A is an aryl group selected from the group consisting of unsubstituted 5- or 6-membered aryl groups and substituted 5- or 6-membered aryl groups; L is a linking group comprising ##STR00166## Y.sub.1 is CR.sub.1 or N, wherein R.sub.1 is a hydrogen, or a C.sub.1-C.sub.6 alkyl group, OR.sub.h, SR.sub.h, N(R)R.sub.h, wherein R is selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group and R.sub.h is a hydrocarbyl group; Y.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, or a C.sub.1-C.sub.6 alkyl group; Y.sub.3 is CR.sub.3 or N, wherein R.sub.3 is H, or a C.sub.1-C.sub.6 alkyl group; each of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is independently selected from the group consisting of CR and N, wherein R is H or a C.sub.1-C.sub.6 alkyl group; and R.sub.4 is H, a C.sub.1-C.sub.6 alkyl group, N(R)R, N(R)C(O)R, N(R)C(O)NHR, ROR, wherein each of R and R is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group, wherein R.sub.4 and Y.sub.1 optionally may join together to form a 5- to 8-membered ring, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

    25-30. (canceled)

    31. A unit dosage form comprising a pharmaceutical composition according to claim 24.

    32. A method for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula of (I): ##STR00167## wherein, A is an aryl group selected from the group consisting of unsubstituted 5- or 6-membered aryl groups and substituted 5- or 6-membered aryl groups; L is a linking group comprising ##STR00168## Y.sub.1 is CR.sub.1 or N, wherein R.sub.1 is a hydrogen, or a C.sub.1-C.sub.6 alkyl group, OR.sub.h, SR.sub.h, N(R)R.sub.h, wherein R is selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group and R.sub.h is a hydrocarbyl group; Y.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, or a C.sub.1-C.sub.6 alkyl group; Y.sub.3 is CR.sub.3 or N, wherein R.sub.3 is H, or a C.sub.1-C.sub.6 alkyl group; each of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is independently selected from the group consisting of CR and N, wherein R is H or a C.sub.1-C.sub.6 alkyl group; and R.sub.4 is H, a C.sub.1-C.sub.6 alkyl group, N(R)R, N(R)C(O)R, N(R)C(O)NHR, ROR, wherein each of R and R is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group, wherein R.sub.4 and Y.sub.1 optionally may join together to form a 5- to 8-membered ring, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of autoimmune disease or disorder, cancer, a cardiovascular disease or disorder, inflammatory disease or disorder and diabetes, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

    33-38. (canceled)

    39. The method of claim 32, wherein the compound effectively inhibits serum and glucocorticoid-regulated kinase (SGK) 1 and/or 2.

    Description

    DETAILED DESCRIPTION OF THE INVENTION

    [0068] The invention is based on the unexpected discovery of novel, orally available, selective and potent compounds and pharmaceutical compositions thereof that effectively modulate the activity of SGK, in particular SGK1 and SGK2. The compounds and pharmaceutical compositions of the invention are suitable for use in treating, preventing, or reducing one or more of autoimmune diseases, cancer, cardiovascular diseases, inflammatory diseases and diabetes, or a related disease or disorder thereof.

    [0069] For example, studies have shown that SGK1 selectively and reciprocally regulates helper T cell differentiation downstream of mTORC2. Inhibition of SGK1 impacts autoimmune diseases mediated by Th2 immune responses. In regard to cancer and tumors, inhibition SGK1 influences cell proliferation and apoptosis, thus can be therapeutically used to treat cancers and tumors.

    [0070] In one aspect, the invention generally relates to a compound having the structural formula of (I):

    ##STR00007##

    wherein,

    [0071] A is an aryl group selected from the group consisting of unsubstituted 5- or 6-membered aryl groups and substituted 5- or 6-membered aryl groups;

    [0072] L is a linking group comprising

    ##STR00008##

    [0073] Y.sub.1 is CR.sub.1 or N, wherein R.sub.1 is a hydrogen, or a C.sub.1-C.sub.6 alkyl group, OR.sub.h, SR.sub.h, N(R)R.sub.h, wherein R is selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group and R.sub.h is a hydrocarbyl group;

    [0074] Y.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, or a C.sub.1-C.sub.6 alkyl group;

    [0075] Y.sub.3 is CR.sub.3 or N, wherein R.sub.3 is H, or a C.sub.1-C.sub.6 alkyl group;

    [0076] each of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is independently selected from the group consisting of CR and N, wherein R is H or a C.sub.1-C.sub.6 alkyl group; and

    [0077] R.sub.4 is H, a C.sub.1-C.sub.6 alkyl group, N(R)R, N(R)C(O)R, N(R)C(O)NHR, ROR, wherein each of R and R is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group, wherein R.sub.4 and Y.sub.1 optionally may join together to form a 5- to 8-membered ring, or a pharmaceutically acceptable form thereof.

    [0078] L may be any suitable linking group. In certain preferred embodiments, L is a group that comprises

    ##STR00009##

    wherein R.sub.7 is H or a C.sub.1-C.sub.6 alkyl group.

    [0079] A may be any suitable unsubstituted or substituted 5- or 6-membered aryl group, including hetero-aryl groups. In certain preferred embodiments, A is selected from the group consisting of:

    ##STR00010##

    wherein X is a halogen atom and R.sub.8 is OR.sub.7, wherein R.sub.7 is H or a C.sub.1-C.sub.6 alkyl group.

    [0080] Embodiments of the invention include none of, one of, two of Y.sub.1, Y.sub.2 and Y.sub.3 being N atoms. In certain embodiments, Y.sub.1=CR.sub.1, Y.sub.2=CR.sub.2, Y.sub.3=CR.sub.3. In certain embodiments, Y.sub.1=CR.sub.1, Y.sub.2=N, Y.sub.3=CR.sub.3. In certain embodiments, Y.sub.1=CR.sub.1, Y.sub.2=CR.sub.2, Y.sub.3=N. In certain embodiments, Y.sub.1=N, Y.sub.2=N, Y.sub.3=CR.sub.3. In certain embodiments, Y.sub.1=N, Y.sub.2=CR.sub.2, Y.sub.3=N. Here, each R.sub.1 is independently selected from a hydrogen, or a C.sub.1-C.sub.6 alkyl group, OR.sub.h, SR.sub.h, N(R)R.sub.h, wherein R is selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group and R.sub.h is a hydrocarbyl group; each R.sub.2 is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group; and each R.sub.3 is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group. In certain embodiments, each of R.sub.1, R.sub.2 and R.sub.3 is H.

    [0081] Each of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is independently selected from the group consisting of CR and N, wherein R is H or a C.sub.1-C.sub.6 alkyl group. Embodiments of the invention include none of, one of, two of, or three of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 being N atoms. In certain preferred embodiments, one of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is N. In certain preferred embodiments, one of Z.sub.1 and Z.sub.3 is N and one of Z.sub.2 and Z.sub.4 is N.

    [0082] In certain preferred embodiments, Z.sub.3 is CR.sub.5 and Z.sub.4 is CR.sub.6, and the compound has the structural formula:

    ##STR00011##

    wherein R.sub.5 is H or a C.sub.1-C.sub.6 alkyl group; and R.sub.6 is H or a C.sub.1-C.sub.6 alkyl group.

    [0083] In certain embodiments, each of Z.sub.1 and Z.sub.2 is N and each of Z.sub.3 and Z.sub.4 is not N. In certain preferred embodiments, Z.sub.1=Z.sub.2=CR. In certain embodiments, Z.sub.1=Z.sub.2=N. In certain embodiments, Z.sub.1=N, Z.sub.2=CR. In certain embodiments, Z.sub.1=CR, Z.sub.2=N. In certain embodiments, each R is H.

    [0084] In certain embodiments, a compound of the invention has the structural formula:

    ##STR00012##

    wherein X, Y.sub.2, Y.sub.3, Z.sub.1, Z.sub.2, R.sub.1, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are as herein defined.

    [0085] In certain embodiments, a compound of the invention has the structural formula:

    ##STR00013##

    wherein X, Y.sub.2, Y.sub.3, Z.sub.1, Z.sub.2, R.sub.1, R.sub.5, R.sub.6, R.sub.7 and R.sub.9 are as herein defined.

    [0086] In certain preferred embodiments of (III) or (IV), X is F or Cl, R.sub.5=R.sub.6=R.sub.7=H, R.sub.4 is NH.sub.2, R.sub.8 is OR.sub.9, wherein R.sub.9 is a hydrogen or a C.sub.1-C.sub.6 alkyl group.

    [0087] In certain preferred embodiments of (III) or (IV), at least one of Z.sub.1 and Z.sub.2 is N.

    [0088] In certain preferred embodiments of (III) or (IV), at least one of Y.sub.2 and Y.sub.3 is not N.

    [0089] In certain embodiments, a compound of the invention has the structural formula:

    ##STR00014##

    [0090] In certain embodiments of (V), X is F, R.sub.9 is CH.sub.3, Y.sub.2 is CH, Y.sub.3 is N, and R.sub.1 is a C.sub.1-C.sub.6 alkyl group. In certain preferred embodiments, R.sub.1 is CH.sub.3.

    [0091] In certain embodiments of (V), X is F, R.sub.9 is CH.sub.3, Y.sub.2 is N, Y.sub.3 is CH, and R.sub.1 is a C.sub.1-C.sub.6 alkyl group. In certain preferred embodiments, R.sub.1 is CH.sub.3.

    [0092] In certain embodiments of (V), X is F, R.sub.9 is CH.sub.3, Y.sub.2 is CH, Y.sub.3 is CH, and R.sub.1 is a C.sub.1-C.sub.6 alkyl group. In certain preferred embodiments, R.sub.1 is CH.sub.3.

    [0093] In certain embodiments of (I), R.sub.4 and Y.sub.1 optionally may join together to form a 5- to 8-membered ring Q, having the structural formula:

    ##STR00015##

    [0094] Q may be any suitable a 6- or 7-membered cyclic moiety, including hetero-cyclic rings.

    [0095] In certain embodiments of (VI), Y.sub.1=CR.sub.1, Y.sub.2=CR.sub.2, Y.sub.3=CR.sub.3. In certain embodiments, Y.sub.1=CRI, Y.sub.2=N, Y.sub.3=CR.sub.3. In certain embodiments, Y.sub.1=CR.sub.1, Y.sub.2=CR.sub.2, Y.sub.3=N. In certain embodiments, Y.sub.1=N, Y.sub.2=N, Y.sub.3=CR.sub.3. In certain embodiments, Y.sub.1=N, Y.sub.2=CR.sub.2, Y.sub.3=N.

    [0096] In certain embodiments of (VI), each of Z.sub.1 and Z.sub.2 is N and each of Z.sub.3 and Z.sub.4 is not N. In certain embodiments, Z.sub.3=Z.sub.4=CH. In certain preferred embodiments, Z.sub.1=Z.sub.2=CR. In certain embodiments, Z.sub.1=Z.sub.2=N. In certain embodiments, Z.sub.1=N, Z.sub.2=CR. In certain embodiments, Z.sub.1=CR, Z.sub.2=N. In certain embodiments, each R is H.

    TABLE-US-00001 TABLE 1 Exemplary Compounds [00016]embedded image [00017]embedded image [00018]embedded image [00019]embedded image [00020]embedded image [00021]embedded image [00022]embedded image [00023]embedded image [00024]embedded image [00025]embedded image [00026]embedded image [00027]embedded image [00028]embedded image [00029]embedded image [00030]embedded image [00031]embedded image [00032]embedded image [00033]embedded image [00034]embedded image [00035]embedded image [00036]embedded image [00037]embedded image [00038]embedded image [00039]embedded image [00040]embedded image [00041]embedded image [00042]embedded image [00043]embedded image [00044]embedded image [00045]embedded image [00046]embedded image [00047]embedded image [00048]embedded image [00049]embedded image [00050]embedded image [00051]embedded image [00052]embedded image [00053]embedded image [00054]embedded image [00055]embedded image [00056]embedded image [00057]embedded image [00058]embedded image [00059]embedded image [00060]embedded image [00061]embedded image [00062]embedded image [00063]embedded image [00064]embedded image [00065]embedded image [00066]embedded image [00067]embedded image [00068]embedded image [00069]embedded image [00070]embedded image [00071]embedded image [00072]embedded image [00073]embedded image [00074]embedded image

    [0097] In another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the structural formula of (I):

    ##STR00075##

    wherein,

    [0098] A is an aryl group selected from the group consisting of unsubstituted 5- or 6-membered aryl groups and substituted 5- or 6-membered aryl groups;

    [0099] L is a linking group comprising

    ##STR00076##

    [0100] Y.sub.1 is CR.sub.1 or N, wherein R.sub.1 is a hydrogen, or a C.sub.1-C.sub.6 alkyl group, OR.sub.h, SR.sub.h, N(R)R.sub.h, wherein R is selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group and R.sub.h is a hydrocarbyl group;

    [0101] Y.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, or a C.sub.1-C.sub.6 alkyl group;

    [0102] Y.sub.3 is CR.sub.3 or N, wherein R.sub.3 is H, or a C.sub.1-C.sub.6 alkyl group;

    [0103] each of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is independently selected from the group consisting of CR and N, wherein R is H or a C.sub.1-C.sub.6 alkyl group; and

    [0104] R.sub.4 is H, a C.sub.1-C.sub.6 alkyl group, N(R)R, N(R)C(O)R, N(R)C(O)NHR, ROR, wherein each of R and R is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group, wherein R.sub.4 and Y.sub.1 optionally may join together to form a 5- to 8-membered ring, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

    [0105] Pharmaceutical compositions of the invention may be used to effectively treat, prevent, or reduce various diseases and conditions, including one or more of autoimmune diseases, cancer, cardiovascular diseases, inflammatory diseases and diabetes, or a related disease or disorder thereof.

    [0106] In certain embodiments, the pharmaceutical composition of the invention is effective to treat, prevent, or reduce an autoimmune disease or disorder.

    [0107] In certain embodiments, the pharmaceutical composition of the invention is effective to treat, prevent, or reduce cancer, or a related disease or disorder.

    [0108] In certain embodiments, the pharmaceutical composition of the invention is effective to treat, prevent, or reduce a cardiovascular disease or disorder.

    [0109] In certain embodiments, the pharmaceutical composition of the invention is effective to treat, prevent, or reduce an inflammatory disease or disorder.

    [0110] In certain embodiments, the pharmaceutical composition of the invention is effective to treat, prevent, or reduce diabetes, or a related disease or disorder.

    [0111] In yet another aspect, the invention relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

    [0112] In yet another aspect, the invention relates to a method for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula of (I):

    ##STR00077##

    wherein,

    [0113] A is an aryl group selected from the group consisting of unsubstituted 5- or 6-membered aryl groups and substituted 5- or 6-membered aryl groups;

    [0114] L is a linking group comprising

    ##STR00078##

    [0115] Y.sub.1 is CR.sub.1 or N, wherein R.sub.1 is a hydrogen, or a C.sub.1-C.sub.6 alkyl group, OR.sub.h, SR.sub.h, N(R)R.sub.h, wherein R is selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group and R.sub.h is a hydrocarbyl group;

    [0116] Y.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, or a C.sub.1-C.sub.6 alkyl group;

    [0117] Y.sub.3 is CR.sub.3 or N, wherein R.sub.3 is H, or a C.sub.1-C.sub.6 alkyl group;

    [0118] each of Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 is independently selected from the group consisting of CR and N, wherein R is H or a C.sub.1-C.sub.6 alkyl group; and

    [0119] R.sub.4 is H, a C.sub.1-C.sub.6 alkyl group, N(R)R, N(R)C(O)R, N(R)C(O)NHR, ROR, wherein each of R and R is independently selected from the group consisting of H and a C.sub.1-C.sub.6 alkyl group, wherein R.sub.4 and Y.sub.1 optionally may join together to form a 5- to 8-membered ring, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of autoimmune disease or disorder, cancer, a cardiovascular disease or disorder, inflammatory disease or disorder and diabetes, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

    [0120] Therapeutic methods of the invention may be used to effectively treat, prevent, or reduce various diseases and conditions, including one or more of autoimmune diseases, cancer, cardiovascular diseases, inflammatory diseases and diabetes, or a related disease or disorder thereof.

    [0121] In certain embodiments, the method of the invention is for treating, preventing, or reducing an autoimmune disease or disorder.

    [0122] In certain embodiments, the method of the invention is for treating, preventing, or reducing cancer, or a related disease or disorder.

    [0123] In certain embodiments, the method of the invention is for treating, preventing, or reducing a cardiovascular disease or disorder.

    [0124] In certain embodiments, the method of the invention is for treating, preventing, or reducing an inflammatory disease or disorder.

    [0125] In certain embodiments, the method of the invention is for treating, preventing, or reducing diabetes, or a related disease or disorder.

    [0126] In yet another aspect, the invention relates to effectively inhibition of serum and glucocorticoid-regulated kinase (SGK) 1 and/or 2 by administering to a subject in need thereof an SGK inhibitor disclosed herein.

    [0127] In yet another aspect, the invention relates to effectively inhibition of serum and glucocorticoid-regulated kinase (SGK) 1 and/or 2 by administering to a subject in need thereof a pharmaceutical composition comprising an SGK inhibitor disclosed herein.

    [0128] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

    [0129] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

    [0130] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

    [0131] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

    [0132] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

    [0133] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

    [0134] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

    EXAMPLES

    Compound Syntheses

    I. Preparation of 2-fluoro-5-methoxy-N-(4-(4-(morpholin-2-ylmeth-oxy)-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)benzenesulfonamide (A)

    [0135] ##STR00079## ##STR00080##

    1. Preparation of tert-butyl 2-(((2,6-dichloropyridin-4-yl)oxy)-methyl)morpholine-4-carboxylate

    [0136] To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (2.17 g, 10 mmol) in THF, cooled in ice bath, was added NaH (60%, 400 mg, 10 mmol). The mixture was allowed to warm to room temperature, stirred for 30 min, and recooled in ice-water bath, followed by the addition of 2,4,6-trichloropyridine (1.82 g, 10 mmol). The reaction mixture was allowed to warm to room temperature (rt), stirred for 0.5 h, quenched with saturated aqueous NH.sub.4Cl solution, and extracted with EtOAc (100 mL). The organic phase were collected, washed with water (50 mL5), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by FCC (Petroleum ether:EtOAc=10:1) to give the title compound as a colorless oil, which solidified upon standing at room temperature overnight (2.1 g, yield: 58%).

    2. Preparation of tert-butyl 2-(((2,6-dichloro-3-formylpyridin-4-yl)oxy)methyl)morpholine-4-carboxylate

    [0137] A solution of tert-butyl 2-(((2,6-dichloropyridin-4-yl)oxy)methyl)-morpholine-4-carboxylate (2.0 g, 5.5 mmol) in THF was cooled to 78 C., and n-butyl lithium (2.5M, 2.2 mL, 5.5 mmol) was added dropwise via a syringe. The mixture was stirred at 78 C. for 0.5 h, followed by the addition of HCOOEt (1.22 g, 4.65 mmol). After stirred at 78 C. for 2 h, the mixture was quenched with saturated aqueous NH.sub.4Cl (30 mL) and extracted with EtOAc (100 mL). The organic phase was collected, washed with brine (30 mL2), dried over Na.sub.2SO.sub.4, and concentrated to give the crude title compound, which was used in the next step without any further purification.

    3. Preparation of tert-butyl 2-(((6-chloro-1H-pyrazolo[3,4-b]-pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate

    [0138] The previous crude compound was dissolved in EtOH (20 mL) and hydrazine hydrate (825 mg, 16.5 mmol) was added. The resultant mixture was stirred at 100 C. in a capped vial for 0.5 h. TLC indicated the reaction was complete. The mixture was concentrated. The residue was taken up in EtOAc (100 mL), washed with water (20 mL2), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by FCC (petroleum ether:EtOAc=1:1) to give a light yellow foam (500 mg, yield: 24% (two steps)).

    4. Preparation of tert-butyl 2-(((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate

    [0139] To a solution of tert-butyl 2-(((6-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate (500 mg, 1.356 mmol) in THF (5 mL) were added PPTS (34 mg, 0.136 mmol) and DHP (125 mg, 1.491 mmol). The mixture was stirred at 60 C. for 1 h. TLC indicated the reaction was complete. The mixture was concentrated and the residue was purified by FCC (petroleum ether:EtOAc=5:1) to give the title compound (316 mg, yield: 52%).

    5. Preparation of tert-butyl 2-(((6-(4-(2-fluoro-5-methoxyphenyl-sulfonamido)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate

    [0140] A solution of tert-butyl 2-(((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate (100 mg, 0.221 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (94 mg, 0.232 mmol), Pd.sub.2dba.sub.3 (20 mg, 0.0221 mmol), SPhos (36 mg, 0.0884 mmol), and 5M aqueous K.sub.3PO.sub.4 (0.3 mL, 1.105 mmol) in dioxane (2 mL) was stirred at 110 C. overnight. LCMS indicated the reaction was complete. The mixture was poured into water (10 mL) and extracted with DCM (30 mL). The organic layer was collected, washed with water (15 mL2), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by FCC (petroleum ether:EtOAc=5:1 to 3:1) to give the title compound (130 mg, yield: 84%).

    6. Preparation of 2-fluoro-5-methoxy-N-(4-(4-(morpholin-2-ylmeth-oxy)-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)benzenesulfonamide

    [0141] To a solution of tert-butyl 2-(((6-(4-(2-fluoro-5-methoxyphenylsulfon-amido)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate (130 mg, 0.186 mmol) in 4M HCl/dioxane (2 mL) was added iPrOH (1 mL). The mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The mixture was adjusted with 2M NaOH to PH=78, and extracted with DCM (30 mL). The organic phase was partitioned and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=10:1) to give title compound (60 mg, yield: 63%). MS-ESI: 513.2 (M+1).sup.+, .sup.1H NMR (400 MHz, cd.sub.3od) 8.09 (s, 1H), 7.96 (d, J=8.9 Hz, 2H), 7.34 (dd, J=5.6, 3.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.19-7.09 (m, 2H), 7.07 (s, 1H), 4.46 (d, J=4.5 Hz, 2H), 4.32-4.21 (m, 1H), 4.14-4.10 (m, 1H), 3.97-3.88 (m, 1H), 3.77 (s, 3H), 3.53-3.48 (m, 1H), 3.25-3.19 (m, 3H).

    II. Preparation of 2-fluoro-5-methoxy-N-(4-(4-(morpholin-2-ylmeth-oxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)phenyl)benzenesulfonamide (B)

    [0142] ##STR00081##

    1. Preparation of 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

    [0143] To a solution of 4,6-dichloro-1H-pyrazolo[4,3-c]pyridine (360 mg, 1.91 mmol) in THF (5 mL) were added PPTS (24 mg, 0.095 mmol) and DHP (0.8 mL). The mixture was stirred at 60 C. for 2 h. TLC indicated the reaction was complete. The mixture was concentrated and the residue was purified by FCC (petroleum ether:EtOAc=10:1) to give the title compound (465 mg, yield: 89%).

    2. Preparation of tert-butyl 2-(((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate

    [0144] To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (158 mg, 0.73 mmol) in THF, cooled in ice bath, was added NaH (60%, 34 mg, 0.84 mmol). The mixture was allowed to warm to room temperature, stirred for 30 min, and recooled in ice-water bath, followed by the addition of 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (200 mg, 0.73 mmol). The reaction mixture was allowed to warm to rt, stirred for overnight, diluted with water, and extracted with EtOAc (100 mL). The organic phase were collected, washed with water (50 mL5), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by FCC (Petroleum ether:EtOAc=2:1) to give the title compound (258 mg, yield: 78%).

    3. Preparation of tert-butyl 2-(((6-(4-(2-fluoro-5-methoxyphenylsulf-onamido)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate

    [0145] A solution of tert-butyl 2-(((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate (50 mg, 0.11 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (47 mg, 0.11 mmol), Pd.sub.2dba.sub.3 (10 mg, 0.011 mmol), SPhos (18 mg, 0.044 mmol), and 5M aqueous K.sub.3PO.sub.4 (0.3 mL) in dioxane (2 mL) was stirred at 110 C. overnight. LCMS indicated the reaction was complete. The mixture was poured into water (10 mL) and extracted with EA (30 mL). The organic layer was collected, washed with water (15 mL2), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by FCC (petroleum ether:EtOAc=2:1 to 1:2) to give the title compound (67 mg, yield: 87%).

    4. Preparation of 2-fluoro-5-methoxy-N-(4-(4-(morpholin-2-ylme-thoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)phenyl)benzenesulfonamide

    [0146] To a solution of tert-butyl 2-(((6-(4-(2-fluoro-5-methoxyphenylsulfona-mido)-phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-yl)oxy)methyl)morpholine-4-carboxylate (67 mg, 0.09 mmol) in 4M HCl/dioxane (1 mL) was added iPrOH (1 mL). The mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The mixture was adjusted with 2M NaOH to PH=78, and extracted with DCM (30 mL). The organic phase was partitioned and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=10:1) to give the title compound (20 mg, yield: 43%). MS-ESI: 514.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 13.46 (s, 1H), 8.09 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.50 (s, 1H), 7.33 (d, J=9.4 Hz, 1H), 7.31-7.26 (m, 1H), 7.21-7.15 (m, 3H), 4.49 (d, J=4.4 Hz, 2H), 3.81 (d, J=11.8 Hz, 1H), 3.75 (s, 3H), 3.54 (dd, J=11.5, 8.8 Hz, 2H), 2.87-2.63 (m, 4H).

    III. Preparation of N-(4-(3-amino-4-methoxy-1H-indazol-6-yl)-phenyl)-2-fluoro-5-methoxybenzenesulfonamide (C)

    [0147] ##STR00082##

    1. Preparation of 4-bromo-2-fluoro-6-methoxybenzonitrile

    [0148] To a solution of 4-bromo-2,6-difluorobenzonitrile (218 mg, 1.0 mmol) in THF (8 mL) at 0 C. was slowly added sodium methoxide (65 mg, 1.2 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated and partitioned between EtOAc (30 mL) and water (15 mL). The organic extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-5 percent) to afford the title compound (90 mg, yield: 39%).

    2. Preparation of N-(4-cyano-3-fluoro-5-methoxy-[1,1-biphenyl]-4-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0149] A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (90 mg, 0.39 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (275 mg, 0.43 mmol), Pd(dppf)Cl.sub.2.DCM (32 mg, 0.039 mmol) and Cs.sub.2CO.sub.3 (252 mg, 0.78 mmol) in dioxane (8 mL) and H.sub.2O (0.5 mL) was heated under N.sub.2 at 90 C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-30 percent) to afford the title compound (130 mg, yield: 80%).

    3. Preparation of N-(4-(3-amino-4-methoxy-1H-indazol-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0150] To a solution of N-(4-cyano-3-fluoro-5-methoxy-[1,1-biphenyl]-4-yl)-2-fluoro-5-methoxybenzenesulfonamide (130 mg, 0.3 mmol) in EtOH (8 mL) was added 85% hydrazine hydrate (1 mL). The mixture was heated to 100 C. in a capped vial for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-TLC to give the title compound (60 mg, yield: 45%). MS-ESI: 443.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.40 (s, 1H), 10.71 (s, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.34 (t, J=9.4 Hz, 1H), 7.27 (dd, J=5.6, 3.2 Hz, 1H), 7.21 (t, J=3.5 Hz, 1H), 7.17 (d, J=8.6 Hz, 2H), 6.86 (d, J=0.7 Hz, 1H), 6.46 (d, J=0.6 Hz, 1H), 4.95 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H).

    IV. Preparation of N-(4-(3-amino-4-methyl-1H-pyrazolo[4,3-c]pyr-idin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (D)

    [0151] ##STR00083##

    1. Preparation of N-(4-(4-chloro-5-cyano-6-methylpyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0152] A mixture of 4,6-dichloro-2-methylnicotinonitrile (100 mg, 0.53 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (218 mg, 0.53 mmol), Pd(dppf)Cl.sub.2.DCM (43 mg, 0.053 mmol) and Cs.sub.2CO.sub.3 (348 mg, 1.06 mmol) in dioxane (5 mL) and H.sub.2O (0.8 mL) was heated under N.sub.2 at 90 C. for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (10-50 percent) to afford the title compound (150 mg, yield: 55%).

    2. Preparation of N-(4-(3-amino-4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0153] To a solution of N-(4-(4-chloro-5-cyano-6-methylpyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (150 mg, 0.34 mmol) in n-butanol (3 mL) was added 85% hydrazine hydrate (70 mg, 6 eq.). The mixture was heated to 130 C. in a capped vial for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-TLC to give the title compound (75 mg, yield: 48%). MS-ESI: 428.3 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.90 (s, 1H), 10.75 (s, 1H), 7.97 (d, J=8.6 Hz, 2H), 7.37 (dd, J=16.0, 6.5 Hz, 2H), 7.30 (dd, J=5.5, 3.2 Hz, 1H), 7.22 (dd, J=9.1, 6.2 Hz, 3H), 5.33 (s, 2H), 3.78 (s, 3H), 2.75 (s, 3H).

    V. Preparation of N-(4-(3-amino-4-methyl-1H-pyrazolo[3,4-b]-pyridin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (E)

    [0154] ##STR00084##

    1. Preparation of N-(4-(6-chloro-5-cyano-4-methylpyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0155] A mixture of 2,6-dichloro-4-methylnicotinonitrile (100 mg, 0.54 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (241 mg, 0.59 mmol), Pd(dppf)Cl.sub.2.DCM (44 mg, 0.054 mmol) and Cs.sub.2CO.sub.3 (352 mg, 1.08 mmol) in dioxane (8 mL) and H.sub.2O (0.5 mL) was heated under N.sub.2 at 90 C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-30 percent) to afford the title compound (180 mg, yield: 78%).

    2. Preparation of N-(4-(3-amino-4-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0156] To a solution of N-(4-(6-chloro-5-cyano-4-methylpyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (180 mg, 0.42 mmol) in EtOH (10 mL) was added 85% hydrazine hydrate (1.5 mL). The mixture was heated to 100 C. in a capped vial for 8 h. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with methanol to give a title compound (18 mg, yield: 10%). MS-ESI: 428.3 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.94 (s, 1H), 10.80 (b, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.32 (m, 2H), 7.22 (m, 4H), 5.18 (s, 2H), 3.79 (s, 3H), 2.64 (s, 3H).

    VI. Preparation of N-(4-(3-amino-4-methoxy-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (F)

    [0157] ##STR00085##

    1. Preparation of 2,6-dichloro-4-methoxyypyridine

    [0158] To a solution of 2,4,6-trichloropyridine (3.64 g, 20.0 mmol) in DMF (20 mL) at 0 C. were slowly added NaH (60% in mineral oil, 840 mg, 21 mmol) and MeOH (673 mg, 21 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and partitioned between EtOAc (30 mL) and water (15 mL). The organic extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-5 percent) to afford the title compound (3.0 g, yield: 94%).

    2. Preparation of 2,6-dichloro-4-methoxynicotinaldehyde

    [0159] To a mixture of 2,6-dichloro-4-methoxypyridine (3.49 g, 19.6 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 8.63 ml, 21.56 mmol) at 78 C. The mixture was stirred at that temperature for 30 min, and ethyl formate (4.4 g, 59 mmol) was added at 78 C. The resultant mixture was stirred at that temperature for 30 min, and saturated aqueous NH.sub.4Cl was added to quench the reaction at 78 C. The mixture was warmed to room temperature, extracted with EtOAc (30 mL), concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-30 percent) to afford the title compound (3.3 g, yield: 53%).

    3. Preparation of 2,6-dichloro-4-methoxynicotinaldehyde oxime

    [0160] To a solution of 2,6-dichloro-4-methoxynicotinaldehyde (2.0 g, 10 mmol) in THF (40 mL) was added hydroxylamine hydrochloride (765 mg, 11 mmol) and DIPEA (2.0 g, 15 mmol) at 0 C. The mixture was stirred at room temperature for 2 h and diluted with EtOAc (30 mL) and water (5 mL). The organic phase was collected, dried over Na.sub.2SO.sub.4, and concentrated to give the crude product (3.3 g).

    4. Preparation of 2,6-dichloro-4-methoxynicotinonitrile

    [0161] A solution of 2,6-dichloro-4-methoxynicotinaldehyde oxime (3.3 g, 10 mmol) in CNCl.sub.3 (30 mL) was stirred at 88 C. for 3 h. The reaction mixture was diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel chromatography (petroleum ether:EtOAc=4:1) to give the desired product as white solid (3.0 g, 94%).

    5. Preparation of N-(4-(6-chloro-5-cyano-4-methoxypyridin-2-yl)-phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0162] A mixture of 2,6-dichloro-4-methoxynicotinonitrile (812 mg, 2 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (1.75 g, 2.2 mmol), Pd(dppf)Cl.sub.2.DCM (160 mg, 0.1 mmol) and Cs.sub.2CO.sub.3 (2.6 g, 4 mmol) in dioxane (24 mL) and H.sub.2O (4 mL) was heated under N.sub.2 at 80 C. for 6 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-30 percent) to afford the crude title compound (1.0 g).

    6. Preparation of N-(4-(3-amino-4-methoxy-1H-pyrazolo[3,4-b]-pyridin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0163] To a solution of N-(4-(6-chloro-5-cyano-4-methoxypyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (1.0 g, crude) in EtOH (15 mL) was added 85% hydrazine hydrate (1.2 mL). The mixture was heated to 95 C. in a capped vial for 3 h. The reaction mixture was cooled to RT, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-TLC to give the title compound (110 mg). MS-ESI: 444.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.84 (s, 1H), 10.82 (s, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.38-7.26 (m, 2H), 7.20 (d, J=8.6 Hz, 3H), 6.90 (s, 1H), 5.06 (s, 2H), 3.99 (s, 3H), 3.76 (s, 3H).

    VII. Preparation of N-(4-(3-amino-4-methyl-1H-indazol-6-yl)-phenyl)-2-fluoro-5-methoxybenzenesulfonamide (G)

    [0164] ##STR00086##

    1. Preparation of N-(4-cyano-3-fluoro-5-methyl-[1,1-biphenyl]-4-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0165] A mixture of 4-bromo-2-fluoro-6-methylbenzonitrile (107 mg, 0.5 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (215 mg, 0.53 mmol), Pd(dppf)Cl.sub.2.DCM (40 mg, 0.05 mmol) and Cs.sub.2CO.sub.3 (325 mg, 1.0 mmol) in dioxane (4 mL) and H.sub.2O (0.5 mL) was heated under N.sub.2 at 85 C. for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-30 percent) to afford the title compound (170 mg, yield: 88%).

    2. Preparation of N-(4-(3-amino-4-methyl-1H-indazol-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0166] To a solution of N-(4-cyano-3-fluoro-5-methyl-[1,1-biphenyl]-4-yl)-2-fluoro-5-methoxybenzenesulfonamide (160 mg, 0.39 mmol) in EtOH (15 mL) was added 85% hydrazine hydrate (1.5 mL). The mixture was heated to 100 C. in a capped vial for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was concentrated and purified by pre-TLC (DCM:MeOH=12:1) to give the title compound (27 mg, yield: 16%). MS-ESI: 427.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.44 (s, 1H), 10.69 (s, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.35 (t, J=9.4 Hz, 1H), 7.27 (dd, J=5.4, 3.2 Hz, 1H), 7.23-7.10 (m, 4H), 6.82 (s, 1H), 4.93 (s, 2H), 3.75 (s, 3H), 2.60 (s, 3H).

    VIII. Preparation of 2-fluoro-5-methoxy-N-(4-(4-oxo-1,3,4,5-tetra-hydro-[1,4]oxazepino[5,6,7-cd]indazol-8-yl)phenyl)benzenesulfonamide (H)

    [0167] ##STR00087## ##STR00088##

    1. Preparation of tert-butyl 2-(5-bromo-2-cyano-3-fluorophenoxy)-acetate

    [0168] To a solution of tert-butyl 2-hydroxyacetate (1.45 g, 11.0 mmol) in THF (15 mL), cooled to 0 C., was added sodium hydride (60% in mineral oil, 242 mg, 6.05 mmol). The mixture was warmed up to room temperature, followed by the addition of 4-bromo-2,6-difluorobenzonitrile (1.2 g, 5.5 mmol). The mixture was stirred at room temperature overnight, diluted with EtOAc (50 mL), washed with water (30 mL3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by FCC (Petroleum Ether:EtOAc=40:1 to 10:1) to give the desired compound (1.4 g, yield; 77%).

    2. Preparation of tert-butyl 2-((4-cyano-5-fluoro-4-(2-fluoro-5-me-thoxyphenylsulfonamido)-[1,1-biphenyl]-3-v)oxy)acetate

    [0169] A mixture of tert-butyl 2-(5-bromo-2-cyano-3-fluorophenoxy)acetate (1.55 g, 4.69 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (1.9 g, 4.69 mmol), Pd(dppf)Cl.sub.2.DCM (383 mg, 0.469 mmol) and Cs.sub.2CO.sub.3 (3.05 g, 9.38 mmol) in dioxane (25 mL) and H.sub.2O (5 mL) was heated under N.sub.2 at 90 C. for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (10-50 percent) to afford the title compound (2.1 g, yield: 84%).

    3. Preparation of tert-butyl 2-((3-amino-6-(4-(2-fluoro-5-methoxy-phenylsulfonamido)phenyl)-1H-indazol-4-yl)oxy)acetate

    [0170] To a solution of tert-butyl 2-((4-cyano-5-fluoro-4-(2-fluoro-5-methoxy-phenylsulfonamido)-[1,1-biphenyl]-3-yl)oxy)acetate (1.8 g, 3.39 mmol) in n-butanol (15 mL) was added 98% hydrazine hydrate (543 mg, 5 eq.). The mixture was heated to 105 C. in a capped vial for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel chromatography eluting with dichloromethane in methyl alcohol (10 percent) to afford the title compound (890 mg, yield: 43%).

    4. Preparation of 2-((3-amino-6-(4-(2-fluoro-5-methoxyphenyl-sulfonamido)phenyl)-1H-indazol-4-yl)oxy)acetic acid

    [0171] A solution of tert-butyl 2-((3-amino-6-(4-(2-fluoro-5-methoxyphenylsulfon-amido)phenyl)-1H-indazol-4-yl)oxy)acetate (890 mg, 1.64 mmol) in TFA (5 mL) and DCM (15 mL) was stirred at room temperature overnight. The mixture was concentrated, neutralized with saturated aqueous Na.sub.2CO.sub.3, and extracted with DCM (50 mL). The organic layer was washed with water (30 mL3), dried over Na.sub.2SO.sub.4, and concentrated to give the crude product (530 mg, yield: 66%), which was used in the next step without further purification.

    5. Preparation of 2-fluoro-5-methoxy-N-(4-(4-oxo-1,3,4,5-tetra-hydro-[1,4]oxazepino[5,6,7-cd]indazol-8-yl)phenyl)benzenesulfonamide

    [0172] To a mixture of 2-((3-amino-6-(4-(2-fluoro-5-methoxyphenylsulfon-amido)phenyl)-1H-indazol-4-yl)oxy)acetic acid (330 mg, 0.678 mmol), HATU (387 mg, 1 mmol) in DMF (50 mL) was added DIPEA (262 mg, 2.0 mmol). The mixture was stirred at RT, diluted with EtOAc (100 mL), filtered through celite, concentrated and purified by prep-TLC to give the title compound (110 mg, yield: 34%). MS-ESI: 469.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 12.57 (s, 1H), 11.22 (s, 1H), 10.77 (s, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.35 (t, J=9.4 Hz, 1H), 7.28 (dd, J=5.5, 3.2 Hz, 1H), 7.26-7.13 (m, 4H), 6.75 (d, J=0.7 Hz, 1H), 4.75 (s, 2H), 3.76 (s, 3H).

    IX. Preparation of N-(6-(3-amino-4-methoxy-1H-indazol-6-yl)pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide (I)

    [0173] ##STR00089##

    1. Preparation of N-(6-(4-cyano-3-fluoro-5-methoxyphenyl)-pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0174] A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (300 mg, 1.3 mmol), bisdiboron (331 mg, 1.3 mmol), potassium acetate (510 mg, 5.2 mmol) Pd(dppf)Cl.sub.2.DCM (106 mg, 0.13 mmol) in dioxane (10 mL) was heated under N.sub.2 at 80 C. for overnight. To the reaction mixture was added N-(6-bromopyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide (234 mg, 0.65 mmol), Cs.sub.2CO.sub.3 (348 mg, 1.06 mmol) and H.sub.2O (2 mL). The mixture was heated under N.sub.2 at 100 C. overnight. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (10-50 percent) to afford the title compound (160 mg, yield: 57%).

    2. Preparation of N-(6-(3-amino-4-methoxy-1H-indazol-6-yl)pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0175] To a solution of N-(6-(4-cyano-3-fluoro-5-methoxyphenyl)pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide (140 mg, 0.324 mmol) in n-butanol (3 mL) was added 85% hydrazine hydrate (114 mg, 6 eq.). The mixture was heated to 105 C. in a capped vial for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-TLC to give the title compound (46 mg, yield: 32%). MS-ESI: 444.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.52 (s, 1H), 10.96 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.7, 2.6 Hz, 1H), 7.42-7.33 (m, 2H), 7.33-7.19 (m, 2H), 6.94 (s, 1H), 4.99 (s, 2H), 3.97-3.86 (m, 3H), 3.74 (d, J=17.4 Hz, 3H).

    X. Preparation of N-(4-(3-amino-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenyl)-2-fluoro-5-methoxybenzenesulfonamide (J)

    [0176] ##STR00090##

    1. Preparation of N-(4-(6-chloro-5-cyanopyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0177] A mixture of 2,6-dichloronicotinonitrile (100 mg, 0.57 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (259 mg, 0.63 mmol), Pd(dppf)Cl.sub.2.DCM (47 mg, 0.057 mmol) and Cs.sub.2CO.sub.3 (376 mg, 1.15 mmol) in dioxane (5 mL) and H.sub.2O (0.8 mL) was heated under N.sub.2 at 100 C. for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (10-50 percent) to afford the title compound (168 mg, yield: 69%).

    2. Preparation of N-(4-(3-amino-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0178] To a solution of N-(4-(6-chloro-5-cyanopyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (168 mg, 0.4 mmol) in n-butanol (3 mL) was added 85% hydrazine hydrate (120 mg, 6 eq.). The mixture was heated to 130 C. in a capped vial for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-TLC to give the title compound (60 mg, yield: 36%). MS-ESI: 414.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.88 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.31 (m, 2H), 7.19 (t, J=8.6 Hz, 3H), 5.53 (s, 2H), 3.75 (s, 3H).

    XI. Preparation of N-(4-(3-amino-1H-indazol-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (K)

    [0179] ##STR00091##

    [0180] A mixture of 6-bromo-1H-indazol-3-amine (50 mg, 0.236 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (106 mg, 0.259 mmol), Pd(dppf)Cl.sub.2.DCM (10 mg, 0.012 mmol) and Cs.sub.2CO.sub.3 (154 mg, 0.472 mmol) in dioxane (3 mL) and H.sub.2O (0.3 mL) was heated under N.sub.2 at 90 C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with DCM:MeOH (100:1 to 50:1) to afford the title compound (77 mg, yield: 79%). ESI-MS: 413.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.41 (s, 1H), 10.75 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.39-7.26 (m, 3H), 7.25-7.17 (m, 3H), 7.11 (d, J=8.5 Hz, 1H), 5.35 (s, 2H), 3.76 (s, 3H).

    XI. Preparation of N-(4-(3-amino-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenyl)-2-chloro-5-methoxybenzenesulfonamide (L)

    [0181] ##STR00092##

    1. Preparation of 2-chloro-N-(4-(6-chloro-5-cyanopyridin-2-yl)-phenyl)-5-methoxybenzenesulfonamide

    [0182] A mixture of 4-bromo-2-fluoro-6-methylbenzonitrile (60 mg, 0.34 mmol), 2-chloro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (161 mg, 0.38 mmol), Pd(dppf)Cl.sub.2.DCM (28 mg, 0.03 mmol) and Cs.sub.2CO.sub.3 (225 mg, 0.69 mmol) in dioxane (4 mL) and H.sub.2O (0.5 mL) was heated under N.sub.2 at 100 C. for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (10-50 percent) to afford the title compound (70 mg, yield: 46%).

    2. Preparation of N-(4-(3-amino-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenyl)-2-chloro-5-methoxybenzenesulfonamide

    [0183] To a solution of 2-chloro-N-(4-(6-chloro-5-cyanopyridin-2-yl)phenyl)-5-methoxybenzenesulfonamide (70 mg, 0.16 mmol) in n-butanol (2 mL) was added 85% hydrazine hydrate (48 mg). The mixture was heated to 130 C. in a capped vial for 18 h. The reaction mixture was cooled to room temperature and concentrated. The residue was concentrated and purified by pre-TLC (DCM:MeOH=12:1) to give the title compound (50 mg, yield: 72%). MS-ESI: 430.2 (M+1).sup.+, 1H NMR (400 MHz, DMSO) 11.86 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.56-7.38 (m, 4H), 7.22-7.09 (m, 3H), 5.51 (s, 2H), 3.78 (s, 3H).

    XIII. Preparation of N-(4-(3-amino-1H-pyrazolo[4,3-c]pyridin-6-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (M)

    [0184] ##STR00093##

    1. Preparation of N-(4-(4-chloro-5-cyanopyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0185] A mixture of 4,6-dichloronicotinonitrile (100 mg, 0.58 mmol), 2-fluoro-5-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (259 mg, 0.636 mmol), Pd(dppf)Cl.sub.2.DCM (24 mg, 0.024 mmol) and Cs.sub.2CO.sub.3 (381 mg, 1.16 mmol) in dioxane (3 mL) and H.sub.2O (0.5 mL) was heated under N.sub.2 at 100 C. for 6 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-30 percent) to afford the title compound (244 mg, yield: 100%).

    2. Preparation of N-(4-(3-amino-1H-pyrazolo[4,3-c]pyridin-6-yl)-phenyl)-2-fluoro-5-methoxybenzenesulfonamide

    [0186] To a solution of N-(4-(4-chloro-5-cyanopyridin-2-yl)phenyl)-2-fluoro-5-methoxybenzenesulfonamide (100 mg, 0.239 mmol) in iPrOH (15 mL) was added 85% hydrazine hydrate (72 mg, 1.435 mmol). The mixture was heated to 85 C. in a capped vial for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was concentrated and purified by pre-TLC (DCM:MeOH=10:1) to give the title compound (20 mg, yield: 20%). MS-ESI: 413.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 10.89 (s, 1H), 8.39 (m, 1H), 8.03-7.78 (m, 2H), 7.44-7.06 (m, 5H), 4.51 (s, 2H), 3.74 (s, 3H).

    XIV. Preparation of N-(6-(3-amino-1H-indazol-6-yl)pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide (N)

    [0187] ##STR00094##

    1. Preparation of N-(6-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0188] A mixture of N-(6-bromopyridin-3-yl)-2-fluoro-5-methoxybenzene-sulfonamide (300 mg, 0.83 mmol), (4-cyano-3-fluorophenyl)boronic acid (137 mg, 0.83 mmol), Pd(dppf)Cl.sub.2.DCM (68 mg, 0.083 mmol) and Cs.sub.2CO.sub.3 (541 mg, 1.66 mmol) in dioxane (5 mL) and H.sub.2O (0.8 mL) was heated under N.sub.2 at 100 C. for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (10-50 percent) to afford the title compound (150 mg, yield: 45%).

    2. Preparation of N-(6-(3-amino-1H-indazol-6-yl)pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0189] To a solution of N-(6-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-fluoro-5-methoxybenzenesulfonamide (150 mg, 0.373 mmol) in n-butanol (3 mL) was added 85% hydrazine hydrate (132 mg, 6 eq.). The mixture was heated to 120 C. in a capped vial for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-TLC to give the title compound (30 mg, yield: 19%). MS-ESI: 414.3 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.48 (s, 1H), 10.96 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.58 (dd, J=8.7, 2.6 Hz, 1H), 7.51 (dd, J=8.5, 1.1 Hz, 1H), 7.37 (t, J=9.4 Hz, 1H), 7.29 (dd, J=5.5, 3.2 Hz, 1H), 7.22 (m, 1H), 5.35 (s, 2H), 3.76 (s, 3H).

    XV. Preparation of N-(2-(3-amino-1H-indazol-6-yl)pyrimidin-5-yl)-2-fluoro-5-methoxybenzenesulfonamide (O)

    [0190] ##STR00095##

    1. Preparation of N-(2-(4-cyano-3-fluorophenyl)pyrimidin-5-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0191] A mixture of N-(2-chloropyrimidin-5-yl)-2-fluoro-5-methoxybenze-nesulfonamide (200 mg, 0.63 mmol), (4-cyano-3-fluorophenyl)boronic acid (104 mg, 0.63 mmol), Pd.sub.2dba.sub.3 (57 mg, 0.063 mmol) and Cs.sub.2CO.sub.3 (410 mg, 1.26 mmol) in dioxane (5 mL) and H.sub.2O (0.8 mL) was heated under N.sub.2 at 110 C. for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (10-50 percent) to afford the title compound (125 mg, yield: 49%).

    2. Preparation of N-(2-(3-amino-1H-indazol-6-yl)pyrimidin-5-yl)-2-fluoro-5-methoxybenzenesulfonamide

    [0192] To a solution of N-(2-(4-cyano-3-fluorophenyl)pyrimidin-5-yl)-2-fluoro-5-methoxybenzenesulfonamide (125 mg, 0.31 mmol) in n-butanol (3 mL) was added 98% hydrazine hydrate (40 mg, 4 eq.). The mixture was heated to 135 C. in a capped vial for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-TLC to give the title compound (10 mg, yield: 7%). MS-ESI: 414.2 (M+1).sup.+, .sup.1H NMR (400 MHz, DMSO) 11.61 (s, 1H), 8.69-8.62 (m, 2H), 8.18 (s, 1H), 7.86 (dd, J=8.5, 1.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.40 (t, J=9.4 Hz, 1H), 7.34 (dd, J=5.5, 3.2 Hz, 1H), 7.27 (dt, J=9.0, 3.6 Hz, 1H), 5.35 (dd, J=23.3, 18.5 Hz, 2H), 3.80 (s, 3H).

    Exemplary Assay Protocols:

    1. Enzyme Based Assays for SGK1, SGK2, SGK3, and Akt1

    [0193] The kinase enzymatic reaction is carried out with a biotinylated Akt Substrates-2 peptide substrate. The phosphorylated substrate is then detected using a specific anti-phospho peptide antibody which is coupled with Eu.sup.3+ Cryptate and XL665 conjugated with streptavidin.

    Exemplary Assay Conditions

    [0194] Enzyme: 0.1 nM [0195] Substrate: 0.2 M [0196] ATP: 50 M and 1 mM [0197] Mg.sup.2+: 10 mM [0198] Reaction time: 60 min with 50 M ATP and 30 min with 1 mM ATP [0199] SA-XL to Biotin: 1:10

    [0200] Detailed Steps [0201] 1. prepare the enzyme and substrate solution with the buffer from Cisbio [0202] 2. add the enzyme and substrate solution to the diluted compound plate [0203] 3. transfer 5 L of compound, enzyme, and substrate mixture to an 384-well assay plate [0204] 4. add 5 L ATP (with Mg.sup.2+) solution to initiate the reaction [0205] 5. after certain time, add 10 L of stop solution containing SA-XL and specific antibody [0206] 6. read the plate after 2 h incubation at rt [0207] 7. process the data using prizm software
    (Exemplary results are shown in FIG. 1.)

    2. PK Studies Protocol

    [0208] 3 Male mice/group, 8 groups total with Intravenous and Oral Administration, then measure the compound concentration in plasma.

    ##STR00096##

    [0209] An example is shown in FIG. 2, which shows a concentration-time curve of Compound N in male ICR mice following intravenous and oral administration.

    Selected Pharmacokinetics Parameters of Compound N in Male ICR Mice Following Intravenous and Oral Administration

    [0210]

    TABLE-US-00002 AUC.sub.(0-t) AUC.sub.(0-) MRT.sub.(0-) t.sub.1/2z T.sub.max Vz CLz C.sub.max F* g/L*hr g/L*hr hr hr Hr L/kg L/hr/kg g/L % IV (2 mg/kg) 151052.68 165159.99 8.84 6.99 0.08 0.12 0.01 29080.03 PO (20 mg/kg) 957290.48 1530870.55 24.12 17.27 0.25 NA NA 71907.48 63.37 *F is calculated from AUC.sub.(0-t).

    3. Kinase Profiling Protocol

    [0211] Kinase profiling is performed against 50 kinase targets at 1 concentration (1 M) in duplicates using radiometric assay. All kinase selected are human kinases with their specific substrates. The results are observed as % activity change compared to control. An exemplary data showing kinase profiling provided in FIG. 3.

    4. hERG Assay Protocol: [0212] Assay platform & method: Automated patch clamp (Qpatch-48) [0213] Cell source: CHO cell line stably expressing hERG channels [0214] Measured parameter: Whole-cell tail current of hERG channels [0215] Test concentration: 6 concentrations (30, 10, 3, 1, 0.3, 0.1 M)

    Example: Qpatch hERG Assay

    [0216]

    TABLE-US-00003 Qpatch hERG Compound IC50 (M) Comments J >30 Highest test concentration: 30 M C >30 Highest test concentration: 30 M E >30 Highest test concentration: 30 M D 12.22 Fitting curve Hillslope = 0.88

    5. Exemplary IL-23 Animal Model Protocol:

    [0217] Animal: 15 BALB/C Female mice from CRL (9 wks)
    Model: IL-23 from Biolegend, qd4 at 0.4 mcg/ear, both sides of ears, starting on Day 1
    Treatment: 5 groups and 3 per group [0218] 1) Vehicle: 0.5% CMCNa [0219] 2) Dexamethasone: 2 mg/kg, ip qd4, 5% DMSO in saline [0220] 3) Compound N: 25 mg/kg, po, bid4, 0.5% CMC-Na [0221] 4) Compound N: 50 mg/kg, po, bid4, 0.5% CMC-Na [0222] 5) Compound N: 100 mg/kg, po, bid4, 0.5% CMC-Na
    Marker: body weight, and ear thickness (prior to IL-23 administration and ever the other day) during study.
    Spleen weight and IL-17 levels in ear homogenates with protease PBS at the end

    [0223] Exemplary data (Compound N) showing change of ear thickness is provided in FIG. 4. FIG. 5 shows data on % Inhibition In Ear Thickness (Compound N) After Daily IL-23 injection.

    6. Exemplary IL-17A ELISA Assay Protocol:

    [0224] Use the Mouse IL-17A ELISA Max Deluxe assay kit from BioLegend.

    [0225] Sample: Mouse ear homogenates in protease buffer

    [0226] Positive control: Mouse IL-17A standard

    [0227] Example: Compound N

    [0228] Exemplary data (Compound N) on IL-17A measured in ear samples by ELISA assay is shown in FIG. 6.

    7. Imiquimod-Induced Psoriasis-Like Skin Inflammation Protocol

    [0229] Animal: BALB/C Female mice from BK. Ltd. Shanghai, China (8 wks)
    Model: The psoriasis-like skin inflammation mouse model will be generated by daily topical application of a dose of 10 mg/cm.sup.2 IMQ cream (5%) on the inside of the right ear for 7 consecutive days.
    Treatment: 6 groups and 6 per group [0230] 1) 20 mg/cm2 IMQ cream (5%), Vehicle: bid7, 0.5% CMCNa [0231] 2) 20 mg/cm2 IMQ cream (5%), Dexamethasone: 2 mg/kg, ip qd7, 5% DMSO in saline [0232] 3) 20 mg/cm2 IMQ cream (5%), Compound N: 25 mg/kg, po, bid7, 0.5% CMC-Na [0233] 4) 20 mg/cm2 IMQ cream (5%), Compound N: 50 mg/kg, po, bid7, 0.5% CMC-Na [0234] 5) 20 mg/cm2 IMQ cream (5%), Compound N: 100 mg/kg, po, bid7, 0.5% CMC-Na [0235] 6) Blank (untreated)
    Marker: body weight, and ear thickness during study.

    [0236] Exemplary data is shown in FIG. 7.

    8. EAE Animal Model Protocol:

    [0237] Animal: 40 C57BL/6 female 10 weeks old, mice from CRL

    [0238] Mice will be administered antigen (MOG35-55/CFA) emulsion s.c. at two sites, 0.1 mL/site (0.2 mL/mouse total head and tail), and inject of freshly prepared PTX solution i.p. (0.1 mL/dose) within 1 to 6 hours after. Next day, mice will be injected freshly prepared PTX solution i.p. again.

    [0239] Mice will be assigned into 5 groups with 8 mice per group.

    [0240] G1: Vehicle 1% CMCNa

    [0241] G2: FTY720 3 mg/kg QD, po 5 mL/kg,

    [0242] G3: Compound N 25 mg/kg, BID, po 5 mL/kg, 1% CMCNa, 4 wks D0-D35

    [0243] G4: Compound N 50 mg/kg, BID, po 5 mL/kg, 1% CMCNa, 4 wks D0-D35

    [0244] G5: Compound N 100 mg/kg, BID, po 5 mL/kg, 1% CMCNa, 4 wks D0-D35

    Starting Day 0 after immunization, disease severity will be scored daily on a 5 point scale and body weight will be monitored as well.

    [0245] Exemplary data is shown in FIG. 8.

    TABLE-US-00004 TABLE 2 Exemplary Testing Results Sgk2 Sgk2 Sgk1 Sgk1 (50 M (1 mM (50 M (1 mM Structure ATP) ATP) ATP) ATP) Sgk3 HeLa 293T 293T_O [00097]embedded image 0.0035 0.0098 0.0034 0.0107 [00098]embedded image 0.0008 0.0056 0.0031 0.0097 35.8 47.89 61.18 [00099]embedded image 0.002 0.0158 0.0025 0.0069 11.7 20.39 35.11 [00100]embedded image 0.0018 0.0252 0.0018 0.0319 [00101]embedded image 0.002 0.0038 0.0023 0.0039 [00102]embedded image 0.0034 0.0041 0.0023 0.0066 15.6 17.93 24.46 [00103]embedded image 0.0053 0.0035 0.0081 0.0042 [00104]embedded image 0.0016 0.01 0.0013 0.0134 0.1 [00105]embedded image 0.0041 0.0082 0.0032 0.0116 0.15 [00106]embedded image 0.0017 0.0066 0.0019 0.0124 0.15 [00107]embedded image 0.0051 0.0089 0.0024 0.0178 0.04 [00108]embedded image 0.0079 0.0062 0.0051 0.0077 0.09 [00109]embedded image 0.0031 0.0053 0.0106 0.0085 0.05 [00110]embedded image 0.0041 0.0037 0.0028 0.0055 0.03 [00111]embedded image 0.003 0.0357 0.0171 0.1121 [00112]embedded image 0.0385 0.0327 0.0706 [00113]embedded image 0.0123 0.0299 0.0118 0.002 0.13 [00114]embedded image 0.008 0.0213 0.0277 0.0928 0.1 [00115]embedded image 0.0103 0.0164 0.0052 0.0029 [00116]embedded image 0.0046 0.0093 0.0055 0.0015 [00117]embedded image 0.0044 0.0065 0.0086 0.0038 [00118]embedded image 0.0383 0.0393 0.0361 [00119]embedded image 0.0084 0.0715 0.0215 0.0499 [00120]embedded image 0.0243 0.222 0.0306 0.9701 [00121]embedded image 0.0096 0.0694 0.0287 0.0104 [00122]embedded image 0.0091 0.1037 0.027 0.02 [00123]embedded image 0.006 0.0388 0.0177 0.0113 [00124]embedded image 0.064 0.1918 0.0423 0.0588 [00125]embedded image 0.005 0.0065 0.013 0.0111 [00126]embedded image 0.0072 0.0297 0.0297 0.1331 [00127]embedded image 0.035 0.3231 0.0776 0.3436 [00128]embedded image 0.0034 0.0186 0.0048 0.0126 [00129]embedded image 0.0078 0.0101 0.0162 0.0082 [00130]embedded image 0.0042 0.04 0.045 0.1869 [00131]embedded image 0.0076 0.0076 0.0247 0.0089 [00132]embedded image 0.005 0.0079 0.0101 0.0092 [00133]embedded image 0.075 0.0198 0.0141 0.1096 [00134]embedded image 0.0045 0.0332 0.04 0.0153 [00135]embedded image 0.0146 0.0178 0.109 0.1812 [00136]embedded image 0.004 0.036 0.0085 0.0103 [00137]embedded image 0.0059 0.169 0.0979 0.077 2.17 [00138]embedded image 0.0018 0.066 0.0052 0.15 >50 [00139]embedded image 0.002 0.0065 0.0029 0.0065 0.07 21.4 [00140]embedded image 0.0218 0.5689 0.238 >2.0 20.1 [00141]embedded image 0.0321 0.664 0.124 0.352 2.47 [00142]embedded image 0.0067 0.068 0.0032 0.113 6.6 27.57 66.85 [00143]embedded image 0.0097 >0.2 0.16 >0.2 [00144]embedded image 0.0059 0.0121 [00145]embedded image 0.0061 0.016 0.0109 0.0358 13.7 56.12 47.1 [00146]embedded image 0.0021 0.0651 0.0126 0.0677 21.9 60.74 45.46 [00147]embedded image 0.0086 0.0034 >0.2 0.1911 0.0046 >0.2 13.8 66.52 >100 [00148]embedded image 0.0055 0.0055 0.0541 0.0733 0.0023 >0.2 68.4 94.39 >100 [00149]embedded image 0.1088 >2.00 [00150]embedded image 0.0046 0.0208 0.025 0.1582 [00151]embedded image 0.0314 0.2671 0.0925 0.144 [00152]embedded image 0.0278 0.1341 0.1413 0.2079 [00153]embedded image 0.0037 0.0075 0.0141 0.0622 [00154]embedded image 0.0054 0.004 0.0179 0.0273 [00155]embedded image 0.0171 0.0134 0.1504 0.5422

    [0246] Applicant's disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to one embodiment, an embodiment, or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases in one embodiment, in an embodiment, and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

    [0247] The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant's composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

    [0248] In this specification and the appended claims, the singular forms a, an, and the include plural reference, unless the context clearly dictates otherwise.

    [0249] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.

    INCORPORATION BY REFERENCE

    [0250] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

    EQUIVALENTS

    [0251] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.