Gamma-diketones for treatment and prevention of aging skin and wrinkles.

DIVISIONAL DEPUTY DIRECTOR OF PATENT FUND EXAMINATION BIOTECHNOLOGICAL, PHARMACEUTICAL AND CHEMICAL AREAS

<img file="MX368248B_D0001.tif" />

EMELIA HERNÁNDEZ PRIEGO

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EMELIA HERNANDEZ PRIEGO | 00001000000405397295 | Administration Service

Tr¡butar¡a | 56 || MX / 2019/88238 | MX / a / 2017/002285 | Patent title PCT | 1223 | GAGV | Page (s) 2 | XLLYP + wPmhkN27YOudXETObVx1 A =

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NDOBcpe1QZBZcFJ93jOWp5o1Rtc58vpOTmesTQjPWknYBQ1jczq5IBRb8SMeu9yevzXyE7HURMUbajhT8HOZFGKXWXKQX5KXQXP5 / YPVM1QBXQ05

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MX 2019'88238

GAMMA-DICETONES FOR TREATMENT AND PREVENTION OF AGED SKIN AND WRINKLES

Related requests

This application claims the benefit of provisional US Application No. 62 / 039,786, filed on August 20, 2014, which is incorporated herein by reference in its entirety.

Background of the Invention

Technical field

The present description refers to compounds, cosmetic or dermopharmaceutical compositions comprising the same and methods for using the compounds or compositions to treat, protect and / or improve the aesthetic condition and / or appearance of the skin, for example, treating, preventing, improve, reduce and / or eliminate expression lines and / or skin wrinkles, or improve the appearance of expression lines and / or skin wrinkles, the methods comprising the application of the described compounds or compositions.

Background

The mammalian epidermis and its appendages (for example, hair, nails, sebaceous and sweat glands) provide a barrier to keep harmful elements out of the body and essential body fluids inside. As the first line of defense against various physical trauma to the environment, the epidermis must protect itself as well as the underlying tissues. The epidermis is also exposed to mutagenic ultraviolet radiation. In hairless or sparse regions, such as most human skin, the epidermis is thicker than that of hairy skin, and in these locations the skin functions primarily in a protective role. The constant assaults on the epidermis need self-renewal, making the epidermis a good example of an adult tissue that experiences continuous and rapid flow.

Aged skin differs from young skin in both appearance and function. The aged epidermis is devoid of keratinocytes and is physically thinner, but mainly from the erasure of the epithelial ridges. In addition to weight loss, aging slows wound healing, prolongs epidermal rotation, and impairs barrier formation. The skin appears thin, wrinkled, bruised, and rough. Wrinkles and bruises can also result from age-related changes in the dermis. The dermis is also characteristically thinner in older people. Aging fibroblasts are less likely to synthesize normal amounts of collagen, elastin, laminin glycosaminoglycans, and fibronectin. The dermis may, in such cases, lack elasticity, strength, container support, remodeling capabilities, and base substances. For example, epithelial ridges can be erased and basal cells may no longer deploy hairy projections into the dermis. Epidermal cell turnover is reduced by up to 50% in the elderly compared to the young. For example, the amounts of melanocytes can decrease 8-20% per decade. There are fewer Langerhans cells in the elderly, and those present frequently deteriorate functionally. Collagen synthesis decreases, for example, up to 30% within 4 years of menopause in women. The numbers of collagen and elastic fibers also decrease. The dermis may also become less echogenic on ultrasound, consistent with changes in collagen and elastic tissues.

Brief description of the invention

The present disclosure relates to compounds, compositions comprising the same, and methods of using the compounds or compositions to treat, protect, and / or alter (eg, improve) the condition and / or aesthetic appearance of the skin, including, for example , treat, prevent, improve, reduce and / or eliminate expression lines and / or wrinkles of the skin and / or improve the aesthetic appearance of expression lines and / or wrinkles of the skin, caused by, for example, cellular senescence, environmental damage or dermatoheliosis. The description also relates to methods for stimulating skin cell turnover, promoting fibroblast proliferation, and / or synthesizing elastin, collagen, proteoglycans, or new connective tissue, thereby reducing wrinkles, restoring elasticity, resilience, and / or flexibility of the skin.

The compounds and compositions described herein can be used for cosmetic uses, dermopharmaceutical uses, or both cosmetic and dermopharmaceutical uses. A "cosmetic" as used herein can be contacted with the skin, such as by being rotated, emptied, sprayed, sprayed onto the skin, or otherwise introduced into or onto the skin, and is intended to improve the aesthetic appearance of the skin, such as when cleaning, beautifying, promoting attractiveness, or altering, for example, improving, the aesthetic appearance of the contacted skin. A cosmetic benefit is usually visual or aesthetic and can be evaluated using subjective or objective tests.

A "dermopharmaceutical" as used herein, can be similarly contacted with the skin and is intended to be used in the treatment, mitigation or prevention of a skin disease or disorder and / or is intended to affect the structure or a function of the skin. A dermopharmaceutical normally has a physiological, pharmacological and / or therapeutic effect on the skin. A dermopharmaceutical can result in an improved aesthetic appearance of the skin by virtue of its physiological, pharmacological, or therapeutic effects. A dermopharmaceutical benefit can be evaluated using subjective or objective tests.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for improving the condition and / or aesthetic appearance of the skin, wherein the composition comprises a compound according to formula I, II, Illa, lllb and / or

IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition to alter the aesthetic appearance of skin associated with or affected by, or to prevent or reduce, wrinkles, dry skin, sensitive skin, or dermatological symptoms caused by ineffective homeostatic regulation of healthy skin, wherein the composition comprises a compound according to formula I, II, Illa, IIIb and / or IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for altering the aesthetic appearance of skin associated with or affected by wrinkles, sagging and / or loss of skin elasticity, wherein the composition comprises a compound according to formula I , II, Illa, lllb and / or IV.

In another embodiment, the description refers to the use of a compound according to formula I, II, Illa, lllb and / or IV to alter the aesthetic appearance of skin associated with or affected by wrinkles and / or expression lines, skin lean, a lack of elasticity and / or skin tone, thinning of the dermis, degradation of collagen fibers, sagging skin, thinned skin and / or internal skin breakdown following exposure to ultraviolet radiation.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition to alter the aesthetic appearance of the skin associated with or affected by, or to treat or prevent, a skin condition / disorder accompanied by a loss of skin elasticity, in where compassion comprises a compound according to formula I, II, Illa, lllb and / or

IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for altering the aesthetic appearance of skin associated with or affected by, or for treating or preventing, acne, wherein the composition comprises a compound according to formula I, II, Illa, lllb and / or IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for treating or preventing deterioration in skin viscoelasticity, wherein the composition comprises a compound according to formula I, II, Illa, lllb and / or IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for treating or preventing vitiligo (a skin condition in which there is a loss of brown color (pigment) from skin areas), wherein the composition comprises a compound of according to formula I, II, Illa, lllb and / or IV.

In one embodiment, the disclosure provides methods of increasing cell or tissue regeneration. Such methods include administering to a vertebrate subject in need thereof, a compound according to formula I, II, Illa, lllb and / or IV, or a dermatologically acceptable salt thereof.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for activating or promoting the proliferation and / or mobility of skin keratinocytes and / or dermis fibroblasts, for example, to perform skin regeneration, wherein the composition comprises a compound according to formula I, II, Illa, IIIb and / or IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for increasing or improving epidermal cell repair activity, eg, in a human, wherein the composition comprises a compound according to formula I, II, Illa, lllb and / or IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for increasing or improving the barrier function and / or viability of the skin, wherein the composition comprises a compound according to formula I, II, Illa, lllb and / or IV.

In one embodiment, the present disclosure provides a cosmetic or dermopharmaceutical composition for increasing fibroblast proliferation, keratinocyte proliferation and / or collagen expression, or reducing collagenase activity, wherein the composition comprises a compound according to formula I, II, Illa, lllb and / or IV.

In another embodiment, the disclosure relates to the use of a compound according to formula I, II, Illa, lllb and / or IV as a medicament for treating or preventing a wound healing disorder in a mammal.

In another embodiment, the disclosure refers to the use of a compound according to formula I, II, Illa, lllb and / or IV as a medicament for treating or preventing a wound, such as an ulcer in a mammal.

Some embodiments provided herein include cosmetic or dermopharmaceutical compositions comprising one or more of the compounds provided herein and a dermatologically acceptable carrier.

An embodiment provided herein includes compounds of formula I:

<img file="MX368248B_D0002.tif" />

or a dermatologically acceptable salt thereof.

In some forms of formula I:

Ring A is a 7-12 membered heteroaryl, provided that a carbon atom on the ring is attached to the carbonyl carbon;

Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, provided that one carbon atom in the ring is attached to the carbonyl carbon;

R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of Ci.₆ unsubstituted alkyl, -C1.3 haloalkyl, halide, -OR³ and CN;

R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of

Cve unsubstituted alkyl, -CH₂OH, -CH₂N (R^3b)₂, -C_V3 haloalkyl, halide, -OR³ and CN;

each R³ is independently selected from the group consisting of H, -Ci_₆ unsubstituted alkyl and -Ci_₃ haloalkyl;

each R^3b is independently selected from the group consisting of H and C ^ to unsubstituted alkyl;

each n is 0 to 10; and each m is 0 to 5.

Another embodiment provided herein includes compounds of formula II:

<img file="MX368248B_D0003.tif" />

or a dermatologically acceptable salt thereof.

In some forms of formula II:

Ring C is a 5-6 membered heteroaryl, provided that one carbon atom on the ring is attached to the carbonyl carbon;

Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, provided that one carbon atom on the ring is attached to the carbonyl carbon;

R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of Ci.e unsubstituted alkyl, -C1.3 haloalkyl, halide, -OR^and and CN;

R⁵ is a substituent attached to ring D and is independently selected at each occurrence from the group consisting of Ci.e unsubstituted alkyl, -CH2OH, -CH2N (R^5b) 2, -C1.3 haloalkyl, halide, -OR⁶ and CN;

each R⁶ is independently selected from the group consisting of H, -C_V8 unsubstituted alkyl and -C1.3 haloalkyl;

each R^eb is independently selected from the group consisting of H and C₁₃ unsubstituted alkyl;

each q is 0 to 4; and each p is 0 to 5.

Another embodiment provided herein includes compounds of formula III:

(R⁸)_p '£ Λύ °

III or a dermatologically acceptable salt thereof.

In some forms of formula III:

R⁷ is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of Cve unsubstituted alkyl, -CH2OH, -CH2N (R^9a) 2, -Ci.₃ haloalkyl, halide, -OR⁹ and CN;

R⁸ is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of Ci-e alkyl, -CH2OH, -CH2N (R^9a) 2&gt; -C ^ haloalkyl, halide, -OR⁹ Y

CN;

each R⁹ is independently selected from the group consisting of H, -Ove unsubstituted alkyl and -C1.3 haloalkyl;

each R^9a is independently selected from the group consisting of H and C₁₃ unsubstituted alkyl; and each q is 1 to 5; and each p is 0 to 5.

Another embodiment provided herein includes compounds of formula Illa:

<img file="MX368248B_D0004.tif" />

Illa or a dermatologically acceptable salt thereof.

In some forms of the Illa formula:

R¹⁰ is selected from the group consisting of H, -Ci_₆ unsubstituted alkyl, ^_Ci-3 haloalkyl, halide, -OR¹³ and CN;

R¹¹ is selected from the group consisting of -C ^ unsubstituted alkyl, -CH2OH, -CH2N (R^13b) 2, -Ci.3 haloalkyl, halide, -OR¹³ and CN;

R¹² is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of Cve unsubstituted alkyl, -CH2OH, -CH2N (R^13b) 2, -C ^ a haloalkyl, halide, -OR¹³ and CN;

each R¹³ is independently selected from the group consisting of -C ^ g unsubstituted alkyl and -C_V3 haloalkyl;

each R^13b it is independently selected from the group consisting of H and -Ci.₃ unsubstituted alkyl; and each q is 0 to 5.

Another embodiment provided herein includes compounds of formula lllb:

<img file="MX368248B_D0005.tif" />

II Ib or a dermatologically acceptable salt thereof.

In some modalities of lllb formula:

R¹⁴ is selected from the group consisting of -Ci._and unsubstituted alkyl and -C-_₃ haloalkyl;

R¹⁵ is selected from the group consisting of -Ci._and unsubstituted alkyl and -Ci_₃ haloalkyl;

R¹⁶ is a ring-linked substituent and is independently selected at each occurrence from the group consisting of Cve unsubstituted alkyl, CH2OH, -CH2N (R^17b) 2, -Ci.3 haloalkyl, halide, -OR¹⁷ and CN;

each R¹⁷ is independently selected from the group consisting of -C ^ e unsubstituted alkyl and -C₁₃ haloalkyl;

each R^17b is independently selected from the group consisting of H and C₁₃ unsubstituted alkyl; and each q is 0 to 5.

Another embodiment provided herein includes compounds of formula IV:

IV or a dermatologically acceptable salt thereof.

In some forms of formula IV:

ring F is ^r ring G is selected from the group consisting of R¹* _R19b

<img file="MX368248B_D0006.tif" />

and a heteroaryl (R^19d)_z 5-6 membered, with the proviso that a carbon atom on the heteroaryl ring binds to the carbonite carbon;

each R¹⁸ is a substituent attached to ring F and is independently selected at each occurrence from the group consisting of C1.3 haloalkyl, halide, -OR²⁰ and CN;

R^19th is a substituent attached to the para position of phenyl and is selected from the group consisting of H, -C2.e unsubstituted alkyl, -CH2OH, -CH2N (R²¹) 2, -C1.3 haloalkyl, F, Br, I, -OR²⁰ and CN;

R^19b is a substituent attached to the meta or ortho position of phenyl and is selected from the group consisting of H, -C₂._and unsubstituted alkyl, -CH₂OH, -CH₂N (R²¹)₂, -Ci.₃ haloalkyl, halide, -OR²⁰ and CN;

r^19c is a phenyl-linked substituent and is independently selected at each occurrence from the group consisting of CH2OH, -CH2N (R²¹) 2, -0, .3 haloalkyl, halide, -OR²⁰ and CN;

R^19d is a substituent attached to the heteroaryl ring and is independently selected at each occurrence from the group consisting of -CH2OH, -CH2N (R²¹) 2, -C1.3 haloalkyl, halide, -OR²⁰ and CN;

each R²⁰ is independently selected from the group consisting of H, -C₃.₆ unsubstituted alkyl and -C1.3 haloalkyl;

each R²¹ is independently selected from the group consisting of H and -C1.3 unsubstituted alkyl;

k is 0 to 5;

p is 0 to 13;

r is 1 to 5;

z is 0 to 4.

Some embodiments include stereoisomers of a compound of formula I, II, Illa, lllb and / or IV.

Some embodiments include prodrugs of a compound of formula I, II, Illa, lllb and / or IV. For example, prodrugs of a compound of formula I, II, Illa, lllb and / or IV can be prodrug polymer conjugates for delayed release or prolonged release.

Also provided herein are cosmetic or dermopharmaceutical compositions comprising a compound of formula I, II, Illa, lllb and / or IV and a dermatologically acceptable carrier, diluent or excipient.

It is understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the description as claimed.

Detailed description of the drawings

The figure is a linear graph showing the average change in roughness of the skin baseline of test subjects after topical treatment of the periorbital areas using compound # 222 (0.05% in oil, 005% in PEG, 0.15% in oil and 0.15% in PEG). The roughness was determined by Visioscan. Each data point is the average of 20 or 21 test subjects.

Figure 2 is a line graph showing the average percentage of wrinkle reduction of the skin baseline of test subjects after topical treatment of the periorbital areas by compound # 222 (0.05% in oil, 0.05% in PEG 0.15% in oil and 0.15% in PEG). Wrinkle reduction was determined by Visioscan. Each data point is the average of 20 or 21 test subjects.

Detailed description of the invention

Provided herein are γ-diketones useful for treating, protecting and improving the cosmetic condition and / or appearance of the skin, for example, treating, preventing, improving, reducing and / or eliminating and / or improving the appearance of fine lines. and / or wrinkles of the skin. The inventors have discovered that in some embodiments, the application of the γ-diketones provided herein may increase collagen replacement and retention and may, in some embodiments, also increase cell proliferation of the epidermis and dermis.

Cosmetic or dermopharmaceutical compositions comprising one or more compounds according to formulas I, la, Ib, le, Id, le, If, Ig, Ih, Ii, II, Ha, llb, He, lid, He, llf, III, Illa, lllb, lile, Hld and / or IV, or a dermatologically acceptable salt and a dermatologically acceptable carrier are also provided herein.

Compounds

Some embodiments of the present disclosure include compounds of formula (I):

<img file="MX368248B_D0007.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of formula I, ring A is a 7-12 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some embodiments of formula I, ring A is a 7-12 membered heteroaryl, wherein a carbon atom in the benzene ring is attached to the carbonyl carbon.

In some embodiments of formula I, ring A is a 7-12 membered heteroaryl, wherein a carbon atom in the heteroaromatic ring is attached to the carbonyl carbon.

In some embodiments of formula I, ring A is a 7-12 membered heteroaryl, wherein a carbon atom in the heterocyclic aliphatic ring is attached to the carbonyl carbon.

In some embodiments of formula I, ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, provided that one carbon atom in the ring is attached to the carbonyl carbon.

In some forms of formula I, R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -C ^ unsubstituted alkyl, Ci.3 haloalkyl, halide, -OR³ and CN.

In some forms of formula I, R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -Ci__and unsubstituted alkyl, Ci_3 haloalkyl, halide, -OR³ and CN.

In some forms of formula I, R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of H, -C_b5 unsubstituted alkyl, -CH₂OH, -CH₂N (R^3b)₂, -0, .3 haloalkyl, halide, -OR³ and CN.

In some forms of formula I, R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of -C, .e unsubstituted alkyl, CH2OH, -CH2N (R^3b) 2, -Ci-₃ haloalkyl, halide, -OR³ and CN.

In some forms of formula I, each R³ is independently selected from the group consisting of H, -C_V6 unsubstituted alkyl and -Ci_₃ haloalkyl.

In some forms of formula I, each R^3b is independently selected from the group consisting of H and -C¹’³ unsubstituted alkyl.

In some forms of formula I, n is 0 to 10. In some forms of formula I, n is 1 to 10.

In some modalities of formula I, m is 0 to 5.

In some modalities of formula I, m is 1 to 5.

In some embodiments of formula I, ring A is a 9-membered bicyclic heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.

In some embodiments of formula I, ring A is a 10-membered bicyclic heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.

In some embodiments of formula I, ring A is selected from the group consisting of:

<img file="MX368248B_D0008.tif" />

Otherwise designated, the carbonyl carbon of formula I can bond with an unsubstituted carbon in ring A.

In some embodiments of formula I, ring A is selected from the group consisting of:

<img file="MX368248B_D0009.tif" />

where the carbonyl carbon of formula I can bond with any unsubstituted carbon in ring A.

In some embodiments of formula I, ring A is selected from the group consisting of:

<img file="MX368248B_D0010.tif" />

<img file="MX368248B_D0011.tif" />

wherein the carbonyl carbon of formula I can bond with any unsubstituted carbon in ring A.

In some embodiments of formula I, the ring is selected from the group consisting of:

<img file="MX368248B_D0012.tif" />

<img file="MX368248B_D0013.tif" />

<img file="MX368248B_D0014.tif" />

wherein the carbonyl carbon of formula I can bond with any unsubstituted carbon in ring A.

In some embodiments of formula I, ring A is selected from the group consisting of

<img file="MX368248B_D0015.tif" />

<img file="MX368248B_D0016.tif" />

<img file="MX368248B_D0017.tif" />

<img file="MX368248B_D0018.tif" />

<img file="MX368248B_D0019.tif" />

<img file="MX368248B_D0020.tif" />

<img file="MX368248B_D0021.tif" />

wherein the carbonyl carbon of formula I can bond with any unsubstituted carbon in ring A.

In some embodiments of formula I, ring A is selected from the group consisting of

<img file="MX368248B_D0022.tif" />

<img file="MX368248B_D0023.tif" />

<img file="MX368248B_D0024.tif" />

<img file="MX368248B_D0025.tif" />

wherein the carbonyl carbon of formula I can bond with any unsubstituted carbon in ring A.

In some embodiments of formula I, ring A is selected from the group consisting of

<img file="MX368248B_D0026.tif" />

<img file="MX368248B_D0027.tif" />

where the carbonyl carbon of formula I can bond with any unsubstituted carbon in ring A.

In some embodiments of formula I, ring A is selected

<img file="MX368248B_D0028.tif" />

In some embodiments, ring A is selected from the group consisting of

<img file="MX368248B_D0029.tif" />

<img file="MX368248B_D0030.tif" />

Some formula modalities

I include compounds of formula (la):

<img file="MX368248B_D0031.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some modalities of formula la, ring A is

<img file="MX368248B_D0032.tif" />

In some embodiments of formula la, ring B is selected from the group consisting of

<img file="MX368248B_D0033.tif" />

_R2b

<img file="MX368248B_D0034.tif" />

<img file="MX368248B_D0035.tif" />

<img file="MX368248B_D0036.tif" />

<img file="MX368248B_D0037.tif" />

<img file="MX368248B_D0038.tif" />

<img file="MX368248B_D0039.tif" />

<img file="MX368248B_D0040.tif" />

(R²·), (R^2f)&lt;

<img file="MX368248B_D0041.tif" />

(R²⁰).

<img file="MX368248B_D0042.tif" />

(R^2e) t (R^2ek

In some modalities of formula la, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci_₆ unsubstituted alkyl, -Ci-3 haloalkyl, halide, -OR³ and CN.

In some modalities, of formula la, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -C &lt;._and unsubstituted alkyl, -Cv ₃ haloalkyl, halide, -OR³ and CN.

In some modalities of formula la, R^2nd is a substituent attached to the para position of phenyl and is selected from the group consisting of -Ci.e unsubstituted alkyl, -CH₂OH, -CH₂N (R^3b)₂, -Ci_₃ haloalkyl, Cl, Br, I, -OR^3rdand CN.

In some modalities of formula la, R^2b is a substituent attached to the meta or ortho position of phenyl and is selected from the group consisting of -Ci.e unsubstituted alkyl, -CH₂OH, -CH₂N (R^3b)₂, Ο_μ3 haloalkyl, halide, -OR^3rd and CN.

In some modalities of formula la, R^{2 C} is a phenyl-linked substituent and are independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl, CH₂OH, -CH₂N (R^3b)₂, -Cva haloalkyl, halide, -OR³ and CN; m is 2 to 5.

In some modalities of formula la, R^2d is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of -Cve unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C ^ s haloalkyl, halide, -OR³ and CN; s is 1 to 4.

In some modalities of formula la, R^2e is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of -Cb8 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -Ci_₃ haloalkyl, halide, -OR³ and CN; t is 1 to 4.

In some modalities of formula la, R^2e is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of H, -Ci_e unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C- |.₃ haloalkyl, halide, -OR³ and CN; t is 0 to 4.

In some modalities of formula la, R^2e is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of -Ci_e unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -Ci_₃ haloalkyl, halide, -OR³ and CN; u is 1 to 3.

In some modalities of formula la, R^{2 g} is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of H, -Ci_6 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C1.3 haloalkyl, halide, -OR³ and CN; v is 1 to 3.

In some modalities of formula la, R²⁹ is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of -Cb6 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -Cvs haloalkyl, halide, -OR³ and CN; v is 0 to 3.

In some modalities of formula la, R³ is independently selected from the group consisting of H, -C_b6 unsubstituted alkyl and -C₁₃ haloalkyl.

In some modalities of formula la, each R^3rd is independently selected from the group consisting of -C₂.₆ unsubstituted alkyl and -Ci_₃ haloalkyl.

In some modalities of formula la, each R^3b is independently selected from the group consisting of H and -C₁₃ unsubstituted alkyl.

In some modalities of formula la, each W is independently N or C.

In some modalities of formula la, at least two W must be N.

In some modalities of formula la, each U is independently N or C.

In some modalities of formula la, at least one U must be N and at least one U must be C.

In some modalities of formula la, G is NH or O.

In some modalities of formula la, each J is independently N or C.

C.

In some modalities of formula la, at least one J must be

In some modalities of formula la, n is 0 to 7.

In some modalities of formula la, n is 1 to 7.

In some modalities of select from the group consisting of the ring is formulated

<img file="MX368248B_D0043.tif" />

FF and ^F

TO

<img file="MX368248B_D0044.tif" />

B se

In some modalities of formula la, the ring

<img file="MX368248B_D0045.tif" />

CN

<img file="MX368248B_D0046.tif" />

In some modalities of formula la, the ring

B se

<img file="MX368248B_D0047.tif" />

<img file="MX368248B_D0048.tif" />

<img file="MX368248B_D0049.tif" />

In some embodiments of formula la, ring B is selected from the group consisting of

<img file="MX368248B_D0050.tif" />

<img file="MX368248B_D0051.tif" />

In some modalities of formula la, ring B is

<img file="MX368248B_D0052.tif" />

<img file="MX368248B_D0053.tif" />

select from the group consisting of

<img file="MX368248B_D0054.tif" />

<img file="MX368248B_D0055.tif" />

In some formula modalities select from the group consisting of

<img file="MX368248B_D0056.tif" />

<img file="MX368248B_D0057.tif" />

<img file="MX368248B_D0058.tif" />

<img file="MX368248B_D0059.tif" />

<img file="MX368248B_D0060.tif" />

In some modalities of formula la, ring B is

<img file="MX368248B_D0061.tif" />

<img file="MX368248B_D0062.tif" />

select from the group consisting of

<img file="MX368248B_D0063.tif" />

<img file="MX368248B_D0064.tif" />

In some modalities of formula la, ring B is

<img file="MX368248B_D0065.tif" />

<img file="MX368248B_D0066.tif" />

In some modalities of formula la, t is 0.

In some modalities of formula la, at least one R^2e it is a halide.

In some forms of formula the.

at least one

R^2e it is

In some modalities of formula la, at least one

R^2e it is

Cl.

In some types of formula, minus one

R^2e it is

I.

In

In

OMe.

I.

CF₃.

OMe.

In

In

In

In

In

In

In

In

In

In

In some modalities of formula la, at least one

R^2e it is

Oh

some modalities of formula la, some modalities of formula la, some modalities of formula la, at least one minus R^2e minus an R^2e

R²® is is CF₃.

it's CN.

some modalities of formula la, t is 1 and R^2e is F.

some modalities of formula la, t is 2 and both R^2e some modalities of formula la, t is 1 and R²® is Me.

some modalities of formula la, t is 2 and both R^2e some modalities of formula la, t is 1 and R^2e is CF₃.

some modalities of formula la, t is 2 and both R^2e some modalities of formula la, t is 1 and R²® is OMe.

some modalities of formula la, t is 2 and both R^2e some modalities of formula la, t is 2 and an R^2e is F other R^2e is Me.

In some modalities of formula la, t is 2 and an R^2e is F other R²® is CF₃.

are are are are and he and he

In some modalities of formula la, t is 2 and an R^2e is F and the other R^2e is OMe.

In some modalities of formula la, t is 1 and R^2e it's CN.

In some modalities of formula la, t is 2 and both R^2e they are CN.

In some modalities of formula la, t is 2 and an R^2e is F and the other R^2e it's CN.

In some modalities of formula la, at least one R^2e is -C ,.

I rent.

In some modalities of formula la, at least one R^2e is -C ,.

I rent.

In some modalities of formula la, at least one R^2eeis -C1.4 alkyl.

In some modalities of formula la, at least one R^2e is -Cv alkyl.

In some modalities of formula la, at least one R^2e is -C_b₆ I rent.

In some modalities of formula la, at least one R^2e is -C₂. and alkyl.

In some modalities of formula la, at least one R^2e is -C₃. and alkyl.

In some modalities of formula la, at least one R^2e is -C₄. ₆ I rent.

In some modalities of formula la, at least one R^2e is -C₂.

I rent.

In some modalities of formula la, at least one R^2e is -C₃.

I rent.

In some modalities of formula la, at least one R^2f it is halide.

In some modalities of formula la, at least one

R^2f it is

F.

In some modalities of formula la, at least one R^2f is Cl.

In some modalities of formula la, at least one R^2f is Me.

In some modalities of formula la, at least one R^2f it's OH.

In some modalities of formula la, at least one R^2f it is

OMe.

In some modalities of formula la, at least one R^2f is CF₃.

In some modalities of formula la, at least one R^2f it's CN. In some modalities of formula la, u is 1 and R^2f is F.

In some modalities of formula la, u is 2 and both R^2f are 15 F.

In some modalities of formula la, u is 1 and R^2f is Me.

In some modalities of formula la, u is 2 and both R^2f are Me.

In some modalities of formula la, u is 1 and R^2f is CF₃.

In some modalities of formula la, u is 2 and both R^2f are

CF₃.

In some modalities of formula la, u is 1 and R^2f is OMe.

In some modalities of formula la, u is 2 and both R^2f are

OMe.

In some modalities of formula la, u is 2 and an R^2f is F and the other

R^2f is Me.

In some modalities of formula la, is

2and a

R^2f is F and the other

R^2f is CF₃.

In some forms of formula it is

2and a

R^2f is F and the other

CN.

other

R^2f is OMe.

In

In

In some some some

R^2f it's CN.

For rent.

For rent.

For rent.

For rent.

For rent.

In the rent.

In the rent.

In some some some some some some some some modalities of the formula the is

R^2f it's CN.

modalities of formula ia, u is 2 and both R^2f Modalities Modalities Modalities Modalities Modalities Modalities Modalities Modalities Modalities are of formula of of of the, u is 2 and an R^2f is F and the formula formula formula la, la, la, at least at least minus a one

R^2f

R^2f

R^2f is is is of formula la, at least one R^{2f is} formula formula formula formula

-Ci-2

-Ci-₃

-C1-4

-C1-5 la, la, la, at least minus minus at least one one one one

R^2f is -Cf.e

R^2f

R^2f

R^2f is is is

-C₂.

-C₃.

-c₄.

β alkyl.

In some modalities of formula la, at least one R^2f is -C₂. 5 alkyl.

In some modalities of formula la, at least one R^zf is -C₃.

I rent.

In some modalities of formula la, v is 0.

In some modalities of formula la, v is 1.

In some modalities of formula la, v is 2.

In some modalities of formula la, at least one R²⁹ it is halide.

In some modalities of formula la, at least one R²⁹ is F.

In some modalities of formula la, at least one R²⁹ is CL

In some modalities of formula la, at least one R^{2 g} is Me.

In some modalities of formula la, at least one R²⁹ it's OH.

In some modalities of formula la, at least one R^{2 g} is OMe.

In some modalities of formula la, at least one R^{2 g} is CF₃.

In some modalities of formula la, at least one R²⁹ it's CN.

In some modalities of formula la, v is 1 and R^{2 g} is F.

In some modalities of formula la, v is 2 and both R^{2 g} are

F.

In some modalities of formula la, v is 1 and R^{2 g} is Me.

In some modalities of formula la, v is 2 and both R^{2 g} are

I.

In some modalities of formula la, v is 1 and R^{2 g} is CF₃.

In some modalities of formula la, v is 2 and both R^{2 g} are

CF₃.

In some modalities of formula la, v is 1 and R²⁰ is OMe.

In some modalities of formula la, v is 2 and both R^{2 g} they are OMe.

In some modalities of formula la, v is 2 and an R^{2 g} is F and the other R²⁹ is Me.

In some modalities of formula la, v is 2 and an R^{2 g} is F and the other R^{2 g} is CF₃.

In some modalities of formula la, v is 2 and an R^{2 g} is F and the other R^{2 g} is OMe.

In some modalities of formula la, v is 1 and R^{2 g} it's CN.

In some modalities of formula la, v is 2 and both R^{2 g} they are CN.

In some modalities of formula la, v is 2 and an R^{2 g} is F and the other R^{2 g} it's CN.

In some modalities of formula la, at least one R^{2 g} is -Cv alkyl.

In some modalities of formula la, at least one R^{2 g} is -C).

I rent.

In some modalities of formula la, at least one R^{2 g} is -Ci.

I rent.

In some modalities of formula la, at least one R^{2g is} -Ci_₅I rent.

In some modalities of formula la, at least one R²⁹ is -C_v₆ I rent.

In some modalities of formula la, at least one R²⁹ is -C₂. to alkyl.

In some modalities of formula la, at least one R²⁹ is -C₃. ₆ I rent.

In some modalities of formula la, at least one R²⁹ is -C₄. to alkyl.

In some modalities of formula la, at least one R²⁹ is -C₂. ₅ I rent.

In some modalities of formula la, at least one R^{2 g} is -C₃.

₄ I rent.

Some formula modalities

I include compounds of formula (Ib):

or you go out

<img file="MX368248B_D0067.tif" />

dermatologically acceptable, or prodrugs thereof.

In some formula modalities

Ib, the ring is

<img file="MX368248B_D0068.tif" />

In some formula modalities

Ib, the ring is selected from the group consisting of phenyl and a heteroaryl of

5-6 members, where a carbon atom in the ring is attached to the carbonyl carbon atom.

In some forms of formula Ib, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci__s unsubstituted alkyl, ^_Ci-3 haloalkyl, halide, -OR³ and CN.

In some forms of formula Ib, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -C₁₆ unsubstituted alkyl, -Ci_3 haloalkyl, halide, -OR³ and CN.

In some forms of formula Ib, each R² it is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of H, -C ^ e alkyl, CH2OH, -CH2N (R^3b)2 C₁₃ haloalkyl, halide, -OR³ and CN.

In some forms of formula Ib, each R² is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C16 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -Cvs haloalkyl, halide, -OR³ and CN.

In some forms of formula Ib, each R³ is independently selected from the group consisting of H, -Ci__s unsubstituted alkyl and -C ^ to haloalkyl.

In some forms of formula Ib, each R^3b it is independently selected from the group consisting of H and -C ^ unsubstituted alkyl.

In some embodiments of formula Ib, each M is independently selected from the group consisting of N, C, S, and O.

In some forms of formula Ib, both M are not O.

In some forms of formula Ib, both M's are not C.

In some modalities of formula Ib, m is 0 to 5.

In some forms of formula Ib, m is 1 to 5.

In some forms of formula Ib, n is 0 to 10.

In some modalities of formula Ib, n is 1 to 10.

In some embodiments of formula Ib, ring A is selected from the group consisting of

<img file="MX368248B_D0069.tif" />

<img file="MX368248B_D0070.tif" />

<img file="MX368248B_D0071.tif" />

Some formula modalities

They include compounds of formula (le):

<img file="MX368248B_D0072.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some modalities of formula le, ring A is

In some embodiments of formula le, ring b is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of formula le, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci._s unsubstituted alkyl, -Ci-₃ haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -C_vs unsubstituted alkyl, -C1.3 haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of H, -C ^ g unsubstituted alkyl, -CH2OH, -CH2N (R^3b)2 C₁₃ haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of -CVe unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C1.3 haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R³ is independently selected from the group consisting of H, -Ci__and unsubstituted alkyl and -C1.3 haloalkyl.

In some modalities of formula le, each R^3b is independently selected from the group consisting of H and -Ci_₃ unsubstituted alkyl.

In some embodiments of formula le, each M is independently selected from the group consisting of N, C, S, and O.

In some embodiments of the formula le, if one M is C, the other M is selected from the group consisting of N, S, and

OR.

In some modalities of formula le, it is 0 to 5.

In some modalities of formula it is 1 to 5.

In some modalities of formula c, n is 0 to 10.

In some modalities of the formula le, n is 1 to 10.

In some modalities of formula le, ring A is selected

<img file="MX368248B_D0073.tif" />

In some embodiments of formula I include compounds of formula (Id):

<img file="MX368248B_D0074.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some forms of formula Id, ring A is

<img file="MX368248B_D0075.tif" />

In some forms of formula Id, ring B is _R2b

<img file="MX368248B_D0076.tif" />

select from the group consisting of ^R2a

<img file="MX368248B_D0077.tif" />

R^{2 C} (R^2dd) w

<img file="MX368248B_D0078.tif" />

and a heteroaryl (R^2ee)_Y 5-6 membered, where one carbon atom in the ring binds to carbonyl carbon.

In some forms of formula Id, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci_₆ unsubstituted alkyl, -C1.3 haloalkyl, halide, -OR³ and CN.

In some forms of formula Id, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -C_b6 unsubstituted alkyl, -C1.3 haloalkyl, halide, -OR³ and CN.

In some forms of formula Id, R^2nd is a substituent attached to the para position of phenyl and is selected from the group consisting of H, -Ci, and unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C1. 3 haloalkyl, Cl, Br, I, -OR^3rdyCN.

In some forms of formula Id, R^2b is a substituent attached to the phenyl meta position and is selected from the group consisting of H, -C2.6 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C1. 3 haloalkyl, F, I, -OR³ and CN.

In some forms of formula Id, R^{2 C} is a substituent attached to the ortho phenyl position and is selected from the group consisting of -C-i_₆ unsubstituted alkyl, -CH₂OH, -CH₂N (R^3b)₂, -C ^ a haloalkyl, F, Br, I, -OR³ and CN.

In some forms of formula Id, R^2dd is a phenyl-linked substituent and is independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl, CH₂OH, -CH₂N (R^3b)₂, -Ci_₃ haloalkyl, halide, -OR³ and CN; w is 1 to 5.

In some forms of formula Id, R^2ee it is a substituent attached to the heteroaryl ring and is independently selected at each occurrence from the group consisting of -Ci.₆ unsubstituted alkyl, -CH₂OH, -CH₂N (R^3b)₂, -C1.3 haloalkyl, halide, -OR³ and CN; y is 0 to 3.

In some forms of formula Id, R^{2 C} it's an F.

In some

In some

In some

In some

In some

In some

In some

In some

In some

In some

In some

In some modalities modalities modalities modalities modalities modalities modalities modalities modalities modalities modalities formula formula formula formula formula formula formula formula formula formula formula formula formula

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

Go, R^{2 C} is a

I.

Oh

OMe.

CF₃.

CN.

-Cj_2 alkyl.

-Ci.₃ I rent.

-Ci-4 alkyl.

-Cvs alkyl.

-Ci_6 alkyl.

—C₂.e rent.

—C₃.g alkyl.

In some formula modalities

Go

R^{2 C} It's a c₄._and I rent.

In some formula modalities

Go

R^{2 C} It's a c₂-5 alkyl.

In some formula modalities

Id, r2C is a

-C₃.₄ I rent.

In some formula modalities

Go, at least one

R^2dd it is

In some formula modalities

Go, at least one

R^2dd it is

Cl.

In some formula modalities

Go, at least one

R^2dd it is

I.

In some forms of

Oh

In some OMe modalities.

In some forms of CF₃.

In some types of CN.

formula Id, at least one R^2dd is formula Id, at least one R^2dd is formula Id, at least one R^2dd is formula Id, at least one R^2dd it is

In some modalities of formula Id, w is 2 to 5.

In some forms of formula Id, w is 1.

In some forms of formula Id, w is 2.

In some modalities of formula Id, w is 1 and R^2dd is F.

In some forms of formula Id, w is 2 and both R^2dd They are f.

In some modalities of formula Id, w is 1 and R^2dd is Me.

In some forms of formula Id, w is 2 and both R^2ddare Me.

In some modalities of formula Id, w is 1 and R^2dd is CF₃.

In some forms of formula Id, w is 2 and both R^2dd are CF₃.

In some modalities of formula Id, w is 1 and R^2dd is OMe.

In some forms of formula Id, w is 2 and both R^2ddthey are OMe.

In some modalities of formula Id, w is 2 and an R^2dd is F and the other R^2dd is Me.

In some modalities of formula Id, w is 2 and an R^2dd is F and the other R^2dd is CF₃.

In some modalities of formula Id, w is 2 and an R^2dd is F and the other R^2dd is OMe.

In some modalities of formula Id, w is 1 and R^2dd it's CN.

In some forms of formula Id, w is 2 and both R^2ddthey are CN.

In some modalities of formula Id, w is 2 and an R^2dd is F and the other R^2dd it's CN.

<td>In some formula modalities</td><td>Go, at least an R^2dd it is -</td>

Ci.₂ I rent.

<td>In some formula modalities</td><td>Go, at least an R^2dd it is -</td>

Cva alkyl.

<td>In some formula modalities</td><td>Go, at least an R^2dd it is -</td>

C_b4 I rent.

<td>In some formula modalities</td><td>Go, at least an R^2dd it is -</td>

Ci-5 alkyl.

<td>In some formula modalities</td><td>Go, at least an R^2dd it is -</td>

Cve alkyl.

In some formula modalities

Go, at least one

R^2dd it is

C₂.e rent.

In some formula modalities

Go, at least one

R^2dd it is

C₃.e rent.

C4-6

C₂_5

C3.4

In some formula modalities

Go, at least one

R^2dd it's alkyl.

In some formula modalities

Go, at least one

R^2dd it's alkyl.

In some formula modalities

Go, at least one

R^2dd it's alkyl.

In some modalities of formula Id y is 0.

In some modalities of formula Id y is 1.

In some modalities of formula Id y is 2.

In halide.

Oh

OMe.

CF₃.

In

In

In

In

In

In

In some forms of Id formula, at least one R^2ee is some some some some some some some formula modalities formula modalities formula modalities modalities modalities modalities modalities of of of of

Go to

Go to

Go to formula formula formula formula

Go

Go

Go

Go, minus minus minus al al al un a minus minus minus minus

R^2ee

R^2ee

R^2ee a one a one is is is

Cl.

I.

R^2ee

R^2ee

R^2ee

R^2ee is is is is

CN.

In some modalities of formula Id y is 1 and R^2ee is F.

In some modalities of formula Id y is 2 and both R^2ee They are f.

In some modalities of formula Id y is 1 and R^2ee is Me.

In some modalities of formula Id y is 2 and both R^2ee are Me.

In some modalities of formula Id y is 1 and R^2ee is CF₃.

In some modalities of formula Id y is 2 and both R^2ee are

CF₃.

In some modalities of formula Id y is 1 and R^2ee is OMe.

In some modalities of formula Id y is 2 and both R^2ee are

OMe.

In some modalities of formula Id y is 2 and an R^2ee is F and the other R^2ee is Me.

In some modalities of formula Id y is 2 and an R^2ee is F and the other R^2ee is CF₃.

In some modalities of formula Id y is 2 and an R^2ee is F and the other R^2ee is OMe.

In some modalities of formula Id y is 1 and R^2ee it's CN.

In some modalities of formula Id y is 2 and both R^2ee they are CN.

In some modalities of formula Id y is 2 and an R^2ee is F and the other R^2ee it's CN.

In some forms of Id formula, at least one R^2ee is 45

C₁₂ I rent.

In some formula modalities

Go, at least one

R^2ee it is

Cv3 alkyl.

In some formula modalities

Go, minus one

R^2ee it is

C₁₄ I rent.

In some formula modalities

Go, minus one

R^2ae it is

Ci.5 alkyl.

In some formula modalities

Go, at least one

R^2ee it is

Cve alkyl.

In some formula modalities

Go, minus one

R^2ee it is

C₂-6 alkyl.

In some formula modalities

Go, at least one

R^2ee it is

C₃_e rent.

In some formula modalities

Go, at least one

R^2ee it is

C₄._and I rent.

In some formula modalities

Go, at least one

R^2ee it is

C₂.₅ I rent.

In some formula modalities

Go, minus one

R^2ee it is

C₃_4 alkyl.

In some formula modalities

Go, every R³ it is independently selected from the group consisting of H, -Cve unsubstituted alkyl and -C ^ haloalkyl.

In some forms of formula Id, each R^3rd is independently selected from the group consisting of H, -C₂.₆ unsubstituted alkyl and -Ci.₃ haloalkyl.

In some forms of formula Id, each R^3b it is independently selected from the group consisting of H and -Ci.₃ unsubstituted alkyl.

In some modalities of formula Id, Q is S or NH.

In some modes of formula Id, n is 0 to 5.

In some forms of formula Id, n is 1 to 5.

In some embodiments of formula Id, ring A is selected from the group consisting of

<img file="MX368248B_D0079.tif" />

In some forms of formula Id, R^2nd it's H.

In some forms of formula Id, R^2b it's H.

In some forms of formula Id, w is 0.

Some forms of the formula include compounds of formula (le):

<img file="MX368248B_D0080.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some modalities of formula le, ring A is

<img file="MX368248B_D0081.tif" />

In some embodiments of formula le, ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of formula le, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of Η, unsubstituted alkyl, -Ci-₃ haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -Ci.₆ unsubstituted alkyl, -C1-3 haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of H, -C18 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -0 ^ 3 haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of -Cve unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 21 -Ci_₃ haloalkyl, halide, -OR³ and CN.

In some modalities of formula le, each R³ it is independently selected from the group consisting of H, -Ci._and unsubstituted alkyl and -C-i_₃ haloalkyl.

In some modalities of formula le, each R^3b is independently selected from the group consisting of H and -Cv₃ unsubstituted alkyl.

In some embodiments of formula le, each W is independently N or C.

In some modalities of formula le, at least one W must be N.

In some modalities of the formula le, Q is S or NH.

In some modalities of the formula le, m is 0 to 5.

In some modalities of formula le, m is 1 to 5.

In some modalities of the formula le, n is 0 to 4.

In some modalities of formula le, n is 1a 4.

In some embodiments of formula le, ring A is selected from the group consisting of

<img file="MX368248B_D0082.tif" />

Some formula modalities include compounds of formula (If):

<img file="MX368248B_D0083.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some modalities of the If formula, ring A is

<img file="MX368248B_D0084.tif" />

In some embodiments of the If formula, ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some If formula modalities, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -C ^ unsubstituted alkyl, ~ Ci-3 haloalkyl, halide, -OR³ and CN.

In some If formula modalities, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci_₆ unsubstituted alkyl, -Cbj haloalkyl, halide, -OR³ and CN.

In some If formula modalities, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of H, -Ci, and unsubstituted alkyl, -CH2OH, -CH2N (R^3b)2 C₁₃ haloalkyl, halide, -OR³ and CN.

In some If formula modalities, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -Ci_₃ haloalkyl, halide, -OR³ and CN.

In some If formula modalities, each R³ is independently selected from the group consisting of Η, -Ο_Ί.₆ unsubstituted alkyl and -C ^ haloalkyl.

In some If formula modalities, each R^3b it is independently selected from the group consisting of H and -C-.₃ unsubstituted alkyl.

In some modalities of the If formula, each W is independently N or C.

In some modalities of the If formula, m is 0 to 5.

In some modalities of the If formula, m is 1 to 5.

In some modalities of the If formula, n is 0 to 5.

In some modalities of the If formula, n is 1 to 5.

In some modalities of the If formula, ring A is selected from the group consisting of

<img file="MX368248B_D0085.tif" />

Some forms of the formula include compounds of the formula (Ig):

<img file="MX368248B_D0086.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of formula Ig, ring A is

<img file="MX368248B_D0087.tif" />

In some modalities of formula Ig, ring B is _R2b

<img file="MX368248B_D0088.tif" />

select from the group consisting of R^2nd

<img file="MX368248B_D0089.tif" />

R^2b (R^{2 C}) m

<img file="MX368248B_D0090.tif" />

and a heteroaryl (R^2d)_s 5-6 membered where a carbon atom in the ring binds to the carbonyl carbon.

In some forms of the Ig formula, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci._and unsubstituted alkyl, -Cj.3 haloalkyl, halide, -OR³ and CN.

In some forms of the Ig formula, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -Ci._and unsubstituted alkyl, -C1.3 haloalkyl, halide, -OR³ and CN.

In some forms of formula Ig, R^2nd is a bonded substituent for the para position of phenyl and is selected from the group consisting of -Ci.6 unsubstituted alkyl, -CH2OH, -CH2N (R^3b)2 C₁₃haloalkyl, F, I, -OR³_YCN.

In some forms of formula Ig, R^2b is a substituent attached to the phenyl meta or ortho position and is selected from the group consisting of -C2.e unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, C1.3 haloalkyl, halide, -OR³ and CN.

In some forms of formula Ig, R^{2 C} is a phenyl-linked substituent and is independently selected at each occurrence from the group consisting of -Cve unsubstituted alkyl, CH₂OH, -CH₂N (R^3b)₂, -Cj.3 haloalkyl, halide, -OR³ and CN; m is 2-5.

In some forms of formula Ig, R^2d is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, -CH₂OH, -CH₂N (R^3b)₂, -Ο ,.₃ haloalkyl, halide, -OR³ and CN; s is 1-3.

In some forms of formula Ig, R^2d is a substituent attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of -Cve unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C- |.₃ haloalkyl, halide, -OR³ and CN; s is 0-4.

In some forms of the Ig formula, each R³ 15 is independently selected from the group consisting of H, -C ,.₆ unsubstituted alkyl and -0, .3 haloalkyl.

In some forms of the Ig formula, each R^3b is independently selected from the group consisting of H and -0, .3 unsubstituted alkyl.

In some embodiments of formula Ig, Q is selected from the group consisting of O, S, and NH.

In some modalities of the Ig formula, n is 0 to 5.

In some modalities of the Ig formula, n is 1 to 5.

In some embodiments of formula Ig, ring A is selected from the group consisting of

<img file="MX368248B_D0091.tif" />

<img file="MX368248B_D0092.tif" />

NH

In

In

In

In

CH₂Oh

In some some some some some

CH₂N (R^3b)₂.

In some

CH₂NH₂.

In some

CH₂NHMe

In some

CH₂NMe₂.

In some

CH₂NHEt

In some

CH₂N (Me) (Et).

In some

CH₂NEt₂.

formula modalities formula modalities formula modalities modalities modalities modalities modalities modalities modalities modalities de de de de de de de lg, R^2nd lg, R^2nd lg, R^2nd formula formula formula formula formula formula formula formula

Some modalities of formula I formula (Ih):

es es es lg, al g, al lg, al lg, al lg, al lg, al lg, al lg, al un un un

F.

Oh

OMe.

minus minus minus minus minus minus minus one one one one one one one

R2d

R^2d

R^2d

R2d _R2d

R2d

R^2d

R2d is is is is is is is is include compounds of (R¹) n ·

<img file="MX368248B_D0093.tif" />

(R²) m

Ih or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of formula Ih, ring A is

<img file="MX368248B_D0094.tif" />

In some embodiments of formula Ih, ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of formula Ih, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci_₅ unsubstituted alkyl, - &lt;7-3 haloalkyl, halide, -OR³ and CN.

In some modalities of formula Ih, each R¹ it is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -C_vs unsubstituted alkyl, -Ci_3 haloalkyl, halide, -OR³ and CN.

In some modalities of formula Ih, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C ^ s haloalkyl, halide, -OR³ Y

CN.

In some modalities of formula Ih, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of -CV6 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -Ci_₃ haloalkyl, halide, -OR³ and CN.

In some modalities of formula Ih, each R³ is independently selected from the group consisting of Η, -Ο ·.₀ unsubstituted alkyl and -Ci_₃ haloalkyl.

In some modalities of formula Ih, each R^3b is independently selected from the group consisting of H and a -C₁.₃ unsubstituted alkyl.

In some modalities of formula Ih, each W is independently

No.

In some modalities of formula Ih, at least one W must be

N.

In some embodiments of formula Ih, it is selected from the group consisting of O, S, and NH.

In some formula modalities

Ih it's

5.

In some formula modalities

Ih it's

5.

In some formula modalities

Ih, it's 0 to 4.

In some formula modalities

Ih, it's 1 to 4.

In some formula modalities

Ih, ring A is selected from the group consisting of

<img file="MX368248B_D0095.tif" />

Some formula modalities

I include compounds of formula (Ii):

<img file="MX368248B_D0096.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

<img file="MX368248B_D0097.tif" />

, where a carbon atom in the ring is attached to the carbonyl carbon.

In some embodiments of formula II, ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of formula Ii, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of H, -Ci_₆ unsubstituted alkyl, -Cvj haloalkyl, halide, -OR³ and CN.

In some modalities of formula Ii, each R¹ is a substituent attached to ring A and is independently selected at each occurrence from the group consisting of -C -,. β unsubstituted alkyl, -Cvs haloalkyl, halide, -OR³ and CN.

In some forms of formula l, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of H, -Ci_6 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C1.3 haloalkyl, halide, -OR³ and CN.

In some forms of formula li, each R² is a substituent attached to ring B and is independently selected at each occurrence from the group consisting of -Ci.6 unsubstituted alkyl, -CH2OH, -CH2N (R^3b) 2, -C1.3 haloalkyl, halide, -OR³ and CN.

In some forms of formula li, each R³ is independently selected from the group consisting of Η, -Ομ_β unsubstituted alkyl and -C1.3 haloalkyl.

In some forms of formula li, each R^3b is independently selected from the group consisting of H and -Ο_ν3 unsubstituted alkyl.

In some embodiments of formula li, each W is independently N or C.

In some forms of formula li, at least one W is C.

In some embodiments of formula li, Q is selected from the group consisting of O, S, and N.

In some forms of formula li, m is 0 to 5.

In some modalities of formula li, m is 1 to 5.

In some modalities of formula li, n is 0 to 7.

In some forms of formula li, n is 1 through 7.

In some embodiments of formula li, ring A is selected from the group consisting of

In some modalities of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, "Cj-3 haloalkyl is CF₃.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, R¹ is selected from the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN.

In some modalities of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, n is 0.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, at least one R¹ it is a halide.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, at least one R¹ is F.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, at least one R¹ is Cl.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, at least one R¹ is Me.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, at least one R¹ it's OH.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is OMe.

In some modalities and II, at least one R¹ is CF₃.

In some modalities and II, at least one R¹ it's CN.

In some modalities and Ii, n is 0 to 8.

In some modalities and Ii, n is 0 to 6.

In some modalities and Ii, n is 0 to 4.

In some modalities and Ii, n is 0 to 2.

In some modalities and II, R¹ is F; and n is 1.

In some modalities and II, R¹ is F; and n is 1 or 2.

In some modalities and II, R¹ is F, and n is 3 or 4.

In some modalities and II, R¹ is OH; and n is 1 or 2.

In some modalities and II, R¹ is OMe; and n is 1 or 2.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le , Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih of formula I, la, Ib you Id, le, If, Ig, Ih of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ it is -0 ^ 2 alkyl.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is -Ci.3 alkyl.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is -0 ^ 4 alkyl.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is -C ^ s alkyl.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is -C₁₆ I rent.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is -C₂.₆ I rent.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is -C₃.₆ I rent.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, at least one R¹ is -C₄._and I rent.

In some modalities, each R¹ is the same.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and Ii, R¹ es is independently selected at each occurrence from the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; and n is 1 or 2.

In some embodiments of formula I, Ib, le, le, If, Ih and Ii, ring B is phenyl.

In some embodiments of formula I, Ib, le, le, If, Ih, and Ii, ring B is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S.

In some embodiments of formula I, Ib, le, le, If, Ih and Ii, ring B is a 6-membered heteroaryl containing 1-2 nitrogen atoms.

In some modalities of formula la, at least one R^2d, R^2e, R^2f, or R²⁹ is -CH₂Oh

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R^{2 C} is -CH₂Oh

In some forms of Id formula, at least one R^2dd or R^2eeis -CH₂Oh

In some forms of formula I, Ib, le, le, If, ig, Ih and Ii, at least one R² is -CH₂Oh

In some modalities of formula la, at least one R^2d, R^2e, R^2f, or R²⁹ is -CH2N (R^3b)2.

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R^{2 C} is -CH2N (R^3b)2.

In some forms of Id formula, at least one R^2dd or R^2eeis -CH2N (R^3b)2.

In some forms of formula I, Ib, le, le, If, Ig, Ih and Ii, at least one R² is -CH2N (R^3b)2.

In some modalities of formula la, at least one R^2d, R^2e, R^2f, or R²⁹ is -CH₂NH₂.

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R^{2 C} is -CH₂NH₂.

In some forms of Id formula, at least one R^2dd or R^2eeis -CH₂NH₂.

In some forms of formula I, Ib, le, le, If, Ig, Ih and Ii, at least one R² is -CH₂NH₂.

In some modalities of formula la, at least one R^2d, R^2e, R²*, or R²⁹ is -CH₂NHMe.

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R^{2 C} is -CH₂NHMe.

In some forms of Id formula, at least one R^2dd or R^2eeis -CH₂NHMe.

In some forms of formula I, Ib, le, le, If, Ig, Ih and Ii, at least one R² is -CH₂NHMe.

In some modalities of formula la, at least one R^2d, R^2e, R^2f, or R²⁹ is -CH₂NMe₂.

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R^{2 C} is -CH₂NMe₂.

In some forms of Id formula, at least one R^2dd or R^2eeis -CH₂NMe₂.

In some forms of formula I, Ib, le, le, If, Ig, Ih and Ii, at least one R² is -CH₂NMe₂.

In some modalities of formula la, at least one R^2d, R²®, R^2f, or R²⁹ is -CH₂NHEt.

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R²⁰ is -CH₂NHEt

In some forms of Id formula, at least one R^2dd or R^2eeis -CH₂NHEt

In some forms of formula I, Ib, le, le, If, Ig, Ih and Ii, at least one R² is -CH₂NHEt.

In some modalities of formula la, at least one R^2d, R^2e,

R^2f, or R²⁹ is -CH₂N (Me) (Et)

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R^{2 C} is -CH₂N (Me) (Et).

In some forms of Id formula, at least one R^2dd or R^2eeis -CH₂N (Me) (Et)

In some forms of formula I, Ib, le, le, If, Ig, Ih and Ii, at least one R² is -CH₂N (Me) (Et).

In some modalities of formula la, at least one R^2d, R^2e, R^2f, or R²⁹ is -CH₂NEt₂.

In some modalities of formula la, Id and Ig, at least one R^2nd, R^2b, or R^{2 C} is -CH₂NEt₂.

In some forms of Id formula, at least one R^2dd or R^2eeis -CH₂NEt₂.

In some forms of formula I, Ib, le, le, If, Ig, Ih and Ii, at least one R² is -CH₂NEt₂.

In some forms of formula I, Ib, le, le, If, Ih and Ii, at least one R² is independently selected at each occurrence from the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN.

In some modalities of formula I, Ib, le, le, If, Ih and Ii, m is 0.

In some forms of formula I, Ib, le, le, If, Ih and II, at least one R² it is halide.

In some forms of formula I, Ib, le, le, If, Ih and Ii, at least one R² is F.

In some forms of formula I, Ib, le, le, If, Ih and Ii, at least one R² is Cl.

In some forms of formula I, Ib, le, le, If, Ih and Ii, at least one R² is Me.

In some forms of formula I, Ib, le, le, If, Ih and II, at least one R² it's OH.

In some forms of formula I, Ib, le, le, If, Ih and Ii, at least one R² is OMe.

In some forms of formula I, Ib, le, le, If, Ih and Ii, at least one R² is CF₃.

In some forms of formula I, Ib, c, le,

Ih and Ii, at least an R² it's CN.

In some forms of formula I,

Ib, le, le, If, Ih and II, m is a 4.

In some modalities of formula I, Ib, le, le, If, Ih and Ii, m is a 2.

In some forms of formula I, Ib, lo, le, If, Ih and II, m is

1.

In some forms of formula I, Ib, le, le, If, Ih and Ii, m is

2.

In some forms of formula I, Ib, le, le, If, Ih and Ii, R² is F; and m is 1.

In some forms of formula I, Ib, le, le, If, Ih and Ii, R² is F; and m is 2.

In some forms of formula I, Ib, le, le, If, Ih and Ii, R² it is

I; and m is 1.

In some formula modalities

Ib, le, le, If,

Ih

R² it is

I; and m is 2.

In some formula modalities

Ib, le, le, If,

Ih

R² it is

CF₃; ym

In some formula modalities

Ib,

If,

Ih

R² it is

CF₃; and m is 2.

In some

OMe; and m is 1.

In some

OMe; and m is 2.

In some

I; and m is 2.

In some modalities of formula modalities of formula modalities of formula modalities

CF₃; and m is 2.

In some modalities

OMe; and m is 2.

In some modalities

Ib,

Ib,

Ib, le, le, le, le, le, of formula of formula of formula

Ib,

Ib,

Ib, le,

If,

If,

If,

If,

If,

If,

Ih

Ih

Ih

Ih

Ih

Ih

CN; and m is 1.

In some formula modalities

Ib, lo, le,

If,

Ih

CN; and m is 2.

In some formula modalities

Ib, le, le,

If,

Ih

F and CN; and m is 2.

In some forms of formula I, Ib, le, le, minus an R² is -C- |.₂ I rent.

In some forms of formula I, Ib, le, le,

If,

If,

R² it is

R² it is

R² it is

R²

R²

R²

R²

R²

Ih and li,

Ih and li, is is is is is at least an R² is -Ci.3 alkyl.

In some forms of formula I, Ib, le, le, lf,

Ih minus an R² is -Ci_₄ I rent.

In some forms of formula I, Ib, le, le, lf,

Ih at least an R² is -C ^ s alkyl.

In some forms of formula I, Ib, le, lf,

Ih minus an R² is -C ^ e alkyl.

In some forms of formula I, Ib, lf,

Ih at least an R² is -C₂._and I rent.

In some forms of formula I, Ib, le, lf,

Ih at least an R² is -C₃.₆ I rent.

In some forms of formula I, Ib, le, lf,

Ih at least an R² is -C₄._and I rent.

In some modalities of formula la,

Ib, le,

Go, le, lf,

Ig, Ih li, R³ is -Ci.₂ I rent.

In some modalities of formula la,

Ib,

Go, le, lf,

Ig, Ih li, R³ is -Cj.3 alkyl.

In some formula modalities

Ib,

Go, le, lf,

Ig, Ih li, R³ is -Ci.4 alkyl.

In some modalities of formula la,

Ib, le,

Go, le, lf,

Ig, Ih li, R³ is -Ci.5 alkyl.

In some modalities of formula la,

Ib,

Go, le, lf,

Ig, Ih li, R³ is -Ci._and I rent.

In some forms of formula I, the,

Ib, le,

Go, le, lf,

Ig, Ih and II, R³ and / or R^3rdeis -C₂._and I rent.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, R³ and / or R^3rd is -C₃.₆ I rent.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, R³ and / or R^3rd is -C₄.e rent.

In some forms of formula I, la, Ib, le, Id, le, If, Ig, Ih and li, R³ and / or R^3rd is -C₂.5 alkyl.

In some forms of formula I, la, Ib, le, Id, le, If,

Ig, Ih and li, R³ and / or R^3rd is -C₃.₄ I rent.

In some embodiments of formula I, Ib, le, le, If, Ih and li, ring B is a 6-membered phenyl or heteroaryl; R² is selected from the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; m is 1; and R² binds to an ortho carbon of the 6-membered ring.

In some embodiments of formula I, Ib, le, le, If, Ih and li, ring B is a phenyl; R² is selected from the group consisting of F, Cl, Me, OMe, OH, CF₃; and CN; m is 1; and R² binds to an ortho position of the phenyl ring.

In some embodiments of formula I, Ib, le, le, If, Ih and li, ring B is a pyridine; R² is selected from the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; m is 1; and R² binds to an ortho carbon of the pyridine ring.

In some forms of formula I, Ib, le, le, If, Ih and li,

<img file="MX368248B_D0098.tif" />

<img file="MX368248B_D0099.tif" />

<img file="MX368248B_D0100.tif" />

carbonite carbon of formula I, Ib, le, le, If, Ih and Ii, can bond with any unsubstituted carbon in ring B.

In some forms of formula I, Ib, le, le, If, Ih and Ii,

<img file="MX368248B_D0101.tif" />

is selected from the group consisting of:

<img file="MX368248B_D0102.tif" />

<img file="MX368248B_D0103.tif" />

<img file="MX368248B_D0104.tif" />

<img file="MX368248B_D0105.tif" />

carbonite carbon of formula I, Ib, le, le, If, Ih and Ii, can bond with any unsubstituted carbon in ring B.

In some forms of formula I, Ib, le, le, If, Ih and Ii,

<img file="MX368248B_D0106.tif" />

(R²) m is selected from the group consisting of:

F Me

YY &amp;. Y. (Y. and ..

<img file="MX368248B_D0107.tif" />

where the carbonyl carbon of formula I, Ib, le, le, If, Ih and can bond with any unsubstituted ring B carbon.

In some forms of formula I,

Ib, le, le, If, el

<img file="MX368248B_D0108.tif" />

(R²) m (F) m

<img file="MX368248B_D0109.tif" />

(NC)_m

<img file="MX368248B_D0110.tif" />

is selected from the group that

Ih and it consists of

<img file="MX368248B_D0111.tif" />

<img file="MX368248B_D0112.tif" />

(F₃C&gt;_m—H

<img file="MX368248B_D0113.tif" />

(MeO)_m

<img file="MX368248B_D0114.tif" />

(I),

<img file="MX368248B_D0115.tif" />

; and m is 1 or 2.

<img file="MX368248B_D0116.tif" />

(R²) m

<img file="MX368248B_D0117.tif" />

is selected from the group consisting

<img file="MX368248B_D0118.tif" />

S 'of

<img file="MX368248B_D0119.tif" />

In some forms of formula I, Ib, le, le, If, Ih and Ii,

<img file="MX368248B_D0120.tif" />

m is 0.

(R²) m is selected from the group

In some forms of

<img file="MX368248B_D0121.tif" />

(R²) m^N (R ') m consisting of

<img file="MX368248B_D0122.tif" />

; and formula I, Ib, le, le, If,

Ih and Ii, is selected from the group consisting of ^(r2)™ and ^{(R2, m} ; and m is 0 to 2.

In some forms of formula I, Ib, le, le, If,

<img file="MX368248B_D0123.tif" />

(R²) m is selected from the group consisting

<img file="MX368248B_D0124.tif" />

; and m is 0.

In

In

In

In

In

In

In

In (R²)_m from

<img file="MX368248B_D0125.tif" />

some formula modalities some some some some some some some la and Id,

R^2nd is to Cl.

modalities of formula modalities of formula modalities of formula modalities of formula modalities of formula modalities of formula la, la, la,

Go

Go

Go

Go

Go

Id lg, R^2nd lg, R^2nd lg, R^2nd lg, R^2nd lg, R^2nd lg, R^2nd is is is is is is

I.

CF₃.

CN.

I.

CF₃.

a CN.

modalities of formula la, Id and lg, R^2nd is a -Ci_₂ I rent.

In some modalities of formula la,

Id ig, R^2nd is a

-Ci-3 alkyl.

In some modalities of formula la,

Id ig, R^2nd is a

-Cl-4 alkyl.

For rent.

For rent.

For rent.

For rent.

For rent.

For rent.

For rent.

In

In

In

In

In

In some some some some some some some modalities modalities modalities modalities modalities modalities of of of of of of formula formula formula formula formula formula formula some modalities of formula some some some some some la, la, la, la, la,

Go

Go

Go

Go

Go

Go

Id modalities modalities modalities of formula formula formula formula formula modalities

Ig, R^2nd

Ig, R^2nd

Ig, R^2nd ig, R^2nd

Ig, R^2nd

Ig, R^2nd ig, R^2nd is a

-C1-5 is is is is is is and Ig, R^2b is a la, Id and Ig, R^2b is the and Ig, R^2b it's a la, R^2b it's a Me.

Id and Ig, R^2b is a

Id and Ig, R^2b is a a a a a a “0-1-6 —C₂-6 ~ C₃-6 - C4-6 —C₂-5 —C3.4 halide.

an F.

Cl.

Oh

OMe.

In some

In some

In some

In some

In some

In some

In some modalities modalities modalities modalities modalities modalities of formula of formula of formula of formula of formula of formula of formula of formula la, Id and Ig, R la, Id and Ig, R la, R^2b it's a la, R^2b it's a la, R^2b it's a la, R^2b it's a la, R^2b is a is a CF₃. ^b it's a CN. -0, .2 alkyl. -C ,.₃ I rent. -C, .4 alkyl. -C ,.₅ I rent. -Cve rent.

In some formula modalities

Go

Ig, R^2b it is a —C2-6 alkyl.

In some modalities of formula la,

Go

Ig, R^2b it is a —C3.6 alkyl.

In some modalities of formula la,

Go

Ig, R^2b it is a —C4-6 alkyl.

In some modalities of formula la,

Go

Ig, R^2b It is a "C2-5 alkyl.

In some modalities of formula la,

Go

Ig, R^2b it is a ~ C3.4 alkyl.

In some modalities of formula la and Ig, at least one R^{2 C} it is halide.

In some modalities of formula la and Ig, at least one R^{2 C} is F.

In some modalities of formula la and Ig, at least one R^{2 C} is CL

In some modalities of formula la and Ig, at least one R^{2 C} it is

I.

In some modalities of formula la and Ig, at least one R^{2 C} it's OH.

In some modalities of formula la and Ig, at least one R^{2 C} is OMe.

In some modalities of formula la and Ig, at least one R^{2 C} is CF₃.

In some modalities of formula la and Ig, at least one R^{2 C} it's CN.

1.

2.

1.

2.

In

In

In

In

In

In

In

In

In some some some formula modalities formula modalities formula modalities some formula modalities some some some some some the other R^{2 C} it is

In some the other R^{2 C} it is

In some the modalities of formula modalities of formula modalities of modalities of modalities of

I.

cf modalities₃.

speak formula formula formula formula formula ig.

ig.

ig.

ig.

R^{2 C}

R^{2 C} r^{2 C}

R^{2 C} is is is is to F.

Fy

I

Me and Ig, R^{2 C} is CF₃ la and Ig, R^{2 C} is CF₃ la la la la la is 2.

is is

Ig, R^{2 C} is OMe

Ig, R^{2 C} is OMe

Ig, m

Ig, m

Ig. m is is is a a is is r2_C r2C _R2_C is is is

F and the other R^{2 C} is OMe.

In some modalities of formula la and Ig, R^{2 C} is CN and m is 1.

In some modalities of formula la and Ig, R^{2 C} is CN and m is 2.

In some modalities of formula la and Ig, m is 2 and an R^{2 C} is F and the other R^{2 C} it's CN.

In some modalities of formula la and Ig, at least one R^{2 C} is Ci-2 alkyl.

In some modalities of formula la and Ig, at least one R^{2 C} it is ^-Ci-3 alkyl.

In some modalities of formula la and Ig, at least one R^{2 C} is -Ci-4 alkyl.

In some modalities of formula la and Ig, at least one R^{2 C} is -Ci-₅ I rent.

In some modalities of formula la and Ig, at least one R^{2 C} is -Cve alkyl.

In some modalities of formula la and Ig, at least one R^{2 C} is -C₂-e rent.

In some modalities of formula la and Ig, at least one R^{2 C} is -C₃._and I rent.

In some modalities of formula la and Ig, at least one R^{2 C} is -C₄._and I rent.

In some modalities of formula la and Ig, at least one R^{2 C} is -C₂.5 alkyl.

In some modalities of formula la and Ig, at least one R^{2 C} it is

-C3.4 alkyl.

In some modalities of formula la and lg, at least one R^2d it is halide.

In some modalities of formula la and lg, at least one R^2d is F.

In some modalities of formula la and lg, at least one R^2d is Cl.

In some modalities of formula la and lg, at least one R^2d is Me.

In some modalities of formula la and lg, at least one R^2d it's OH.

In some modalities of formula la and lg, at least one R^2d is OMe.

In some modalities of formula la and lg, at least one R^2d is CF₃.

In some modalities of formula la and lg, at least one R^2d it's CN.

In some modalities of formula la and lg, s is 1 and R^2d is F.

In some modalities of formula la and lg, s is 2 and both R^2dThey are f.

In some modalities of formula la and lg, s is 1 and R^2d is Me.

In some modalities of formula la and lg, s is 2 and both R^2dare Me.

In some modalities of formula la and lg, s is 1 and R^2d is CF₃.

In some modalities of formula la and lg, s is 2 and both R^2dare CF₃.

In some modalities of formula la and Ig, s is 1 and R^2d is OMe.

In some modalities of formula la and Ig, s is 2 and both R^2dthey are OMe.

In some modalities of formula la and Ig, s is 2 and an R^2d is F and the other R^2d is Me.

In some modalities of formula la and Ig, s is 2 and an R^2d is F and the other R^2d is CF₃.

In some modalities of formula la and Ig, s is 2 and an R^2d is F and the other R^2d is OMe.

In some modalities of formula la and Ig, s is 1 and R^2d it's CN.

In some modalities of formula la and Ig, s is 2 and both R^2dthey are CN.

In some modalities of formula la and Ig, s is 2 and an R^2d is F and the other R^2d it's CN.

In some modalities of formula la and Ig, at least one R^2d is -C₁₂ I rent.

In some modalities of formula la and Ig, at least one R^2d is -Ci_3 alkyl.

In some modalities of formula la and Ig, at least one R^2d is -Ct.4 alkyl.

In some modalities of formula la and Ig, at least one R^2d is -Ci-₅ I rent.

In some modalities of formula la and Ig, at least one R^2d is -Cv_and I rent.

In some modalities of formula la and Ig, at least one R^2d is -C₂-e rent.

In some modalities of formula la and Ig, at least one R^2d is -C₃.₆ I rent.

In some modalities of formula la and Ig, at least one R^2d it is

-C4-6 alkyl.

In some modalities of formula la and Ig, at least one R^2d it is

-C₂-5 alkyl.

In some modalities of formula la and Ig, at least one R^2d it is

-C3.4 alkyl.

Some embodiments of the present disclosure include compounds of formula (II):

<img file="MX368248B_D0126.tif" />

or salts, dermatologically acceptable salts, or drugs thereof.

In some embodiments of formula II, ring C is a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some embodiments of formula II, ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some forms of formula II, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of H, -Ci_₆ unsubstituted alkyl, -0, .3 haloalkyl, halide, -OR⁶ and CN.

In some forms of formula II, each R⁴ is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of -Ci_₆ unsubstituted alkyl, -Ci_3 haloalkyl, halide, -OR⁶ and CN.

In some forms of formula II, each R⁵ is a substituent attached to ring D and is independently selected at each occurrence from the group consisting of H, -Ci.6 unsubstituted alkyl, -CH2OH, -CH2N (R^6b) 2, -C- |.₃ haloalkyl, halide, -OR⁶ and CN.

In some forms of formula II, each R⁵ is a substituent attached to ring D and is independently selected at each occurrence from the group consisting of -CV6 unsubstituted alkyl, -CH2OH, -CH2N (R^6b) 2, -C- |.₃ haloalkyl, halide, -OR⁶ and CN.

In some forms of formula II, each R⁶ it is independently selected from the group consisting of H, -Ci._and unsubstituted alkyl and -Ci.3 haloalkyl.

In some forms of formula II, each R^6b is independently selected from the group consisting of H and -Ci_₃ unsubstituted alkyl.

In some Formula II modalities, each q is 0 to 4.

In some modalities of formula II, each q is 1 to 4.

In some Formula II modalities, each p is 0 to 5.

In some Formula II modalities, each p is 1 to 5.

In some embodiments of formula II, ring C is a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.

In some forms of formula II

<img file="MX368248B_D0127.tif" />

<img file="MX368248B_D0128.tif" />

of the group consisting of

<img file="MX368248B_D0129.tif" />

^XN ' ^XN

In

In

<img file="MX368248B_D0130.tif" />

<img file="MX368248B_D0131.tif" />

; and p is 0 to 2.

some formula modalities some formula modalities

II, p is 0.

<img file="MX368248B_D0132.tif" />

is (R⁴) P

<img file="MX368248B_D0133.tif" />

In some embodiments of formula II, ring C is a 6-membered heteroaryl ring containing 1-2 nitrogens.

In some embodiments of formula II,

<img file="MX368248B_D0134.tif" />

Oh £ h ζ ^ Η ¡£ h of the group consisting of ^(R'p, ^{(R) p} , ^{(R4) p} Y ^(R,p; and p is a 2.

In some forms of formula II,

<img file="MX368248B_D0135.tif" />

(R *) P is

<img file="MX368248B_D0136.tif" />

In some forms of formula II, each R⁴ is independently selected from the group consisting of F, Cl, Me, OMe, OH,

CF₃ and CN.

In some embodiments of formula II, ring C is selected from the group consisting of:

<img file="MX368248B_D0137.tif" />

In some embodiments of formula II, ring D is a 6-membered phenyl or heteroaryl; R⁵ is selected from the group consisting of F, Cl, Me, OMe, OH, CF₃ and CN; q is 1; and R⁵ binds to an ortho carbon of the 6-membered ring.

In some embodiments of formula II, ring D is a phenyl, R⁵ is selected from the group consisting of F, Cl, Me, OMe, OH, CF₃and CN; q is 1; and R⁵ binds to an ortho position of the phenyl ring.

In some embodiments of formula II, ring D is a pyridine, R^s is selected from the group consisting of F, Cl, Me, OMe,

OH CF₃ and CN; q is 1; and R⁵ binds to an ortho carbon of the pyridine ring.

In some forms of formula II,

<img file="MX368248B_D0138.tif" />

is selected from the group consisting of:

<img file="MX368248B_D0139.tif" />

<img file="MX368248B_D0140.tif" />

<img file="MX368248B_D0141.tif" />

<img file="MX368248B_D0142.tif" />

h; wherein the carbonyl carbon of formula II can bond with any unsubstituted carbon in ring D; and q is o 2.

In some forms of formula II, q is 0.

In some forms of formula II,

<img file="MX368248B_D0143.tif" />

is selected from the group consisting of:

<img file="MX368248B_D0144.tif" />

<img file="MX368248B_D0145.tif" />

Carbonyl carbon of formula II can bond with any unsubstituted carbon on ring D.

In some forms of formula II,

<img file="MX368248B_D0146.tif" />

is selected from the group consisting of:

<img file="MX368248B_D0147.tif" />

where the carbonyl carbon of formula II can bond with any unsubstituted carbon in ring D.

Some embodiments of formula II include compounds of formula (Ha):

<img file="MX368248B_D0148.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

<img file="MX368248B_D0149.tif" />

In some forms of formula lia, ring C is

In some embodiments of formula lia, ring D is selected from the group consisting of

<img file="MX368248B_D0150.tif" />

<img file="MX368248B_D0151.tif" />

Carbon atom in the ring binds to carbonyl carbon.

In some modalities of formula Ha, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of H, -Ci_₆ unsubstituted alkyl, -Ci-₃ haloalkyl, halide, -OR⁶ and CN.

In some modalities of formula Ha, each R⁴ is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of -Ci__s alkyl, -C_b3haloalkyl, halide, -OR⁶ and CN.

In some forms of formula Ha, R^5th is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl, CH₂OH, -CH₂N (R^6b) 2, -C1.3 haloalkyl, halide, -OR^6th and CN; j is 1 to 5.

In some forms of formula Ha, R^5b is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -Ci.e unsubstituted alkyl, CH2OH, -CH2N (R^6b)2 C_V3 haloalkyl, F, I, -OR^6th and CN; k is 1 to 4.

In some forms of formula lia, R^Sc is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -Ci, and unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -Ci-₃ haloalkyl, halide, -OR⁶ and CN; x is 1 to 3.

In some forms of formula Ha, R^Sc is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl, CH₂OH, -CH₂N (R^6b)₂, "Ci-3 haloalkyl, halide, -OR⁶ and CN; x is 0 to 3.

In some modalities of formula Ha, x is 0.

In some forms of formula Ha, R^{5 d} is a ring-linked substituent and are independently selected at each occurrence from the group consisting of -Ci_e unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR⁶ and CN; z is 1 or 2.

In some forms of formula Ha, R^5e is a ring-attached substituent and are independently selected at each occurrence from the group consisting of H, -Cve unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR⁶ and CN; s is 1 to 3.

In some forms of formula Ha, R^5e is a ring-linked substituent and are independently selected at each occurrence from the group consisting of -C-.e unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -Cva haloalkyl, halide, -OR⁶ and CN; s is 0 to 3.

In some modalities of formula Ha, each R⁶ is independently selected from the group consisting of H, -C ^ e unsubstituted alkyl, and -Ci.₃ haloalkyl.

In some modalities of formula lia, each R^6th is independently selected from the group consisting of H, -C₂._and unsubstituted alkyl and -Cvs haloalkyl.

In some modalities of formula lia, each R^6b it is independently selected from the group consisting of H and -C1.3 unsubstituted alkyl.

In some formula modalities

Ha, every

A is independently N or C.

In some modalities of formula Ha, at least two A's must be N.

In some modalities of formula independently N or C.

lia, each one is

In some forms of formula Ha, at least

N and at least one J must be C.

In some forms of formula lia, independently N or C.

In being C.

In

In

In

In a J every U must be is some modalities of formula Ha, at least one U must some some some modalities of formula modalities of formula modalities of formula

He has,

He has,

He has,

Q is O or N.

some modalities of formula select from the group consisting of (R *), (R⁵⁰) is 0 is 1 to 4.

to 4.

ring D is

He has,

<img file="MX368248B_D0152.tif" />

(R^5b) k

<img file="MX368248B_D0153.tif" />

(R^M) z

<img file="MX368248B_D0154.tif" />

(R⁵®), (R *).

(R *), (R *),

<img file="MX368248B_D0155.tif" />

<img file="MX368248B_D0156.tif" />

<img file="MX368248B_D0157.tif" />

N

<img file="MX368248B_D0158.tif" />

(R⁸®),

<img file="MX368248B_D0159.tif" />

(R⁸®)^

N

<img file="MX368248B_D0160.tif" />

(R⁸®),

<img file="MX368248B_D0161.tif" />

<img file="MX368248B_D0162.tif" />

<img file="MX368248B_D0163.tif" />

<img file="MX368248B_D0164.tif" />

<img file="MX368248B_D0165.tif" />

where a carbon atom in the ring is attached to the carbonyl carbon.

In some embodiments of formula Ha, ring D is selected from the group consisting of:

<img file="MX368248B_D0166.tif" />

<img file="MX368248B_D0167.tif" />

NC

<img file="MX368248B_D0168.tif" />

<img file="MX368248B_D0169.tif" />

Some formula modalities

II include compounds of formula (llb):

<img file="MX368248B_D0170.tif" />

(R⁶)_what llb or salts, dermatologically acceptable salts, or prodrugs thereof.

In some embodiments of formula llb, ring C is A

In some embodiments of formula llb, ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein one carbon atom in the ring is attached to the carbonyl carbon.

In some forms of formula llb, each R⁴ is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of Η, unsubstituted alkyl, -0 ^ 3 haloalkyl, halide, -OR^6th and CN.

In some forms of formula llb, each R⁴ is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of -C ^ unsubstituted alkyl, -Ci-₃ haloalkyl, halide, -OR^6th and CN.

In some forms of formula llb, each R^s is a substituent attached to ring D and is independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, -CH2OH, -CH2N (R^eb) 2, -Ο_Ί_₃ haloalkyl, halide, -OR⁶ and CN.

In some forms of formula llb, each R⁵ is a substituent attached to ring D and is independently selected at each occurrence from the group consisting of -Ο, .β unsubstituted alkyl, -CH2OH, -CH2N (R^6b) 2, -C ^ s haloalkyl, halide, -OR® and

CN.

In some forms of formula llb, each R⁶ is independently selected from the group consisting of H, -C ,.₈ unsubstituted alkyl and -C ^ to haloalkyl.

In some forms of formula llb, each R^ea is independently selected from the group consisting of -C ^ e unsubstituted alkyl and -C · ^ haloalkyl.

In some forms of formula llb, each R^eb it is independently selected from the group consisting of H and -C1.3 unsubstituted alkyl.

In some forms of formula llb, each

A is independently

No.

In some modalities of formula llb, at least two A's must be N.

In some formula modalities

Hb, is

3.

In some formula modalities

Hb, is

3.

In some formula modalities

Hb, is

5.

In some formula modalities

Hb, is

5.

C se

In some formula modalities

Hb, the ring

<img file="MX368248B_D0171.tif" />

In some embodiments of formula II and llb, ring D is phenyl.

In some forms of formula II and llb,

<img file="MX368248B_D0172.tif" />

select from the group consisting of

<img file="MX368248B_D0173.tif" />

<img file="MX368248B_D0174.tif" />

<img file="MX368248B_D0175.tif" />

<img file="MX368248B_D0176.tif" />

(MeO)_what—N—

<img file="MX368248B_D0177.tif" />

<img file="MX368248B_D0178.tif" />

In some forms of formula II and llb,

<img file="MX368248B_D0179.tif" />

<img file="MX368248B_D0180.tif" />

select from the group consisting of

<img file="MX368248B_D0181.tif" />

In some embodiments of formula II and llb, ring D is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S.

In some forms of formula II

<img file="MX368248B_D0182.tif" />

group consisting of select from

<img file="MX368248B_D0183.tif" />

<img file="MX368248B_D0184.tif" />

<img file="MX368248B_D0185.tif" />

<img file="MX368248B_D0186.tif" />

In some forms of formula II and Ilb,

<img file="MX368248B_D0187.tif" />

is selected from the group consisting of

<img file="MX368248B_D0188.tif" />

In some embodiments of formula II and Ilb, ring D is a 6-membered heteroaryl containing 1-2 nitrogen atoms.

In some forms of formula II and Ilb,

<img file="MX368248B_D0189.tif" />

select from the group consisting of (R ') q; and q is 0 to 2.

In some forms of se

<img file="MX368248B_D0190.tif" />

select from the group consisting of

<img file="MX368248B_D0191.tif" />

<img file="MX368248B_D0192.tif" />

<img file="MX368248B_D0193.tif" />

In some forms of formula II and Ilb, at least one R⁵ it is

-CH₂Oh

In some forms of formula llb, at least one

R⁵ it is

-CH₂N (R^3b)₂.

In some formula modalities

Hb, at least one

R⁵ it is

-CH₂NH₂.

In some

-CH₂NHMe.

In some

-CH₂NMe₂.

In some

-CH₂NHEt

In some

-CH₂N (Me) (Et)

In some

-CH₂NEt₂.

modalities modalities modalities modalities modalities formula formula formula formula formula

II

In some forms of formula llb,

Hb,

Hb,

Hb,

Hb, at least minus minus minus minus one

R⁵ is a

R⁵ it's a one a

R⁵ it is

R⁵ it is

R⁵ it is

II and llb, each R^s is independently selected from the group consisting of F, Cl, Me,

OMe, OH, CF₃ and CN.

In

In

In

In

In

In

In some some some some some some some formula modalities formula modalities formula modalities formula modalities formula modalities formula modalities formula modalities

II some modalities of formula llb, R⁵ llb,

Hb,

Hb,

Hb, llb, llb,

Hb is a halide.

R⁵

R⁵

R⁵

R^s

R⁵

R⁵

R⁵ is is is is is is is

Cl.

I.

Oh

OMe.

CF₃.

CN.

In some forms of formula II and llb, q is 1-4.

In some forms of formula II and llb, q is 1-2.

In some forms of formula II and llb, q is 0.

In some forms of formula II and llb, q is 1.

In some forms of formula II and llb, q is 2.

In some forms of formula II and llb,

In some forms of formula II and llb,

In some forms of formula II and llb,

In some forms of formula II and llb,

R⁵ is F, and q is 1.

R⁵ is F; and q is 2.

R⁵ is Me; and q is 1.

R⁵ is Me; and q is 2.

In some forms of formula II and llb, R⁵ is CF₃; and what is

1.

In some forms of formula II and llb, R⁵ is CF₃; and what is

2.

In some forms of formula II and llb, R^s is OMe; and what is

1.

In some forms of formula II and llb, R⁵ is OMe; and what is

2.

In some forms of formula II and llb, R⁵ is F and Me; and q is 2.

In some forms of formula II and llb, R⁵ is F and CF₃; and q is 2.

In some forms of formula II and llb, R⁵ is F and OMe; and q is 2.

In some forms of formula II and llb, R^s is CN; and q is 1.

In some forms of formula II and llb, R⁵ is CN; and q is 2.

In some forms of formula II and llb, R⁵ is F and CN; and q is 2.

In some forms of formula II and llb, at least one R⁵ is -0, .2 alkyl.

In some forms of formula II and llb, at least one R⁵ is ~ Ci-3 alkyl.

In some forms of formula II and llb, at least one R^s is -C ,.₄ I rent.

In some forms of formula II and llb, at least one R⁵ is -Ci-₅ I rent.

In some forms of formula II and llb, at least one R⁵ is -C ,.₆ I rent.

In some forms of formula II and llb, at least one R⁵ is -C₂-6 alkyl.

In some forms of formula II and llb, at least one R^s is -C₃.₈ I rent.

In some forms of formula II and llb, at least one R^s is -C₄._and I rent.

In some forms of formula II and llb, at least one R^s is -C₂-5 alkyl.

In some forms of formula II and llb, at least one R⁵ is -C₃.₅ I rent.

Some forms of formula II include compounds of formula (He):

(R⁴)_p

<img file="MX368248B_D0194.tif" />

Lie or salts, dermatologically acceptable salts, or prodrugs thereof.

In some modalities of the lie formula, ring C is S

In some embodiments of formula He, ring D is selected from the group consisting of where a carbon atom in the ring is attached to the carbonyl carbon.

In some lie formula modalities, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of H, -Ci_₆ unsubstituted alkyl, -0 -,. 3 haloalkyl, halide, -OR^S and CN.

In some forms of formula He, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of -Ci.₆ unsubstituted alkyl, -C_V3 haloalkyl, halide, -OR⁶ and CN.

In some forms of the formula lie, R^5th is a substituent attached to the para position of phenyl and is selected from the group consisting of -C₂.₆ unsubstituted alkyl, -CH₂OH, -CH₂N (R^6b)₂, -C₂.₃haloalkyl, iodide, -OR^ea and CN.

In some forms of formula He, R^5b is a substituent attached to the phenyl meta position and is selected from the group consisting of -Ci.g unsubstituted alkyl, -CH2OH, -CH2N (R^6b)2 C₂.₃haloalkyl, halide, -OR^ea and CN.

In some forms of the formula lie, R^5c is a substituent attached to the ortho position of phenyl and is selected from the group consisting of -Ci_6 unsubstituted alkyl, -CH2OH, -CH2N (R^eb) 2, -Cvs haloalkyl, F, Br, I, -OR^day and CN.

In some forms of formula He, R^{5 d} is a phenyl-linked substituent and is independently selected at each occurrence from the group consisting of unsubstituted -Ci_e alkyl, CH2OH, -CH2N (R^eb) 2, -Ci-3 haloalkyl, halide, -OR^ea and CN; z is 2 to 5.

In some forms of the formula lie, R^5e is a ring attached substituent and is selected from the group consisting of -C2.5 unsubstituted alkyl, -CH2OH, -CH2N (R^6b) 2, -Ci.₃ haloalkyl, F, I, -OR⁶ and CN; s is 1.

In some forms of formula He, R^5f is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, CH2OH, -CH2N (R^eb) 2, -Ci.₃ haloalkyl, F, Br, I, -OR® and CN; t is 1 or 2.

In some forms of formula He, R^5f is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl, CH₂OH, -CH₂N (R^6b)₂, -Ci_₃ haloalkyl, F, Br, I, -OR⁶ and CN; t is 0 to 2.

In some lie formula modalities, R®⁹ is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C-ι.β unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -Cha haloalkyl, halide, -OR⁶ and CN; u is 1 to 3.

In some forms of formula He, R^5h is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -Ci-3 haloalkyl, halide, -OR⁶ and CN; v is 1 or 2.

In some forms of formula He, R^5h is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -Ci.e unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -Cvs haloalkyl, halide, -OR⁶ and CN; v is 0 to 2.

In some forms of the formula lie, R⁵'is a substituent attached to the ring and is independently selected at each occurrence from the group consisting of Η, H, -Ci and unsubstituted alkyl, -CH2OH, -CH2N (R^6b) 2, -C-1.3 haloalkyl, halide, -OR⁶ and CN; w is 1 to 4.

In some forms of the formula lie, R⁵'is a ring-attached substituent and is independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR⁶ and CN; w is 0 to 4.

In some forms of formula He, each R⁶ is independently selected from the group consisting of H, -Ci_₆ unsubstituted alkyl and -0 ^ 3 haloalkyl.

In some forms of formula He, each R^6th is independently selected from the group consisting of -C₂._and unsubstituted alkyl and -Ci.₃ haloalkyl.

In some forms of formula He, each R^eb is independently selected from the group consisting of H and C ^ to unsubstituted alkyl.

In some embodiments of formula He, each U is independently N or C.

In some modalities of the lie formula, at least one U must be C.

In some modalities of the lie formula, Q is S or O.

In some modalities of the lie formula, at least one U must be N and at least one U must be C.

In some modalities of formula He, p is 0 to 3.

In some modalities of the lie formula, p is 1 to 3.

In some lie formula modalities, the D ring is

<img file="MX368248B_D0195.tif" />

R *^b

<img file="MX368248B_D0196.tif" />

select from the group consisting of

<img file="MX368248B_D0197.tif" />

<img file="MX368248B_D0198.tif" />

(R^to) w

<img file="MX368248B_D0199.tif" />

(R^H) w

<img file="MX368248B_D0200.tif" />

where a carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of the formula He, t is 0.

In some modalities of the formula He, v is 0.

In some modalities of the lie formula, w is 0.

In some forms of formula He, R^5th, R^Sb, or R^Sc is a

CN.

In some formula modalities

I have

R^5b or R^5c it is a halide.

In some formula modalities

I have

R^5b or R^Sc is a

In some formula modalities

I have

R^5b is a Cl.

In some forms of lie formula,

R^5b or R^5c is a

I.

In some formula modalities

I have

R^5c it's a CF₃.

In some formula modalities

I have _R5b

R^5c is a

-C1-2 alkyl.

In some formula modalities

I have

RSb r5_C is a

-Ci-3 alkyl.

In some forms of lie formula, _R5b

CSR is a

-C1-4 alkyl.

In some formula modalities

I have _R5b r^5c is a

-Ci-5 alkyl.

In some forms of formula He, R^5b or R^SW is a

-Ci.e alkyl.

In some formula modalities

R^5th, R^5b, or

R^5c is a

C₂-6 alkyl.

In some

C₃.₆ I rent.

In some

C₄_e rent.

In some

C₂.5 alkyl.

In some

C3-5

R^5h,

R^5h, I rent.

In some modalities modalities modalities modalities modalities or R⁵'is halide.

In some or R⁵ⁱ is F.

In some

R^5h, or R⁵ⁱ is Cl.

In some

R^5h, or R⁵ⁱ is Me.

In some

R^5h, or R⁵ⁱ it's OH.

In some of of of of of formula formula formula formula formula

I have

I have

I have

I have

I have modalities modalities modalities modalities modalities

R^5h, or R⁵ⁱ is OMe.

In some forms of of of of of formula formula formula formula formula formula formula

I have

I have

I have

I have

I have

R^5th, R^5b, or

R^5th, R^5b, or

R^5th, R^5b, or

R^5th, R^5b, at least to at

R^5c

R^5c_r5c

R⁵⁰ a is is is is a a an R^5t, R^5g, minus minus minus minus minus a one a one one

R^5f, R⁵⁹,

R^5f, R⁵⁹,

R^5f, R⁵⁹,

R^5f, R⁵⁹,

R^5f, R^Sg,

R^5f, R^Sg,

100

R^Sh, or R⁵ⁱ is CF₃.

In some forms of formula He, at least one R^5f, R⁵⁹, R^5h, or R^Yes it's CN.

In some modalities of the formula He, t is 1.

In some modalities of the formula He, t is 2.

In some modalities of formula He, t is 1 and R^Sf is F.

In some modalities of the lie formula, t is 2 and both R^5f They are f.

In some modalities of formula He, t is 1 and R^5f is Me.

In some modalities of formula He, t is 2 and both R^5f are Me.

In some modalities of formula He, t is 1 and R⁵'is CF₃.

In some modalities of formula He, t is 2 and both R^5f are CF₃.

In some modalities of formula He, t is 1 and R^5f is OMe.

In some modalities of the lie formula, t is 2 and both R^Sf they are OMe.

In some modalities of formula He, t is 2 and an R^5f is F and the other R^5f is OMe.

In some modalities of the lie formula, t is 2 and an R^5f is F and the other R^Sf is CF₃.

In some modalities of the lie formula, t is 2 and an R^sf is F and the other R^5f is OMe.

In some modalities of formula He, t is 1 and R^5f it's CN.

In some modalities of the lie formula, t is 2 and both R^5f are

101

CN.

In some modalities of formula He, t is 2 and an R^5f is F and the other R^5f it's CN.

In some lie formula modalities, at least one R^sf, R⁵⁹, 5 R^5h, or R⁵¹ is -Ci-₂ I rent.

In some forms of formula lio, at least one R^Sf, R^5g, R^5h, or R⁵'is -C- |.₃ I rent.

In some lie formula modalities, at least one R^5f, R^5g, R^Sh, or R⁵¹ is -Ci-₄ I rent.

In some forms of formula He, at least one R^5f, R^5g,

R^5h, or R⁵¹ is -Cve alkyl.

In some forms of formula He, at least one R^5f, R^5g, R^5h, or R⁵'is -Ci.e alkyl.

In some forms of formula He, at least one R^5f, R^5g, 15 R^5h, or R⁵'is -C₂.e rent.

In some forms of formula He, at least one R^5f, R^5g, R^5h, or R⁵ⁱ is -C₃._and I rent.

In some forms of formula He, at least one R^5f, R^5g, R^5h, or R⁵'is -C₄.₆ I rent.

In some lie formula modalities, at least one R^5f, R^5g,

R^5h, or R⁵'is -C₂.₅ I rent.

In some lie formula modalities, at least one R^5f, R^Sg, R^5h, or R⁵'is -C₃.₅ I rent.

In some forms of the lie formula, u is 1.

In some modalities of the formula He, u is 2.

102

In some modalities of formula He, u is 1 and R⁵⁹ is F.

In some modalities of the formula lie, u is 2 and both R⁵⁹ are

F.

In some modalities of formula He, u is 1 and R^Sg is Me.

In some modalities of the formula lie, u is 2 and both R⁵⁹ are

I.

In some modalities of formula He, u is 1 and R⁵⁹ is CF₃.

In some modalities of the formula lie, u is 2 and both R⁵⁹ are

CF₃.

In some modalities of formula He, u is 1 and R⁵⁹ is OMe.

In some modalities of formula He, u is 2 and both R⁵⁹ are

OMe.

In some modalities of formula He, u is 2 and an R⁵⁹ is F and the other R⁵⁹ is OMe.

In some modalities of formula He, u is 2 and an R⁵⁹ is F and the other R⁵⁹ is CF₃.

In some modalities of the lie formula, u is 2 and an R⁵⁹ is F and the other R^5fl is OMe.

In some modalities of formula He, u is 1 and R⁵⁹ it's CN.

In some modalities of formula He, u is 2 and both R^Sg they are CN.

In some modalities of formula He, u is 2 and an R^Sg is F and the other R⁵⁹ it's CN.

In some modalities of the formula He, v is 1.

In some forms of the lie formula, v is 2.

103

In some modalities of formula He, v is 1 and R^Sh is F.

In some modalities of formula He, v is 2 and both R^5h are

F.

In some modalities of formula He, v is 1 and R^5h is Me.

In some modalities of formula He, v is 2 and both R^5h are

I.

In some modalities of formula He, v is 1 and R^5h is CF₃.

In some modalities of formula He, v is 2 and both R^5h are

CF₃.

In some modalities of formula He, v is 1 and R^5h is OMe.

In some modalities of formula He, v is 2 and both R^5h are

OMe.

In some modalities of the lie formula, v is 2 and an R^5h is F and the other R^5h is OMe.

In some modalities of formula He, v is 2 and an R^5h is F and the other R^5h is CF₃.

In some modalities of formula He, v is 2 and an R^5h is F and the other R^5h is OMe.

In some modalities of formula He, v is 1 and R^5h it's CN.

In some modalities of formula He, v is 2 and both R^5h they are CN.

In some modalities of the lie formula, v is 2 and an R^5h is F and the other R^5h it's CN.

In some modalities of the formula He, w is 1.

In some modalities of the formula He, w is 2.

104

In some modalities of the lie formula, w is 1 and R⁵'is F.

In some forms of formula He, w is 2 and both R⁵ⁱ They are f.

In some modalities of the lie formula, w is 1 and R⁵'is Me.

In some modalities of the lie formula, w is 2 and both R^{S |} are

I.

In some modalities of the lie formula, w is 1 and R⁵'is CF₃.

In some modalities of the lie formula, w is 2 and both R^{S |} are

CF₃.

In some modalities of the lie formula, w is 1 and R^{S |} is OMe.

In some modalities of the lie formula, w is 2 and both R^5í they are OMe.

In some modalities of formula He, w is 2 and an R^{S |} is F and the other R⁵'is OMe.

In some modalities of the lie formula, w is 2 and an R⁵¹ is F and the other R⁵¹ is CF₃.

In some modalities of the lie formula, w is 2 and an R^Yes is F and the other R⁵'is OMe.

In some modalities of the lie formula, w is 1 and R⁵'is CN.

In some modalities of the lie formula, w is 2 and both R⁵'are CN.

In some modalities of the lie formula, w is 2 and an R^Yes is F and the other R⁵¹ it's CN.

In some lie formula modalities, at least one R^5f, R⁵⁹, R^5h, or R⁵ⁱ is -CH₂Oh

105

In some forms of R^5h, or R⁵ⁱ is -CH2N (R^3b)2.

In some forms of R^5h, or R⁵ⁱ is -CH₂NH₂.

In some forms of R^5h, or R⁵ⁱ is -CH₂NHMe.

In some forms of

R^5h, or R⁵ⁱ is -CH₂NMe₂.

In some forms of R^5h, or R⁵ⁱ is -CH₂NHEt.

In some forms of

R^5h, or R⁵ⁱ is -CH₂N (Me) (Et)

In some lie formula modalities, at least one R^5f, R⁵⁹, formula lie, at least one R^5f, R⁵⁹, formula lie, at least one R^5f, R⁵⁹, formula He, at least one R^5f, R⁵⁹, formula lie, at least one R^Sf, R⁵⁹, formula He, at least one R^5f, R⁵⁹, formula lie, at least one R^5f, R⁵⁹,

R^Sh, or R⁵ⁱ is -CH₂NEt₂.

Some forms of formula II include compounds of formula (lid):

<img file="MX368248B_D0201.tif" />

fight

<img file="MX368248B_D0202.tif" />

or salts, dermatologically acceptable salts, or prodrugs thereof.

In some modalities of the lid formula, ring C is

In some forms of lid formula, the D ring is

106 | I / J (^r5c)&gt; &lt;1A select from the group consisting of ^{(R8a) j} (^Ríb) k, (R ^ z'-i — CA ^(RSe)»^ ALA

7? / J ιζ / j ⁰ and n, where a carbon atom in the ring is attached to the carbonyl carbon.

In some forms of lid formula, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of H, -Ci__B unsubstituted alkyl, -Ci.3 haloalkyl, halide, -OR® and CN.

In some forms of lid formula, each R⁴ is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl, -C-1.3 haloalkyl, halide, -OR^and and CN.

In some forms of lid formula, R^Sa is a ring attached substituent and is selected from the group consisting of -C2.e unsubstituted alkyl, -CH2OH, -CH2N (R^6b) 2, -C ^ .a haloalkyl, halide, -OR®^toand CN; j is 1.

In some forms of lid formula, R^5b is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR^ea and CN; k is 1 to 4.

In some forms of lid formula, R^5b is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C ^ e unsubstituted alkyl,

107

CH₂OH, -CH₂N (R^6b)₂, -C1.3 haloalkyl, halide, -OR^6th and CN; k is 0 to 4.

In some forms of lid formula, R^5c is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C2.5 unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR® and CN; x is 1 to 3.

In some forms of lid formula, R^Sd is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -C ^ e unsubstituted alkyl, CH2OH, -CH2N (R^eb) 2, -C-i_₃ haloalkyl, halide, -OR⁶ and CN; z is 1 or 2.

In some forms of lid formula, R^{5 d} is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -Ci_6 unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR® and CN; z is 0 to 2.

In some forms of lid formula, R^5e is a ring-linked substituent and is independently selected at each occurrence from the group consisting of Η, H, -C ^ e unsubstituted alkyl, -CH2OH, -CH2N (R®^b) 2, Ύ_₃ haloalkyl, halide, -OR® and CN; s is 1 to 4.

In some forms of lid formula, R^{I know} is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -Cve unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -Cvs haloalkyl, halide, -OR® and CN; s is 0 to 4.

In some embodiments of the lid formula, each R® is independently selected from the group consisting of H, -Ci.₆ alkyl no

108 substituted and -Ο_ν3 haloalkyl.

In some forms of lid formula, each R^6th is independently selected from the group consisting of -C₂._and unsubstituted alkyl and -Cj.₃ haloalkyl.

In some forms of lid formula, each R^eb it is independently selected from the group consisting of H and -C1.3 unsubstituted alkyl.

<td>In some modalities</td><td>of formula</td><td>fight,</td><td>every</td><td>J</td><td>it is</td>

<td>independently N 0 C.</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2">In some forms of the lid formula,</td><td>less</td><td colspan="2">a J must</td><td>to be</td>

<td>N and at least one J must be C.</td><td></td><td></td><td></td><td></td><td></td>

<td>In some modalities</td><td>of formula</td><td>fight,</td><td>every</td><td>OR</td><td>it is</td>

independently N or C.

In some forms of lid formula, at least one U must be C.

In some modalities of the lid formula, p is 1 to 3.

In some modalities of the lid formula, p is 0 to 3.

In some forms of lid formula, the D ring is

<img file="MX368248B_D0203.tif" />

109

<img file="MX368248B_D0204.tif" />

where a carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of the lid formula, k is 0.

Some forms of formula II include compounds of formula (lie):

<img file="MX368248B_D0205.tif" />

Lie or salts, dermatologically acceptable salts, or prodrugs thereof.

In some modalities of the lie formula, ring C is

<img file="MX368248B_D0206.tif" />

where a carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of the lie formula, ring D is selected from the group consisting of

<img file="MX368248B_D0207.tif" />

<img file="MX368248B_D0208.tif" />

where a carbon atom in the ring is attached to the carbonyl carbon.

In some forms of formula He, each R⁴ is a substituent attached to ring C and is independently selected

110 in each occurrence of the group consisting of H, -Ci._and unsubstituted alkyl, -Ci_3 haloalkyl, halide, -OR^and and CN.

In some forms of formula He, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of -C ,. " unsubstituted alkyl, -Cva haloalkyl, halide, -OR^and and CN.

In some forms of formula He, R^Sa is a substituent attached to the para position of phenyl and is selected from the group consisting of H, -C ^ e unsubstituted alkyl, -CH2OH, -CH2N (R^6b)2 C_b3 haloalkyl, F, Br, I, -OR® and CN.

In some forms of formula He, R^5b is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -Ci, and unsubstituted alkyl, CH2OH, -CH2N (R®^b) 2, -C- |.₃ haloalkyl, halide, -OR® and CN; k is 1 to 4.

In some forms of formula He, R^5b is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -Ci.6 unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR® and CN; k is 0 to 4.

In some forms of formula He, R^5c is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C2.5 unsubstituted alkyl, CH2OH, -CH2N (R®^b) 2, -C1.3 haloalkyl, halide, -OR® and CN; x is 1 to 4.

In some forms of formula He, R^{5 d} it is a substituent attached to the ring and is independently selected at each occurrence from the group consisting of H, -C₂._and unsubstituted alkyl,

111

CH₂OH, -CH₂N (R^6b)₂, ^-Ci_3 haloalkyl, halide, -OR^ea and CN; z is 1 o

2.

In some forms of the formula lie, R^{5 d} is a ring-linked substituent and is independently selected at each occurrence from the group consisting of -C2.e unsubstituted alkyl, CH2OH, -CH2N (R^eb) 2, -Cvs haloalkyl, halide, -OR^6th and CN; z is 0 to 2.

In some lie formula modalities, each R^and it is independently selected from the group consisting of H, -C ^ e unsubstituted alkyl and -C ^ a haloalkyl.

In some lie formula modalities, each R^ea is independently selected from the group consisting of -Ci__and unsubstituted alkyl and -C_V3 haloalkyl.

In some forms of formula He, each R^eb is independently selected from the group consisting of H and C_V3 unsubstituted alkyl.

In some embodiments of formula He, each A is independently N or C.

In some modalities of the lie formula, at least one A must be C.

In some embodiments of formula He, each U is independently N or C.

In some modalities of the lie formula, at least one U must be N and at least one U must be C.

In some modalities of the formula He, p is 0 to 4.

112

In some modalities of the lie formula, p is 1 to 4.

In some modalities of the lie formula, ring C is selected from the group consisting of

<img file="MX368248B_D0209.tif" />

<img file="MX368248B_D0210.tif" />

<img file="MX368248B_D0211.tif" />

<img file="MX368248B_D0212.tif" />

In some modalities of formula He, select from the group consisting of

<img file="MX368248B_D0213.tif" />

ring D is

<img file="MX368248B_D0214.tif" />

<img file="MX368248B_D0215.tif" />

carbonyl carbon.

In some forms of formula He, R^Sa it's an OMe.

In some forms of formula He, R^5th it is a halide.

In some forms of formula He, R^Sa is aF.

In some forms of formula He, R^5th it's a me.

In some forms of the formula lie, R^Sa it is an OH.

In some forms of the formula lie, R^Sa is a CF

In some forms of formula He, R^Sa is a CN.

In some forms of formula He, R^5th is a -Ci_₂ I rent.

In some forms of the formula lie, R^5th is a -Ci_₃ I rent.

113

In

In

In

In

In

In

In

In

In some some some some some some some some some modalities modalities modalities modalities modalities modalities formula formula formula formula formula formula formula formula formula formula modalities

Some modalities of formula (Hf):

He, R^5th

He, R^5th

He, R^5th

I have

I have

I have

I have

He is is is a a

-Ci_₄ I rent.

-C1.5 alkyl.

-Ci_₆ I rent.

R^5th

R^5th_R5th

R^5th

R^5th is a

-C₂-6 alkyl.

it is a —C3-6 alkyl.

It's a c₄-6 alkyl.

it is a —C2-5 alkyl.

it is a —C3.5 alkyl.

lid and He, z is

0.

formula II include compounds of

<img file="MX368248B_D0216.tif" />

or dermatologically acceptable salts or prodrugs thereof.

In some embodiments of formula llf, ring C is where a carbonyl carbon atom is.

In some modalities, select from the group that

<img file="MX368248B_D0217.tif" />

in the ring is attached to the carbon of formula Hf, ring D consists of ^(R6a)J

<img file="MX368248B_D0218.tif" />

of be a

114 heteroaryl (R^Sb)_k, where a carbon atom in the ring is attached to the carbonyl carbon.

In some modalities of formula llf, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of H, -Ci._and unsubstituted alkyl, -C-i_₃ haloalkyl, halide, -OR^and and CN.

In some modalities of formula llf, each R⁴ it is a substituent attached to ring C and is independently selected at each occurrence from the group consisting of -Ci._and unsubstituted alkyl, -Ci_3 haloalkyl, halide, -OR⁶ and CN.

In some modalities of formula llf, R^Sa is a phenyl-linked substituent and is selected from the group consisting of H.-C ^ e unsubstituted alkyl, -CH2OH, -CH2N (R^eb)2 C₁₃ haloalkyl, halide, -OR^6th and CN; j is 1 to 5.

In some modalities of formula llf, R^5th is a phenyl-linked substituent and is selected from the group consisting of -C ^ e unsubstituted alkyl, -CH2OH, -CH2N (R^6b) 2, -C1.3 haloalkyl, halide, -OR^6thand CN; j is 0 to 5.

In some modalities of formula llf, R^Sb is a ring-linked substituent and is independently selected at each occurrence from the group consisting of H, -Cve unsubstituted alkyl, CH2OH, -CH2N (R^6b) 2, -Ci-₃ haloalkyl, halide, -OR⁶ and CN; k is 1 to 4.

In some modalities of formula llf, R^5b is a substituent attached to the ring and is independently selected at each occurrence from the group consisting of -Ci_₆ unsubstituted alkyl,

115

CH₂OH, -CH₂N (R^6b)₂, -Ci.3 haloalkyl, halide, -OR⁶ and CN; k is 0 to 4.

In some modalities of formula llf, each R⁶ is independently selected from the group consisting of H, -0- ,.₆ unsubstituted alkyl and -C ,.₃ haloalkyl.

In some modalities of formula llf, each R^6th is independently selected from the group consisting of -C₂.₆ unsubstituted alkyl and -C ,.₃ haloalkyl.

In some modalities of formula llf, each R^6b is independently selected from the group consisting of H and -Ci_₃ unsubstituted alkyl.

In some modalities of formula llf, each A is independently N or C.

In some modalities of formula llf, at least one A must be N and at least one A must be C.

In some modalities of the formula llf, Q is S or O.

In some modalities of the llf formula, p is 0 to 4.

In some modalities of formula llf, p is 1 to 4.

In some modalities of formula llf, ring C is

N selects from the group consisting of ° ^s , °

116

In some modalities of formula llf, ring D is

<img file="MX368248B_D0219.tif" />

ring binds carbonyl carbon.

In some modalities of the formula He and llf, k is 0.

In some forms of formula II, Ha, He, lid, He and llf, each R⁴ is independently selected from the group consisting of F, CI, Me, OMe, OH, CF₃ and CN; and p is 0 to 2.

In some forms of formula II, lia, Hb, He, lid, He and llf, -Cvs haloalkyl is -CF₃.

In some forms of formula II, lia, Hb, He, lid, He and llf, p is 0.

In some forms of formula II, lia, Hb, He, lid, He and llf, at least one R⁴ it is a halide.

117

In some forms of formula II, lia,

Hb,

I have

Hd,

I have

Hf minus an R⁴ is F.

In some forms of formula II, Ha,

Hb,

I have

Hd,

I have

Hf minus an R⁴ is Cl.

to the

In some modalities less an R⁴ is Me.

In some modalities less an R⁴ it's OH.

In some modalities to that of formula II, Ha,

Hb,

I have

Hd,

Hf, of formula II, lia, lie, Hd, He of formula

He has,

Hb,

I have

Hd, and Hf, al lie

Hf minus an R⁴ is OMe.

In some modalities less an R⁴ is CF₃.

In some modalities less an R⁴ it's CN.

In some modalities es es es es de de de

0-3.

In

0-2.

In

2.

In

1.

In formula formula formula

He has,

Hb,

I have

Hd,

I have

Hf,

He has,

He has,

Hb,

Hb,

I have

I have

Hd,

Hd,

I have lie

Hf,

Hf, some some some some

R⁴ is F; and p is 1.

In some modalities modalities modalities modalities modalities of of of of formula of formula formula formula formula formula lia,

Hb,

I have

Hd,

I have

Hf,

He has,

Hb,

I have,

I have

Hf,

He has,

Hb,

I have

Hd, lie

Hf, lia,

Hb,

I have

Hd, lie

Hf, lia,

Hb,

I have

Hd,

I have

Hf,

118

R⁴ is F; and p is 2.

In some forms of formula II, Ha, He, lid, He and llf, R⁴is OH; and p is 1.

In some forms of formula II, Ha, Hb, He, lid, He and llf, R⁴ is OMe; and p is 1-2.

In some forms of formula II, lia, Hb, He, lid, He and llf, at least one R⁴ is -Ο_Ί.₂ I rent.

In some forms of formula II, Ha, Hb, He, lid, lie and llf, at least one R⁴ is -C ^ s alkyl.

In some forms of formula II, Ha, Hb, He, lid, lie and llf, at least one R⁴ is -C1.4 alkyl.

In some forms of formula II, Ha, Hb, He, lid, lie and llf, at least one R⁴ is -C_b5 I rent.

In some forms of formula II, lia, Hb, He, lid, He and llf, at least one R⁴ is -C ^ e alkyl.

In some forms of formula II, Ha, Hb, He, lid, He and llf, at least one R⁴ is -C₂.₆ I rent.

In some forms of formula II, Ha, Hb, lie, lid, lie and llf, at least one R⁴ is -C₃._and I rent.

In some forms of formula II, lia, Hb, He, lid, He and llf, at least one R⁴ is -C₄._and I rent.

In some forms of formula II, Ha, llb, lie, lid, lie and llf, at least one R⁴ is -C₂.₅ I rent.

In some forms of formula II, Ha, Hb, He, lid, He and llf, at least one R⁴ is -C₃.₅ I rent.

119

In some forms of formula lia,

I have,

I have

Hf, at least an R^5th or R^5b is -CH₂Oh

In some formula modalities

He has,

Hd,

I have

Hf minus an R^5th or R^5b is -CH2N (R^3b)2.

In some formula modalities

He has,

Hd,

I have

Hf minus an R^5th or R^5b is -CH₂NH₂.

In some formula modalities

He has,

I have

Hd, lie

Hf, at least an R^5th or R^5b is -CH₂NHMe.

In some formula modalities

Ha, lie,

Hd, lie

Hf, at least an R^5th or R^5b is -CH₂NMe₂.

In some formula modalities

He has,

I have

Hd,

I have

Hf, at least an R^5th or R^5b is -CH₂NHEt

In some formula modalities

He has,

I have

Hd,

I have

Hf, at least an R^Sa or R^Sb is -CH₂N (Me) (Et).

In some forms of formula lia, lio,

Hd,

I have

Hf, at least an R^5th or R^5b is -CH₂NEt₂

In some modalities of formula Ha, He, lid and He, at least one R^5C or R^{5 d} is -CH₂Oh

In some forms of formula Ha, lie,

Hd and He, at least an R^5c or R^{5 d} is -CH2N (R^3b)2.

In some forms of formula Ha, lie,

Hd and He, at least an R^5C or R^{5 d} is -CH₂NH₂.

In some modalities of formula Ha, He, lid and He, at least one R^5C or R^{5 d} is -CH₂NHMe.

In some forms of formula Ha, He,

Hd and He, at least

120 a R^5c or R^{5 d} is -CH₂NMe₂.

In some modalities of an R^Sc or R^sd is -CH₂NHEt

In some modalities of an R^5c or R^{5 d} is -CH₂N (Me) (Et).

In some modalities of an R^5c or R^{5 d} is -CH₂NEt₂.

In some forms of R^{I know} is -CH₂Oh

In some forms of R^5e is -CH2N (R^3b)2.

In some forms of R^{I know} is -CH₂NH₂.

In some forms of R^{I know} is -CH₂NHMe.

In some forms of R^5e is -CH₂NMe₂.

In some forms of R^5e is -CH₂NHEt

In some forms of R^5e is -CH₂N (Me) (Et).

In some forms of

R^5e is -CH₂NEt₂.

formula Ha, He, lid and He, at least formula Ha, He, lid and He, at least formula Ha, He, lid and He, at least formula Ha, He and lid, at least one formula Ha, He and lid, at least one formula lia, He and lid, at least one formula lia, lie and lid, at least one formula Ha, He and lid, at least one formula lia, lie and lid, at least one formula Ha, He and lid, at least one formula Ha, lie and lid, at least one

In some modalities of formula II, Ha, Hb, He, lid, He and Hf,

R^and is -Ο_ν2 I rent.

121

In some forms of formula II, Ha, llb, He, lid, lie and llf, R⁶ is -C1.3 alkyl.

In some forms of formula II, Ha, Hb, lie, lid, lie and llf, R^and is -0, .4 alkyl.

In some forms of formula II, Ha, llb, He, lid, lie and llf, R⁶ is -Cn-s alkyl.

In some forms of formula II, lia, Hb, He, lid, lie and llf, R® is -0, .6 alkyl.

In some forms of formula II, lia, Hb, lie, lid, lie and llf, R⁶ is -0₂-β alkyl.

In some forms of formula II, lia, llb, He, lid, He and llf, R⁶ is -C₃.₆ I rent.

In some forms of formula II, lia, llb, He, lid, He and llf, R⁶ is -C₄.e rent.

In some forms of formula II, Ha, Hb, He, lid, He, and llf, R® is —C₂-5 alkyl.

In some forms of formula II, Ha, Hb, He, lid, He and llf, R® is -C₃.₅ I rent.

In some modalities of formula lia, lid and llf, at least one R^5th it is halide.

In some modalities of the lid formula, He and llf, at least one R^5b it is halide.

In some modalities of formula lia, lid and He, at least one R^5c it is halide.

In some forms of formula lia, He, lid and He, at least

122 a R^{5 d} it is halide.

In some modalities of formula lia and lid, at least one R^5eit is halide.

In some forms of formula Ha, lid and llf, at least one R^5th is F.

In some modalities of formula lia, lid, He and llf, at least one R^5b is F.

In some modalities of formula Ha, lid and He, at least one R⁵° is F.

In some modalities of formula Ha, He, lid and He, at least one R^{5 d} is F.

In some modalities of formula Ha, He and lid, at least one R^5e is F.

In some modalities of formula lia and lid, at least one R^Sa or R^5e is Cl.

In some modalities of the lid formula, He and llf, at least one R^5b is Cl.

In some modalities of formula lia, lid and lie, at least one R^5C is Cl.

In some modalities of formula lia, He, lid, He and llf, at least one R^{5 d} is Cl.

In some modalities of formula lia and llf, at least one R^5this Me.

In some modalities of formula lia, lid, He and llf, at least one R^5b is Me.

123

In some forms of formula lia, at least one R^5c is Me.

In some modalities of formula lia, lie and llf, at least one R^{5 d} is Me.

In some modalities of formula Ha and lid, at least one R^5eis Me.

In some forms of formula lia, at least one R^5th it's OH.

In some forms of R^5b it's OH.

In some forms of R^5c it's OH.

In some forms of it is OH.

In some forms of R^5e it's OH.

In some forms of it is OMe.

In some forms of R^5C or R^{5 d} is OMe.

In some forms of R^5e is OMe.

In some forms of

R^5th is CF₃.

formula lia, He and llf, at least one formula lia, lid and He, at least one formula lia and lid, at least one R^Sd formula Ha, He and lid, at least one formula He and llf, at least one R^5b formula lia, lid and He, at least one formula lia, He and lid, at least one formula Ha, lid and llf, at least one

In some modalities of formula lia, lid, He and llf, at least one R^5b is CF₃.

124

In some modalities of formula lia, lid and lie, at least one

R^5c is CF₃.

In some modalities of formula lia, lid and lie, at least one R^{5 d} is CF₃.

In some

R^5e is CF₃.

In some

R^5th it's CN.

In some an R^5b it's CN.

In some

R^5c it's CN.

In some an R^{5 d} it's CN.

In some

R^5e it's CN.

In some is is is is

-Ci_2 alkyl.

In some

-C_V3 I rent.

In some

-C -,. 4 alkyl.

In some ~ Ci_5 I rent.

modalities modalities modalities modalities modalities modalities modalities modalities modalities of formula Ha, formula Ha, de de de de de de de de

I have and lid, at least one lid and llf, at least one formula formula formula formula formula formula formula formula formula

He has,

He has,

He has,

He has,

He has

Lid, He and llf, at least lid

I have

I have and lie, at least one lid and lie, at least llf, llf, llf,

Hf, lid, at least one at least at least minus minus one a one _R5th

R^5th_R5th _R5th

In some forms of formula lia and

llf, at least one _R5th

125 is -C₁₆ I rent.

In some modalities of formula lia, lid, lie and llf, at least one R^5th, R^5b, R^5c, R^{5 d}, or R^5e is -C₂._and I rent.

In some modalities of formula lia, lid, He and llf, at least one R^5th, R^5b, R^5c, R^{5 d}, or R^5e is -C₃._and I rent.

In some modalities of formula lia, lid, He and llf, at least one R^5th, R^5b, R^5C, R^{5 d}, or R^5e is -C₄._and I rent.

In some modalities of formula Ha, lid, He and llf, at least one R^Sa, R^Sb, R^sc, R^{5 d}, or R⁵® is -C₂.₅ I rent.

In some modalities of formula Ha, lid, He and llf, at least one R^5th, R^5b, R^5C, R^{5 d}, or R⁵® is -C₃.₅ I rent.

In some modalities of an R^5b is -Ci.3 alkyl.

In some modalities of an R^5b is -C1.4 alkyl.

In some modalities of an R^5b is -C₁₅ I rent.

formula lia, lid, He and llf, at least formula lia, lid, He and llf, at least formula lia, lid, He and llf, at least

In some modalities of formula la, lid, He and llf, at least one R^5b is -Ci._and I rent.

In some forms of formula Ha, at least one R^Sc is -Ci_alkyl.

In some forms of formula Ha, at least one R^sc is -C_v₄ I rent.

In some forms of formula Ha, at least one R^Sc is -C ,.

₅ I rent.

126

In some forms of formula lia, at least one R^Sc is -Ci_ e alkyl.

<td></td><td>In some modalities</td><td>from</td><td>formula</td><td>He has,</td><td>lie</td><td>Y</td><td>fight,</td><td>to the</td><td>less</td><td>a</td>

<td>R^{5 d}</td><td>is -C1.3 alkyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>In some modalities</td><td>from</td><td>formula</td><td>lia,</td><td>lie</td><td>Y</td><td>Hd,</td><td>to the</td><td>less</td><td>a</td>

<td>R^{5 d}</td><td>is -C1.4 alkyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>In some modalities</td><td>from</td><td>formula</td><td>He has,</td><td>I have</td><td>Y</td><td>Hd,</td><td>to the</td><td>less</td><td>a</td>

<td>R^{5 d}</td><td>is -C₁₅ I rent.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>In some modalities</td><td>from</td><td>formula</td><td>lia,</td><td>lie</td><td>Y</td><td>fight,</td><td>to the</td><td>less</td><td>a</td>

R^{5 d} is -Cve alkyl.

<td></td><td>In some</td><td>modalities</td><td>from</td><td>formula</td><td>lia</td><td>Y</td><td>Hd,</td><td>to the</td><td>less</td><td>a</td><td>R^5e</td>

<td>is -C</td><td>V3 alkyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>In some</td><td>modalities</td><td>from</td><td>formula</td><td>lia</td><td>Y</td><td>Hd,</td><td>to the</td><td>less</td><td>a</td><td>_R5e</td>

<td>is -C</td><td>1.4 alkyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>In some</td><td>modalities</td><td>from</td><td>formula</td><td>lia</td><td>Y</td><td>Hd,</td><td>to the</td><td>less</td><td>a</td><td>R^5e</td>

<td>is -C</td><td>vs alkyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>In some</td><td>modalities</td><td>from</td><td>formula</td><td>lia</td><td>Y</td><td>Hd,</td><td>to the</td><td>less</td><td>a</td><td>R^5e</td>

is -Cve alkyl.

In some modalities of formula lia, lid, and llf, j is 1 and R^5th is F.

In some modalities of formula lia, lid and llf, j is 2 and both R^5th They are f.

In some modalities of formula lia and llf, j is 1 and R^5th is Me.

In some modalities of formula lia and llf, j is 2 and both R^5th are Me.

127

CF₃.

In some formula modalities

Ha, lid and llf, j is 1 and

R^5th it is

In some formula modalities

Ha, lid and llf, j is 2 and both

R^5th are CF₃.

In some formula modalities

Ha and llf, j is 2 and a

R^5th it is

F and the other R^5th it is

I.

In some formula modalities

Ha, lid llf, j is an R^5th is F and the other R^5th is CF₃.

In some formula modalities

Ha, lid llf, j es

R^5th it is

CN.

some

R^5th they are CN.

In some it is F and the other R^sa

In some modalities modalities is CN.

formula modalities formula

He has,

Ha, lid lid formula

He has,

Hd,

Hf, j

Hf, j

He is is both a

R^5th llf, is

R^5b is F.

In some formula modalities

He has,

Hd,

I have

Hf, it's both R^5b They are f.

In some

R^5b is Me.

In some modalities modalities both R^5b are Me.

In some modalities

R^5b is CF₃.

of of of formula formula formula

He has,

He has,

Hd,

Hd,

Ha, lid,

I have

I have lie

Hf, llf, llf, is is is

In some modalities of formula lia, lid, lie and

llf, k

is and

128 both R^5b are CF₃.

In some modalities of the formula lia, lid, He and llf, k is 2 and an R^5b is F and the other R^5b is Me.

In some modalities of formula lia, lid, lie and llf, k is 2 and an R^5b is F and the other R^5b is CF₃.

In some modalities of the formula Ha, lid, He and llf, k is 1 and R^5b it's CN.

In some modalities of formula Ha, lid, He and llf, k is 2 and both R^5b they are CN.

In some modalities of the formula lia, lid, He and llf, k is 2 and an R^5b is F and the other R^5t&gt; it's CN.

In some modalities of formula Ha, lid and He, x is 1 and R^5cis F.

In some modalities of formula Ha, lid and lie, x is 2 and both R^5c They are f.

In some modalities of formula Ha, x is 1 and R^5c is Me.

In some modalities of formula Ha, x is 2 and both R^5c are Me.

In some modalities of formula Ha, lid and He, x is 1 and R^5cis CF₃.

In some modalities of formula lia, lid and He, x is 2 and both R^5c are CF₃.

In some modalities of formula Ha, lid and He, x is 1 and R^Scis OMe.

In some modalities of the formula lia, lid, and He, x is 2 and

129 both R^Sc they are OMe.

In some modalities of formula Ha, x is 2 and an R^5c is F and the other R^Sc is Me.

In some modalities of formula lia, lid and lie, x is 2 and an R^5c is F and the other R^5c is CF₃.

In some modalities of formula Ha, lid, and He, x is 2 and an R^5c is F and the other R^5c is OMe.

In some modalities of formula Ha, lid and He, x is 1 and R^5Cit's CN.

In some modalities of formula Ha, lid and lie, x is 2 and both R^5c they are CN.

In some modalities of formula Ha, lid, and He, x is 2 and an R^5C is F and the other R^5c it's CN.

In some modalities of formula Ha, lie, lid and lie, z is 1 and R^{5 d} is F.

In some modalities of formula lia, He, lid, and He, z is 2 and both R^{5 d} They are f.

In some modalities of formula Ha, He, and Hf, z is 1 and R^{5 d} is Me.

In some modalities of formula Ha, He and Hf, z is 2 and both R^{5 d} are Me.

In some modalities of formula lia, He, lid, and He, z is 1 and R^{5 d} is CF₃.

In some modalities of formula lia, He, lid, and lie, z is 2 and both R^{5 d} are CF₃

130 you

In some modalities of formula Ha, lid and lie, z is 1 and R^{5 d}is OMe.

In some modalities of formula lia, lid and He, z is 2 and both R^{5 d} they are OMe.

In some modalities of formula Ha and He, z is 2 and an R^sd is F and the other R^{5 d} is Me.

In some modalities of formula Ha, lie, lid, and He, z is 2 and an R^{5 d} is F and the other R^{5 d} is CF₃.

In some modalities of formula Ha, lid, and He, z is 2 and an R^{5 d} is F and the other R^{5 d} is OMe.

In some modalities of formula lia, lie, lid and lie, z is 1 and R^{5 d} it's CN.

In some modalities of formula Ha, He, lid, and He, z is 2 and both R^{5 d} they are CN.

In some modalities of formula lia, lie, lid and He, z is 2 and an R^{5 d} is F and the other R^{5 d} it's CN.

In some modalities of formula lia and lid, ses 0.

In some modalities of formula Ha and lid, ses 1.

In some modalities of formula lia and lid, ses 2.

In some modalities of formula Ha, He and lid, s is 1 and R^5e is F.

In some modalities of formula lia, He and lid, s is 2 and both R^5e They are f.

In some modalities of formula lia and lid, s is 1 and R^5e is Me.

131

In some modalities of formula lia and lid, s is 2 and both R^5e are Me.

In some modalities of the formula lia, He and lid, s is 1 and R^5eis CF₃.

In some modalities of formula lia, He and lid, s is 2 and both R^5e are CF₃.

In some modalities of the formula lia, He and lid, s is 1 and R^5eis OMe.

In some modalities of formula lia, He and lid, s is 2 and 10 both R^5e they are OMe.

In some modalities of formula Ha and lid, s is 2 and an R^{I know} is F and the other R^5e is Me.

In some modalities of the formula Ha, He, and lid, s is 2 and an R^5e is F and the other R^5e is CF₃.

In some forms of formula lia, He and lid, s is 2 and a

R^5e is F and the other R^5e is OMe.

In some modalities of formula lia, lie and lid, s is 1 and R^5eit's CN.

In some modalities of formula Ha, He and lid, s is 2 and 20 both R^{I know} they are CN.

In some modalities of the formula Ha, He, and lid, s is 2 and an R^5e is F and the other R^5e it's CN.

Some embodiments of the present disclosure include compounds of formula (III):

132

III or salts, dermatologically acceptable salts or prodrugs thereof.

In some forms of formula III, each R⁷ is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of Cva unsubstituted alkyl, -CH2OH, -CH2N (R^9a)2 C_V3 haloalkyl, halide, -OR® and CN.

In some forms of formula III, each R⁸ is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H, -CM unsubstituted alkyl, -CH2OH, -CH2N (R^8a) 2, -C1.3 haloalkyl, halide, -OR® and CN.

In some forms of formula III, each R⁸ is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of Cve unsubstituted alkyl, -CH2OH, -CH2N (R^9a) 2, -Ci_₃ haloalkyl, halide, -OR® and CN.

In some embodiments of formula III, each R® is independently selected from the group consisting of H, -C_Ve unsubstituted alkyl and -C1.3 haloalkyl.

In some Formula III modalities, each R®^to is selected

133 regardless of the group consisting of H and -0, .3 unsubstituted alkyl.

In some forms of formula III, each q is 1 to 5.

In some forms of formula III, each R⁷ is independently selected from the group consisting of F, Cl, Me, OMe, OH,

CF₃ and CN.

In some forms of formula III, at least one R⁷ it is halide.

In some formula modalities

III, minus one is

In some formula modalities

III, at least one

R⁷ it is

Cl.

In some formula modalities at least one

R⁷ it is

I.

In some formula modalities at least one

R⁷ it is

Oh

In some forms of formula III, at least one R⁷ it is

OMe.

In some formula modalities at least one R⁷ is CF₃.

In some formula modalities

III, at least one R⁷ it's CN.

In some formula modalities

III is

In some formula modalities

III is

3.

In some forms of formula it is

2.

In some formula modalities

III is

2.

In some forms of formula it is

1.

In some formula modalities

III is

R⁷ is F.

In some modalities of formula III, q is 2 and both R⁷ are

In some modalities of formula III, q is 1 and R⁷ is Me.

134

In some modalities of formula III, q is 2 and both R⁷ are

I.

In some modalities of formula III, q is 1 and R⁷ is CF₃.

In some modalities of formula III, q is 2 and both R⁷ are

CF₃.

In some modalities of formula III, q is 1 and R⁷ is OMe.

In some modalities of formula III, q is 2 and both R⁷ they are OMe.

In some modalities of formula III, q is 2 and an R⁷ is F and the other R⁷ is Me.

In some modalities of formula III, q is 2 and an R⁷ is F and the other R⁷ is CF₃.

In some modalities of formula III, q is 2 and an R⁷ is F and the other R⁷ is OMe.

In some modalities of formula III, q is 1 and R⁷ it's CN.

In some modalities of formula III, q is 2 and both R⁷ they are CN.

In some modalities of formula III, q is 2 and an R⁷ is F and the other R⁷ it's CN.

In some forms of formula III, at least one R⁷ is -C ^₂I rent.

In some forms of formula III, at least one R⁷ is -C1.3 alkyl.

In some forms of formula III, at least one R⁷ it's alkyl.

135

In some forms of the alkyl formula.

For rent.

For rent.

For rent.

For rent.

For rent.

For rent.

In some some some some some some formula modalities formula modalities formula modalities formula modalities formula modalities formula modalities some modalities select independently

Me, OMe, OH, CF₃ and CN.

In halide.

In

In

In

In

In from

OMe.

some modalities some some some of

III, at least one R⁷ is -C1.5

III,

III,

III,

III, at least one R⁷ is -C- |.₆ at least a is ~ C2-6 al al al formula III, minus minus minus a a a

R⁷ is —C3-6 is —C4-6

R⁷ is —C2.5

R⁷ is —C3.5 at least one

R⁸ is group consisting of H, formula III, at least one modalities of formula modalities of formula modalities of formula some modalities of formula

III,

III,

III,

III, al al al al

Cl, minus minus minus a one a one

R⁸ it is

R⁸

R⁸

R⁸

R⁸ is is is is

F.

Cl.

I.

Oh

some modalities of formula III, at least one R⁸ it is

136

In some forms of formula III, at least one R⁸ is CF₃.

In some forms of formula III, at least one R⁸ it's CN.

In some modalities of formula III, p is 0 to 4.

In some modalities of formula III, p is 0 to 3.

In some modalities of formula III, p is 0 to 2.

In some forms of formula III, p is 1 to 4.

In some forms of formula III, p is 1 to 3.

In some embodiments of formula III, p is 1 or 2.

In some forms of formula III, p is 2.

In some embodiments of formula III, p is 1.

In some forms of formula III, p is 0.

In some modalities of formula III, p is 1 and R⁸ is F.

In some modalities of formula III, p is 2 and both R⁸ are

F.

I.

CF₃

In some modalities of formula III, p is 1 and R⁸ is Me.

In some modalities of formula III, p is 2 and both R⁸ are

In some modalities of formula III, p is 1 and R⁸ is CF₃.

In some modalities of formula III, p is 2 and both R⁸ are

In some modalities of formula III, p is 1 and R⁸ is OMe.

In some modalities of formula III, p is 2 and both R⁸ are

OMe.

In some embodiments of formula III, p is 2 and an R⁸ is F and the other R⁸ is Me.

137

In some embodiments of formula III, p is 2 and an R⁸ is F and the other R® is CF₃.

In some embodiments of formula III, p is 2 and an R⁸ is F and the other R® is OMe.

In some embodiments of formula III, p is 1 and R® is CN.

In some embodiments of formula III, p is 2 and both R® are CN.

In some embodiments of formula III, p is 2 and one R® is F and the other R⁸ it's CN.

In some forms of formula III, at least one R⁸ is -C ^₂I rent.

In some forms of formula III, at least one R⁸ is -C1.3 alkyl.

In some forms of formula III, at least one R⁸ is -8, .4 alkyl.

In some forms of formula III, at least one R⁸ is -C ,.₅I rent.

In some embodiments of formula III, at least one R® is -Ci__andI rent.

In some embodiments of formula III, at least one R® is -C₂.6 alkyl.

In some embodiments of formula III, at least one R® is -C₃.₆I rent.

In some embodiments of formula III, at least one R® is -C₄._andI rent.

138

In some formula modalities at least one R⁸ is -C₂.₅ I rent.

In some formula modalities at least one R⁸ is -C₃.₅ I rent.

In

In

In

In

In

In

In

In

In

In

In is is is is is some some some some some some some some some some some

-CH₂Oh

In some

-CH₂N (R^9a)₂.

In some

-CH₂NH₂.

In some

-CH₂NHMe

In some

-CH₂NMe₂.

In some modalities modalities modalities modalities modalities modalities modalities modalities formula formula formula formula formula formula formula formula formula formula modalities modalities modalities modalities modalities modalities modalities

III,

III,

III,

III,

III,

III,

III,

III,

III,

III, of of of of of of formula formula formula formula formula formula

R⁹

R⁹

R⁹

R⁹

R⁹

R⁹

R⁹

R⁹

R⁹

R⁹

III,

III,

III,

III,

III,

III, is is is is is is is is is is al al al al al

-Ci-2

-Ci_3

-Ci-4

-Ci-5

-C1-6 alkyl.

I rent.

I rent.

I rent.

I rent.

-C₂-e —C3-6 —C4.6 —C₂-5 —C3.5 minus minus minus minus minus alkyl.

I rent.

I rent.

I rent.

I rent.

a one a one one

R⁷

R⁷

R⁷

R⁷

R⁷

R⁷ and / oy / oy / oy / oy / oy / o

R⁸

R⁸

R⁸

R⁸

R⁸

R⁸

139 is -CH₂NHEt.

In some forms of formula III, at least one R⁷ and / or R⁸is -CH₂N (Me) (Et).

In some forms of formula III, at least one R⁷ and / or R⁸is -CH₂NEt₂.

Some forms of formula III include compounds of formula (Illa):

(R¹²)_what

<img file="MX368248B_D0220.tif" />

Illa or salts, dermatologically acceptable or prodrugs thereof.

In some forms of the Illa formula, R¹⁰ is a substituent attached to the ortho position of phenyl and is selected from the group consisting of H, -C ^ e unsubstituted alkyl, -0 ^ 3 haloalkyl, halide, -OR¹³ and CN.

In some forms of the Illa formula, R¹¹ is a substituent attached to the ortho position of phenyl and is selected from the group consisting of unsubstituted -Ci.e alkyl, -CH2OH, CH2N (R^13b) 2, "Cj-3 haloalkyl, halide, -OR¹³ and CN.

In some forms of the Illa formula, each R¹² is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H,

140

-Cve unsubstituted alkyl, -CH₂OH, -CH₂N (R^13b)₂, -C ^ s haloalkyl, halide, -OR¹³ and CN.

In some forms of the Illa formula, each R¹² is a substituent attached to the fenllo ring and is independently selected at each occurrence from the group consisting of Ci-e unsubstituted alkyl, -CH2OH, -CH2N (R^13b) 2, -C1.3 haloalkyl, halide, -OR¹³ and CN.

In some forms of the Illa formula, each R¹³ is independently selected from the group consisting of -Ci__andunsubstituted alkyl and -0, .3 haloalkyl.

In some forms of the Illa formula, each R^13b is independently selected from the group consisting of H and -Cva unsubstituted alkyl.

In some forms of the Illa formula, q is 0 to 5.

In some forms of the Illa formula, q is 1 to 5.

In some Illa formula modalities, at least one R¹² is selected from the group consisting of H, F, Cl, Me, OMe, CF₃ and CN.

In some forms of the Illa formula, q is 0.

In some Illa formula modalities, at least one R¹² it is a halide.

In some Illa formula modalities, at least one R¹² is F.

In some Illa formula modalities, at least one R¹² is Cl.

In some Illa formula modalities, at least one R¹² is Me.

In some Illa formula modalities, at least one R¹² it is

141

Oh

<td>In</td><td>some</td><td>modalities</td><td>from</td><td>formula</td><td>Illa,</td><td>to the</td><td>less</td><td>a</td><td>R¹²</td><td>it is</td>

<td>OMe.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>In</td><td>some</td><td>modalities</td><td>from</td><td>formula</td><td>Illa,</td><td>to the</td><td>less</td><td>a</td><td>R¹²</td><td>it is</td>

<td>cf₃.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>