*Review* **Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades**

**Mohd. Imran 1,\* , Syed Mohammed Basheeruddin Asdaq 2,\* , Shah Alam Khan <sup>3</sup> , Dhanalekshmi Unnikrishnan Meenakshi <sup>3</sup> , Abdulhakeem S. Alamri 4,5 , Walaa F. Alsanie 4,5 , Majid Alhomrani 4,5, Yahya Mohzari <sup>6</sup> , Ahmed Alrashed <sup>7</sup> , Mohammed AlMotairi <sup>8</sup> , Eman H. Alkhaldi <sup>9</sup> , Abeer K. Alorabi <sup>10</sup>, Ahmed Subeh Alshrari <sup>11</sup>, Mohammad Tauseef <sup>12</sup>, Abida <sup>1</sup> , Saleh I. Alaqel <sup>1</sup> , Ozair Alam <sup>13</sup> and Md. Afroz Bakht <sup>14</sup>**

	- Dariyah, Riyadh 13713, Saudi Arabia

**Abstract:** Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved by USFDA in 2001. This review summarizes the compound patents and the essential polymorph patents of the PKIs approved by the USFDA from 2001 to 31 May 2021. The dates on the generic drug availability of the PKIs in the USA market have also been forecasted. It is expected that 19 and 48 PKIs will be genericized by 2025 and 2030, respectively, due to their compound patent expiry. This may reduce the financial toxicity associated with the existing PKIs. There are nearly 535 reported PKs. However, the USFDA approved PKIs target only about 10–15% of the total said PKs. As a result, there are still a large number of unexplored PKs. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed.

**Keywords:** protein kinase inhibitors; USFDA; cancer; inflammation; patent review; generic product

**Citation:** Imran, M.; Asdaq, S.M.B.; Khan, S.A.; Unnikrishnan Meenakshi, D.; Alamri, A.S.; Alsanie, W.F.; Alhomrani, M.; Mohzari, Y.; Alrashed, A.; AlMotairi, M.; et al. Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades. *Pharmaceuticals* **2021**, *14*, 710. https://doi.org/10.3390/ ph14080710

Academic Editors: Mary J. Meegan and Niamh M O'Boyle

Received: 17 June 2021 Accepted: 19 July 2021 Published: 22 July 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

### **1. Introduction**

Protein kinases (PKs) are ubiquitous intracellular and cell surface enzymatic proteins that selectively catalyzes phosphate group's relocation from ATP, GTP, and other phosphate donors to protein substrates [1]. The PKs mainly catalyze the relocation of a γ-phosphatase group of ATP to the oxygen atom of the -OH group of threonine, serine, and tyrosine residues in peptides/polypeptides, thereby making a conformational variation from an inactive to an active form [1,2]. They constitute an extensive family of structurally related enzymes that are known to be implicated in almost all the signal transduction activities, frequently with cascades of phosphorylation proceedings taking place within the cell [3]. The signal transduction involves the reversible phosphorylation of proteins that helps to regulate mature proteins by altering their structure and function [4,5]. To date, nearly 535 human PKs have been identified [6], wherein more than 478 belong to a superfamily whose catalytic domains are sequentially interrelated. These PKs are additionally categorized into groups, families, and subfamilies established on their biochemical activities. The main two classifications are Serine/threonine PKs and Tyrosine-specific PKs [5]. The seven significant groups with the description of families, subfamilies, and functions are listed in Table 1.

TKs form a distinct group, which phosphorylates proteins on tyrosine, whereas others phosphorylate serine and threonine residues. In addition to this category, there are atypical kinases, which are not related to any sequence resemblance to characteristic kinases but are well recognized for their enzymatic activity similar to specific kinases. Some kinases are believed to lack the catalytic domain for effective phosphorylation and are called pseudokinases. Still, they are distributed across all kinase families, indicating that an absence of catalysis is not a formal barricade to the evolution of unique or irreplaceable biological functions [7].


**Table 1.** Families and subfamilies of PKs.


PKs perform a significant function in signal transduction and control of most cellular processes, including cell growth, differentiation, proliferation, angiogenesis, apoptosis, cytoskeletal arrangement, regulation of metabolic reactions, membrane transport, and motility, etc. [6]. Non-catalytic functions of PKs are also essential and include the allosteric effect, subcellular targeting, the scaffolding of protein complexes, competition for protein interactions, and DNA binding [15]. Because PKs regulate most fundamental biological processes, any dysregulation, genetic alteration, and abrupt change in kinase function are typically linked with pathological conditions such as cancer, immunologic, neurological, cardiovascular, and metabolic disorders [3,5]. Hence, manipulation of PKs signaling pathway, regulation, and inhibition constitutes important clinical targets for pharmacological intervention and thus for the identification and development of Protein Kinase Inhibitors (PKIs) to manage and treat several chronic diseases [4,6,16]. Over the past two decades, approximately 1/5th-1/3rd drug discovery programs worldwide have targeted PKs for the drug development of various illnesses.

Kinase mutation frequency is much less, and thus targeting kinases could be helpful in life-saving therapies especially for cancer. A well-known example is receptor tyrosine kinase ALK where gene fusion between EML4 and ALK occurs only in 5% of NSCLC patients and therefore many patients responded to the kinome therapy effectively. Identification of additional effective kinome targets will therefore represent an Achilles heel in a subset of cancer. The use of bioinformatics tools in predicting the likelihood that a given mutation will alter the function of a kinase will be essential in pinpointing cancer-associated kinases [17].

There are about 175 kinase drugs under clinical trials and newer targets are also under evaluation including AKT, Aurora kinases, CHEK1, and CDK1. However, most of the drugs

under investigation are well known for targeting EGFR, VEGFR, PI3K, and mTOR [18]. Even though CAMK, CK1, or AGC kinases groups are well-known and evidenced as the primary targets for cancer, there are no investigational drugs that target these kinases are enrolled. So far only 8% of the entire kinome has been effectively "drugged" and a quarter of human kinases are vastly understudied [19]. A wide-ranging scoring system to rank and prioritize clinically relevant kinase targets of different solid tumor cancers from The Cancer Genome Atlas (TCGA) has been developed [19].

Successful applications and deep insights into the ever-diversifying therapeutic space occupied by kinase targets are also explored. For effective target validation and to avoid complicating off-target mediated response it is essential to achieve the desired selectivity while targeting kinases, though it is still an ongoing challenge. The application of largescale omics data has been modernized to combine multiple parameters to evaluate the protein's potential as a drug target or biomarker [19].

In recent years, intricately selective kinase chemical probes have been generated by the exploitation of unique pockets using molecular modeling and bioinformatics, prioritizing the ligand-efficient leads and novel chemotypes and the extensive use of kinome-wide profiling [20].

Chemical proteomics and broad kinome profiling of compound libraries have been implemented as an efficient method to lead to discovery, analyzing targets, and optimization [21]. Results revealed that unknown targets for established drugs presented a viewpoint on the "druggable" kinome, emphasized non-kinase off-targets, and recommended for potential therapeutic applications. A database of the cellular targets of 243 clinical kinase inhibitors has been made available using kinobead technology [21].

The ongoing research will undoubtedly pave the way for a better understanding of molecular pathways that will further unravel the role of PKs in pathogenesis. As of now, the majority of the USFDA-approved PKIs are Protein Tyrosine Kinase inhibitors (PTKIs) followed by protein-serine/threonine PKIs. Most of these drugs are clinically used to treat solid (breast, lung, colon) and non-solid tumors (leukemia). Some PKIs are also effective in treating non-malignant diseases, including myelofibrosis, rheumatoid arthritis, glaucoma, ulcerative colitis, pulmonary fibrosis, etc. [22,23].

### **2. USFDA Approved Protein Kinase Inhibitors**

In 2001, the USFDA approved the marketing of the first clinical PKI, imatinib. Since then, the USFDA has approved about 70 PKIs for clinical use (Table 2) (Figure 1). The data provided in Table 2 have been obtained from USFDA's Orange Book website (https: //www.accessdata.fda.gov/scripts/cder/ob/index.cfm?resetfields=1 (accessed on 31 May 2021) using the drug's name.


**Table 2.** The Orange Book data of the USFDA approved PKIs.






15



Some drugs are multikinase inhibitors.

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 11 of 60

**Figure 1.** Timeline depicting the approval of the PKIs by the USFDA and their primary targets in **Figure 1.** Timeline depicting the approval of the PKIs by the USFDA and their primary targets in brackets.

### **3. Patent Searching**

brackets.

**3. Patent Searching**  The patent searching was performed using the Sci-finder database (CAS Number search, and the exact structure search of each TKI), USFDA's Orange Book website (mentioned above), and the Drugbank's website (https://go.drugbank.com/ (accessed on 31 May 2021)) using the drug's name. The patents disclosing the specific TKI, its marketed The patent searching was performed using the Sci-finder database (CAS Number search, and the exact structure search of each TKI), USFDA's Orange Book website (mentioned above), and the Drugbank's website (https://go.drugbank.com/ (accessed on 31 May 2021)) using the drug's name. The patents disclosing the specific TKI, its marketed active pharmaceutical ingredient, and important polymorphs from the innovative com-

this review. The expiry dates of the selected patents were calculated (20 years from the patent application filing date comprising patent term extension, if any). Sometimes, the drug's patent term is extended up to five years based on the USPTO's laws. Accordingly,

active pharmaceutical ingredient, and important polymorphs from the innovative com-

pany for the first time were identified and included in this review. The patents of each TKI that claim its treatment methods, dosage forms, formulations, drug combinations, particle size, impurity, preparation process, intermediates, etc., have been excluded from this review. The expiry dates of the selected patents were calculated (20 years from the patent application filing date comprising patent term extension, if any). Sometimes, the drug's patent term is extended up to five years based on the USPTO's laws. Accordingly, the expiry dates of the selected patients were also verified from the USPTO's website. It was also observed that some TKIs were disclosed in different patents of the same patent family and had other expiry dates. In such cases, the patent that had a more extended expiry date was selected for this review because the generic launch of the drug is based on the expiry date of the drug's patent. The legal status of the patents cited herein was obtained from the website of USPTO (https://portal.uspto.gov/pair/PublicPair (accessed on 31 May 2021)).

### **4. Summary of the Patents**

The proprietary name, approved dosage form, approval date, and marketing status of each marketed PKIs are mentioned in Table 2. The patent number, applicant/assignee, expiry date, and legal status of the cited patents of each PKI are provided in Table 3. A brief description of the PKIs and their important patents are provided below.


**Table 3.** Patent number, applicant/assignee, expiry date, and legal status of the cited patents.




\* Based on the patent expiry date.

### *4.1. Imatinib Mesylate*

Imatinib mesylate (Figure 2) is a pyridine-pyrimidine based piperazine derivative (MF: C29H31N7O·CH4SO3; MW: 589.7; CAS Number: 220127-57-1) [24]. **US5521184A** claims *N*-phenyl-2-pyrimidine-amine compounds, including imatinib and its pharmaceutically acceptable salts, as antitumor drugs [25]. **USRE43932E** (Re-issue of US7544799B2) claims the β-crystal form of imatinib mesylate as having favorable thermodynamic stability, flow properties, and low hygroscopicity that makes it a suitable active pharmaceutical ingredient (API) to be used in the tablet/capsule dosage forms [26].

### *4.2. Gefitinib*

Gefitinib (Figure 3) is a morpholine based quinazolinamine derivative (MF: C22H24ClFN4O3; MW: 446.9; CAS Number: 184475-35-2) [27]. **US5457105A** unveils quinazoline derivatives and their salts to treat neoplastic disease. This patent claims gefitinib generically [28]. **US5770599A** also covers quinazoline derivatives as anticancer agents. This patent claims gefitinib specifically, along with its pharmaceutically acceptable acid-addition salts [29].

US9067896B2 Novartis 24 February

US9067896B2 Novartis 24 February

dient (API) to be used in the tablet/capsule dosage forms [26].

dient (API) to be used in the tablet/capsule dosage forms [26].

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 16 of 60

\* Based on the patent expiry date.

\* Based on the patent expiry date.

*4.1. Imatinib Mesylate* 

*4.1. Imatinib Mesylate* 

**Figure 2.** Imatinib mesylate (4-[(4-Methyl-1-piperazinyl)methyl]-*N*-[4-methyl-3-[[4-(3-pyridinyl)-2 pyrimidinyl]amino]phenyl]benzamide methanesulfonate). **Figure 2.** Imatinib mesylate (4-[(4-Methyl-1-piperazinyl)methyl]-*N*-[4-methyl-3-[[4-(3-pyridinyl)- 2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate). agents. This patent claims gefitinib specifically, along with its pharmaceutically acceptable acid-addition salts [29].

Imatinib mesylate (Figure 2) is a pyridine-pyrimidine based piperazine derivative (MF: C29H31N7O.CH4SO3; MW: 589.7; CAS Number: 220127-57-1) [24]. **US5521184A** claims *N*-phenyl-2-pyrimidine-amine compounds, including imatinib and its pharmaceutically acceptable salts, as antitumor drugs [25]. **USRE43932E** (Re-issue of US7544799B2) claims the β-crystal form of imatinib mesylate as having favorable thermodynamic stability, flow properties, and low hygroscopicity that makes it a suitable active pharmaceutical ingre-

Imatinib mesylate (Figure 2) is a pyridine-pyrimidine based piperazine derivative (MF: C29H31N7O.CH4SO3; MW: 589.7; CAS Number: 220127-57-1) [24]. **US5521184A** claims *N*-phenyl-2-pyrimidine-amine compounds, including imatinib and its pharmaceutically acceptable salts, as antitumor drugs [25]. **USRE43932E** (Re-issue of US7544799B2) claims the β-crystal form of imatinib mesylate as having favorable thermodynamic stability, flow properties, and low hygroscopicity that makes it a suitable active pharmaceutical ingre-

2031 Patented (Patent term extension

2031 Patented (Patent term extension

is possible)

is possible)

**Figure 3.** Gefitinib (*N*-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4 quinazolinamine). **Figure 3.** Gefitinib (*N*-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine).

#### *4.3. Erlotinib Hydrochloride 4.3. Erlotinib Hydrochloride*

*4.4. Sorafenib Tosylate* 

safety [35].

*4.5. Sunitinib Malate* 

**Figure 3.** Gefitinib (*N*-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4 quinazolinamine). Erlotinib hydrochloride (Figure 4) is a quinazolinamine derivative (MF: C22H23N3O4·HCl; MW: 429.90; CAS Number: 183319-69-9) [30]. **USRE41065E** (Reissue patent of US5747498) discloses 4-(substituted phenylamino)quinazoline derivatives, which are useful in treating cancers. It also claims erlotinib hydrochloride specifically [31]. **US6900221B1** provides polymorphs of erlotinib hydrochloride and processes for their selective production. It claims homogeneous thermodynamically stable crystalline polymorph of erlotinib hydrochloride (Form B), suitable for making tablet dosage forms [32]. Erlotinib hydrochloride (Figure 4) is a quinazolinamine derivative (MF: C22H23N3O4.HCl; MW: 429.90; CAS Number: 183319-69-9) [30]. **USRE41065E** (Reissue patent of US5747498) discloses 4-(substituted phenylamino)quinazoline derivatives, which are useful in treating cancers. It also claims erlotinib hydrochloride specifically [31]. **US6900221B1** provides polymorphs of erlotinib hydrochloride and processes for their selective production. It claims homogeneous thermodynamically stable crystalline polymorph of erlotinib hydrochloride (Form B), suitable for making tablet dosage forms [32].

**Figure 4.** Erlotinib hydrochloride (*N*-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride). **Figure 4.** Erlotinib hydrochloride (*N*-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride).

Sorafenib tosylate (Figure 5) is a urea-pyridine based diaryl ether derivative (MF: C21H16ClF3N4O3.C7H8O3S; MW: 637.0; CAS Number: 475207-59-1) [33]. **US7235576B1** pro-

.

closes novel polymorphs of sorafenib tosylate, processes for its synthesis, and compositions comprising it. It claims thermodynamically stable polymorph (Form I) of sorafenib tosylate, which can provide quality dosage form concerning bioavailability and patient

**Figure 5.** Sorafenib tosylate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phe-

Sunitinib malate (Figure 6) is an indole based pyrrole-3-carboxamide derivative (MF: C22H27FN4O2.C4H6O5; MW: 532.6; CAS Number: 341031-54-7) [36]. **US7125905B2** covers 3 pyrrole substituted 2-indolinone compounds as PK activity modulators for treating disorders related to abnormal PK activity. It claims sunitinib malate specifically [37]. The

noxy]-*N*-methylpyridine-2-carboxamide 4-methylbenzenesulfonate).

sunitinib malate is also claimed in **US6573293B2** [38].

#### *4.4. Sorafenib Tosylate 4.4. Sorafenib Tosylate*

linamine hydrochloride).

*4.3. Erlotinib Hydrochloride* 

Sorafenib tosylate (Figure 5) is a urea-pyridine based diaryl ether derivative (MF: C21H16ClF3N4O3·C7H8O3S; MW: 637.0; CAS Number: 475207-59-1) [33]. **US7235576B1** provides aryl urea derivatives for treating RAF-mediated diseases like cancer and their pharmaceutical compositions. It claims sorafenib tosylate specifically [34]. **US8877933B2** discloses novel polymorphs of sorafenib tosylate, processes for its synthesis, and compositions comprising it. It claims thermodynamically stable polymorph (Form I) of sorafenib tosylate, which can provide quality dosage form concerning bioavailability and patient safety [35]. Sorafenib tosylate (Figure 5) is a urea-pyridine based diaryl ether derivative (MF: C21H16ClF3N4O3.C7H8O3S; MW: 637.0; CAS Number: 475207-59-1) [33]. **US7235576B1** provides aryl urea derivatives for treating RAF-mediated diseases like cancer and their pharmaceutical compositions. It claims sorafenib tosylate specifically [34]. **US8877933B2** discloses novel polymorphs of sorafenib tosylate, processes for its synthesis, and compositions comprising it. It claims thermodynamically stable polymorph (Form I) of sorafenib tosylate, which can provide quality dosage form concerning bioavailability and patient safety [35].

**Figure 4.** Erlotinib hydrochloride (*N*-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazo-

Erlotinib hydrochloride (Figure 4) is a quinazolinamine derivative (MF: C22H23N3O4.HCl; MW: 429.90; CAS Number: 183319-69-9) [30]. **USRE41065E** (Reissue patent of US5747498) discloses 4-(substituted phenylamino)quinazoline derivatives, which are useful in treating cancers. It also claims erlotinib hydrochloride specifically [31]. **US6900221B1** provides polymorphs of erlotinib hydrochloride and processes for their selective production. It claims homogeneous thermodynamically stable crystalline polymorph of erlotinib hydrochloride (Form B), suitable for making tablet dosage forms [32].

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 17 of 60

**Figure 5.** Sorafenib tosylate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-*N*-methylpyridine-2-carboxamide 4-methylbenzenesulfonate). **Figure 5.** Sorafenib tosylate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]- *N*-methylpyridine-2-carboxamide 4-methylbenzenesulfonate).

### *4.5. Sunitinib Malate 4.5. Sunitinib Malate*

Sunitinib malate (Figure 6) is an indole based pyrrole-3-carboxamide derivative (MF: C22H27FN4O2.C4H6O5; MW: 532.6; CAS Number: 341031-54-7) [36]. **US7125905B2** covers 3 pyrrole substituted 2-indolinone compounds as PK activity modulators for treating disorders related to abnormal PK activity. It claims sunitinib malate specifically [37]. The sunitinib malate is also claimed in **US6573293B2** [38]. Sunitinib malate (Figure 6) is an indole based pyrrole-3-carboxamide derivative (MF: C22H27FN4O2·C4H6O5; MW: 532.6; CAS Number: 341031-54-7) [36]. **US7125905B2** covers 3-pyrrole substituted 2-indolinone compounds as PK activity modulators for treating disorders related to abnormal PK activity. It claims sunitinib malate specifically [37]. The sunitinib malate is also claimed in **US6573293B2** [38]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 18 of 60

**Figure 6.** Sunitinib malate (*N*-[2-(diethylamino)ethyl]-5-[(*Z*)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (2S)-2-hydroxybutanedioic acid). **Figure 6.** Sunitinib malate (*N*-[2-(diethylamino)ethyl]-5-[(*Z*)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3 ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (2S)-2-hydroxybutanedioic acid).

#### *4.6. Dasatinib Monohydrate 4.6. Dasatinib Monohydrate*

Dasatinib monohydrate (Figure 7) is a piperazine-pyrimidine-thiazole based anilide (MF: C22H26ClN7O2S.H2O; MW: 506.02; CAS Number: 863127-77-9) [39]. **US6596746B1** provides cyclic compounds for use as PKIs to treat cancer. It claims dasatinib specifically [40]. **US7491725B2** claims crystalline monohydrate of dasatinib and process for its preparation [41]. Dasatinib monohydrate (Figure 7) is a piperazine-pyrimidine-thiazole based anilide (MF: C22H26ClN7O2S·H2O; MW: 506.02; CAS Number: 863127-77-9) [39]. **US6596746B1** provides cyclic compounds for use as PKIs to treat cancer. It claims dasatinib specifically [40]. **US7491725B2** claims crystalline monohydrate of dasatinib and process for its preparation [41].

### *4.7. Lapatinib Ditosylate Monohydrate*

*4.7. Lapatinib Ditosylate Monohydrate* 

sulfonate) monohydrate).

Lapatinib ditosylate monohydrate (Figure 8) is a furan based quinazolinamine derivative (MF: C29H26ClFN4O4S·(C7H8O3S)2.H2O; MW: 943.5; CAS Number: 388082-78-8) [42]. **US8513262B2** discloses substituted heteroaromatic compounds, their synthesis, compositions, and their use in medicine as PTKIs. It claims lapatinib specifically [43]. **US7157466B2** relates to quinazoline compounds, anhydrate and hydrate ditosylate salts thereof, and the

Lapatinib ditosylate monohydrate (Figure 8) is a furan based quinazolinamine derivative (MF: C29H26ClFN4O4S.(C7H8O3S)2.H2O; MW: 943.5; CAS Number: 388082-78-8) [42]. **US8513262B2** discloses substituted heteroaromatic compounds, their synthesis, compositions, and their use in medicine as PTKIs. It claims lapatinib specifically [43]. **US7157466B2**  relates to quinazoline compounds, anhydrate and hydrate ditosylate salts thereof, and the process for their preparation. It claims lapatinib ditosylate monohydrate specifically. The claimed lapatinib ditosylate possesses physical stability and moisture sorption properties

superior to di-HCl salt, making it suitable for developing tablet formulations [44].

**Figure 8.** Lapatinib ditosylate monohydrate (*N*-(3-chloro-4-{[(3-fluorophenyl) methyl]oxy}phenyl)- 6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzene-

azinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate).

[41].

process for their preparation. It claims lapatinib ditosylate monohydrate specifically. The claimed lapatinib ditosylate possesses physical stability and moisture sorption properties superior to di-HCl salt, making it suitable for developing tablet formulations [44]. vides cyclic compounds for use as PKIs to treat cancer. It claims dasatinib specifically [40]. **US7491725B2** claims crystalline monohydrate of dasatinib and process for its preparation [41]. **Figure 7.** Dasatinib monohydrate (*N*-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate).

Dasatinib monohydrate (Figure 7) is a piperazine-pyrimidine-thiazole based anilide (MF: C22H26ClN7O2S.H2O; MW: 506.02; CAS Number: 863127-77-9) [39]. **US6596746B1** pro-

**Figure 6.** Sunitinib malate (*N*-[2-(diethylamino)ethyl]-5-[(*Z*)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (2S)-2-hydroxybutanedioic acid).

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 18 of 60

**Figure 6.** Sunitinib malate (*N*-[2-(diethylamino)ethyl]-5-[(*Z*)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (2S)-2-hydroxybutanedioic acid).

Dasatinib monohydrate (Figure 7) is a piperazine-pyrimidine-thiazole based anilide (MF: C22H26ClN7O2S.H2O; MW: 506.02; CAS Number: 863127-77-9) [39]. **US6596746B1** provides cyclic compounds for use as PKIs to treat cancer. It claims dasatinib specifically [40]. **US7491725B2** claims crystalline monohydrate of dasatinib and process for its preparation

**Figure 7.** Dasatinib monohydrate (*N*-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate). **Figure 7.** Dasatinib monohydrate (*N*-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-pipe razinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate). process for their preparation. It claims lapatinib ditosylate monohydrate specifically. The claimed lapatinib ditosylate possesses physical stability and moisture sorption properties superior to di-HCl salt, making it suitable for developing tablet formulations [44].

6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate). **Figure 8.** Lapatinib ditosylate monohydrate (*N*-(3-chloro-4-{[(3-fluorophenyl) methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl) ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 19 of 60

#### *4.8. Temsirolimus 4.8. Temsirolimus*

*4.9. Everolimus* 

*4.6. Dasatinib Monohydrate* 

*4.6. Dasatinib Monohydrate* 

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 18 of 60

Temsirolimus (Figure 9) is a piperidine-tetrahydropyran based macrolide lactams (MF: C56H87NO16; MW: 1030.30; CAS Number: 162635-04-3) [45]. **USRE44768E** (Reissue of US5362718) relates to hydroxy esters of rapamycin for treating T-cell leukemia/lymphoma, solid tumors, and hyperproliferative vascular disorders. It claims temsirolimus specifically [46]. Temsirolimus (Figure 9) is a piperidine-tetrahydropyran based macrolide lactams (MF: C56H87NO16; MW: 1030.30; CAS Number: 162635-04-3) [45]. **USRE44768E** (Reissue of US5362718) relates to hydroxy esters of rapamycin for treating T-cell leukemia/lymphoma, solid tumors, and hyperproliferative vascular disorders. It claims temsirolimus specifically [46].

**Figure 9.** Temsirolimus ((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2- [(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26- hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H) pentone 4'-[2,2-bis(hydroxymethyl)propionate]). **Figure 9.** Temsirolimus ((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14, 21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 40 -[2,2-bis(hydro xymethyl)propionate]).

Everolimus (Figure 10) is a piperidine-tetrahydropyran based macrolide lactam (MF: C53H83NO14; MW: 958.25; CAS Number: 159351-69-6) [47]. **US5665772A** provides alkylated

**Figure 10.** Everolimus ((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-

Nilotinib hydrochloride monohydrate (Figure 11) is a pyridine-pyrimidine-imidazole-based benzanilide derivative (MF: C28H22F3N7O.HCl.H2O; MW: 584; CAS Number:

16,24,26,28-tetraene-2,3,10,14,20-pentaone)

*4.10. Nilotinib Hydrochloride Monohydrate* 

### *4.9. Everolimus* pentone 4'-[2,2-bis(hydroxymethyl)propionate]).

*4.8. Temsirolimus* 

specifically [46].

Everolimus (Figure 10) is a piperidine-tetrahydropyran based macrolide lactam (MF: C53H83NO14; MW: 958.25; CAS Number: 159351-69-6) [47]. **US5665772A** provides alkylated derivatives of rapamycin as immunosuppressants. It claims everolimus specifically [48]. *4.9. Everolimus*  Everolimus (Figure 10) is a piperidine-tetrahydropyran based macrolide lactam (MF: C53H83NO14; MW: 958.25; CAS Number: 159351-69-6) [47]. **US5665772A** provides alkylated derivatives of rapamycin as immunosuppressants. It claims everolimus specifically [48].

**Figure 9.** Temsirolimus ((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-

[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26- hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-

9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-

Temsirolimus (Figure 9) is a piperidine-tetrahydropyran based macrolide lactams (MF: C56H87NO16; MW: 1030.30; CAS Number: 162635-04-3) [45]. **USRE44768E** (Reissue of US5362718) relates to hydroxy esters of rapamycin for treating T-cell leukemia/lymphoma, solid tumors, and hyperproliferative vascular disorders. It claims temsirolimus

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 19 of 60

**Figure 10.** Everolimus ((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone) **Figure 10.** Everolimus ((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihy droxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dime thoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28 tetraene-2,3,10,14,20-pentaone).

#### *4.10. Nilotinib Hydrochloride Monohydrate 4.10. Nilotinib Hydrochloride Monohydrate*

Nilotinib hydrochloride monohydrate (Figure 11) is a pyridine-pyrimidine-imidazole-based benzanilide derivative (MF: C28H22F3N7O.HCl.H2O; MW: 584; CAS Number: Nilotinib hydrochloride monohydrate (Figure 11) is a pyridine-pyrimidine-imidazolebased benzanilide derivative (MF: C28H22F3N7O·HCl·H2O; MW: 584; CAS Number: 923288- 90-8) [49]. **US7169791B2** covers substituted pyrimidinyl aminobenzamides, methods of synthesis, and their compositions to treat neoplastic diseases like leukemia. It claims nilotinib and its salts [50]. **US8163904B2** claims nilotinib hydrochloride monohydrate as having physicochemical properties required to develop a good dosage form [51]. **US8415363B2** claims crystalline form B of nilotinib hydrochloride monohydrate having superior crystallinity and physical stability over other polymorphs [52].

### *4.11. Pazopanib Hydrochloride*

Pazopanib hydrochloride (Figure 12) is a benzenesulfonamide bearing benzimidazolepyrimidinyl compound (MF: C21H23N7O2S·HCl; MW: 473.99; CAS Number: 635702-64- 6) [53]. **US7105530B2** reports pyrimidine derivatives as inhibitors of VEGFR-2 to treat disorders, including cancer, associated with inappropriate angiogenesis. It claims pazopanib and its salts [54]. **US8114885B2** claims pazopanib hydrochloride precisely [55]. The claimed hydrochloride salt possesses advantageous properties like stability and solubility to develop quality dosage forms.

### *4.12. Vandetanib*

Vandetanib (Figure 13) is a piperidine based 4-aminoquinazolinamine derivative (MF: C22H24BrFN4O2; MW: 475.36; CAS Number: 443913-73-3) [56]. **USRE42353E** (Reissue of US6414148B1) provides quinazoline derivatives, synthesis, and compositions to treat illness linked with angiogenesis and amplified vascular permeability. It claims vandetanib precisely [57].

923288-90-8) [49]. **US7169791B2** covers substituted pyrimidinyl aminobenzamides, methods of synthesis, and their compositions to treat neoplastic diseases like leukemia. It claims nilotinib and its salts [50]. **US8163904B2** claims nilotinib hydrochloride monohydrate as having physicochemical properties required to develop a good dosage form [51]. **US8415363B2** claims crystalline form B of nilotinib hydrochloride monohydrate having

923288-90-8) [49]. **US7169791B2** covers substituted pyrimidinyl aminobenzamides, methods of synthesis, and their compositions to treat neoplastic diseases like leukemia. It claims nilotinib and its salts [50]. **US8163904B2** claims nilotinib hydrochloride monohydrate as having physicochemical properties required to develop a good dosage form [51]. **US8415363B2** claims crystalline form B of nilotinib hydrochloride monohydrate having

superior crystallinity and physical stability over other polymorphs [52].

superior crystallinity and physical stability over other polymorphs [52].

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 20 of 60

**Figure 12.** Pazopanib hydrochloride (5-[[4-[(2,3-*d*imethyl-2H-indazol-6-yl)methylamino]-2 pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride).

### *4.13. Vemurafenib*

Vemurafenib (Figure 14) is a phenylketone based pyrrolopyridine (MF: C23H18ClF2N3O3S; MW: 489.9; CAS Number: 918504-65-1) [58]. **US8143271B2** describes pyrrolopyridine based compounds as PTKIs to treat diseases and conditions associated with aberrant activity of PTKs. It claims vemurafenib specifically [59].

### *4.14. Crizotinib*

Crizotinib (Figure 15) is a piperidine based pyrazolylpyridine derivative (MF: C21H22Cl2F N5O; MW: 450.34; CAS Number: 877399-52-5) [60]. **US7858643B2** describes aminopyridines and aminopyrazines having PTKI activity, methods of synthesizing and using these compounds as anticancer agents. It claims crizotinib and its salts [61]. **US8217057B2** claims a crystalline form of a free base of crizotinib with improved solubility, stability, and physicochemical properties to develop solid dosage forms, such as capsules [62].

idinyl]amino]-2-methylbenzenesulfonamide monohydrochloride).

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 21 of 60

idinyl]amino]-2-methylbenzenesulfonamide monohydrochloride).

*4.12. Vandetanib* 

precisely [57].

*4.12. Vandetanib* 

precisely [57].

**Figure 13.** Vandetanib (*N*-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine). **Figure 13.** Vandetanib (*N*-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy] quinazolin-4-amine). C23H18ClF2N3O3S; MW: 489.9; CAS Number: 918504-65-1) [58]. **US8143271B2** describes pyrrolopyridine based compounds as PTKIs to treat diseases and conditions associated with aberrant activity of PTKs. It claims vemurafenib specifically [59].

**Figure 12.** Pazopanib hydrochloride (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrim-

**Figure 12.** Pazopanib hydrochloride (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrim-

Vandetanib (Figure 13) is a piperidine based 4-aminoquinazolinamine derivative (MF: C22H24BrFN4O2; MW: 475.36; CAS Number: 443913-73-3) [56]. **USRE42353E** (Reissue of US6414148B1) provides quinazoline derivatives, synthesis, and compositions to treat illness linked with angiogenesis and amplified vascular permeability. It claims vandetanib

Vandetanib (Figure 13) is a piperidine based 4-aminoquinazolinamine derivative (MF: C22H24BrFN4O2; MW: 475.36; CAS Number: 443913-73-3) [56]. **USRE42353E** (Reissue of US6414148B1) provides quinazoline derivatives, synthesis, and compositions to treat illness linked with angiogenesis and amplified vascular permeability. It claims vandetanib

**Figure 14.** Vemurafenib (Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-*b*]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide). **Figure 14.** Vemurafenib (Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-*b*]pyridine-3 carbonyl]-2,4-difluoro-phenyl}-amide). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 22 of 60

**Figure 15.** Crizotinib ((R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine). **Figure 15.** Crizotinib ((R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine).

#### *4.15. Ruxolitinib Phosphate 4.15. Ruxolitinib Phosphate*

Ruxolitinib phosphate (Figure 16) is a pyrrolo[2,3-*d*]pyrimidine based pyrazole derivative (MF: C17H21N6O4P; MW: 404.36; CAS Number: 1092939-17-7) [63]. **US7598257B2**  provides pyrrolo[2,3-*b*]pyridines as JAK modulators, which are beneficial to treat im-Ruxolitinib phosphate (Figure 16) is a pyrrolo[2,3-*d*]pyrimidine based pyrazole derivative (MF: C17H21N6O4P; MW: 404.36; CAS Number: 1092939-17-7) [63]. **US7598257B2**

mune-related disorders, skin diseases, myeloid proliferative ailments, and cancer. It

improved water solubility, dissolution rate, chemical stability, long shelf life, excipients,

**Figure 16.** Ruxolitinib phosphate ((R)-3-(4-(7H-pyrrolo[2,3-*d*]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-

Axitinib (Figure 17) is a pyridine based indazolylphenyl thioether (MF: C22H18N4OS; MW: 386.47; CAS Number: 319460-85-0) [66]. **US6534524B1** relates to indazole com-

and reproducibility compared to the free base [65].

cyclopentylpropanenitrile phosphate).

*4.16. Axitinib* 

provides pyrrolo[2,3-*b*]pyridines as JAK modulators, which are beneficial to treat immunerelated disorders, skin diseases, myeloid proliferative ailments, and cancer. It claims ruxolitinib and its salts [64]. **US8722693B2** claims ruxolitinib phosphate, which has improved water solubility, dissolution rate, chemical stability, long shelf life, excipients, and reproducibility compared to the free base [65]. rivative (MF: C17H21N6O4P; MW: 404.36; CAS Number: 1092939-17-7) [63]. **US7598257B2**  provides pyrrolo[2,3-*b*]pyridines as JAK modulators, which are beneficial to treat immune-related disorders, skin diseases, myeloid proliferative ailments, and cancer. It claims ruxolitinib and its salts [64]. **US8722693B2** claims ruxolitinib phosphate, which has improved water solubility, dissolution rate, chemical stability, long shelf life, excipients, and reproducibility compared to the free base [65].

Ruxolitinib phosphate (Figure 16) is a pyrrolo[2,3-*d*]pyrimidine based pyrazole de-

**Figure 15.** Crizotinib ((R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyra-

zol-4-yl]pyridin-2-amine).

*4.15. Ruxolitinib Phosphate* 

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 22 of 60

#### *4.16. Axitinib 4.16. Axitinib Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 23 of 60

Axitinib (Figure 17) is a pyridine based indazolylphenyl thioether (MF: C22H18N4OS; MW: 386.47; CAS Number: 319460-85-0) [66]. **US6534524B1** relates to indazole com-Axitinib (Figure 17) is a pyridine based indazolylphenyl thioether (MF: C22H18N4OS; MW: 386.47; CAS Number: 319460-85-0) [66]. **US6534524B1** relates to indazole compounds as PTKIs and their pharmaceutical compositions to treat diseases linked with undesirable angiogenesis and cellular proliferation. It claims axitinib specifically [67]. **US8791140B2** claims crystalline forms of axitinib that have advantages in bioavailability, stability, manufacture ability, and suitability for bulk preparation [68]. pounds as PTKIs and their pharmaceutical compositions to treat diseases linked with undesirable angiogenesis and cellular proliferation. It claims axitinib specifically [67]. **US8791140B2** claims crystalline forms of axitinib that have advantages in bioavailability, stability, manufacture ability, and suitability for bulk preparation [68].

**Figure 17.** Axitinib (*N*-methyl-2-[3-((*E*)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide). **Figure 17.** Axitinib (*N*-methyl-2-[3-((*E*)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide).

#### *4.17. Bosutinib Monohydrate 4.17. Bosutinib Monohydrate*

*4.18. Regorafenib Monohydrate* 

Bosutinib monohydrate (Figure 18) is a piperazine based 3-quinolinecarbonitrile derivative (MF: C26H29Cl2N5O3.H2O; MW: 548.46; CAS Number: 918639-08-4) [69]. **USRE42376E** (Reissue of US6297258B1) describes substituted 3-cyano quinoline compounds as PTKIs to treat diseases resulting from deregulation of PTKs, for example, cancer and polycystic kidney disease. It claims bosutinib [70]. **US7767678B2** claims non-hy-Bosutinib monohydrate (Figure 18) is a piperazine based 3-quinolinecarbonitrile derivative (MF: C26H29Cl2N5O3·H2O; MW: 548.46; CAS Number: 918639-08-4) [69]. **USRE42376E** (Reissue of US6297258B1) describes substituted 3-cyano quinoline compounds as PTKIs to treat diseases resulting from deregulation of PTKs, for example, cancer and polycystic kidney disease. It claims bosutinib [70]. **US7767678B2** claims non-hygroscopic and stable

groscopic and stable crystalline bosutinib monohydrate (Form I) having good solubility

**Figure 18.** Bosutinib monohydrate (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-

Regorafenib monohydrate (Figure 19) is pyridinylphenyl urea derivative (MF: C21H15ClF4N4O3.H2O; MW: 500.83; CAS Number: 1019206-88-2) [72]. **US8637553B2** discloses omega-carboxyaryl diphenyl urea derivatives as potent inhibitors of PDGFR, VEGFR, RAF, and p38 kinase to treat cancer, inflammatory diseases, and osteoporosis. It claims regorafenib and its salts [73]. **US9957232B2** claims regorafenib monohydrate with

methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile monohydrate).

crystalline bosutinib monohydrate (Form I) having good solubility that can be used to prepare different solid dosage forms [71]. cer and polycystic kidney disease. It claims bosutinib [70]. **US7767678B2** claims non-hygroscopic and stable crystalline bosutinib monohydrate (Form I) having good solubility that can be used to prepare different solid dosage forms [71].

**Figure 17.** Axitinib (*N*-methyl-2-[3-((*E*)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide).

Bosutinib monohydrate (Figure 18) is a piperazine based 3-quinolinecarbonitrile derivative (MF: C26H29Cl2N5O3.H2O; MW: 548.46; CAS Number: 918639-08-4) [69]. **USRE42376E** (Reissue of US6297258B1) describes substituted 3-cyano quinoline compounds as PTKIs to treat diseases resulting from deregulation of PTKs, for example, can-

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 23 of 60

stability, manufacture ability, and suitability for bulk preparation [68].

pounds as PTKIs and their pharmaceutical compositions to treat diseases linked with undesirable angiogenesis and cellular proliferation. It claims axitinib specifically [67]. **US8791140B2** claims crystalline forms of axitinib that have advantages in bioavailability,

**Figure 18.** Bosutinib monohydrate (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4 methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile monohydrate). **Figure 18.** Bosutinib monohydrate (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4 methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile monohydrate).

#### *4.18. Regorafenib Monohydrate 4.18. Regorafenib Monohydrate*

*4.17. Bosutinib Monohydrate* 

Regorafenib monohydrate (Figure 19) is pyridinylphenyl urea derivative (MF: C21H15ClF4N4O3.H2O; MW: 500.83; CAS Number: 1019206-88-2) [72]. **US8637553B2** discloses omega-carboxyaryl diphenyl urea derivatives as potent inhibitors of PDGFR, VEGFR, RAF, and p38 kinase to treat cancer, inflammatory diseases, and osteoporosis. It claims regorafenib and its salts [73]. **US9957232B2** claims regorafenib monohydrate with Regorafenib monohydrate (Figure 19) is pyridinylphenyl urea derivative (MF: C21H15Cl F4N4O3·H2O; MW: 500.83; CAS Number: 1019206-88-2) [72]. **US8637553B2** discloses omega-carboxyaryl diphenyl urea derivatives as potent inhibitors of PDGFR, VEGFR, RAF, and p38 kinase to treat cancer, inflammatory diseases, and osteoporosis. It claims regorafenib and its salts [73]. **US9957232B2** claims regorafenib monohydrate with high stability and good physicochemical features to manufacture pharmaceutical compositions [74]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 24 of 60 high stability and good physicochemical features to manufacture pharmaceutical compositions [74].

**Figure 19.** Regorafenib monohydrate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-*N*-methylpyridine-2-carboxamide monohydrate). **Figure 19.** Regorafenib monohydrate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)- 3-fluorophenoxy]-*N*-methylpyridine-2-carboxamide monohydrate).

#### *4.19. Tofacitinib Citrate 4.19. Tofacitinib Citrate*

let development [77].

*4.20. Cabozantinib S-Malate* 

Tofacitinib citrate (Figure 20) is an pyrrolo[2,3-*d*]pyrimidine based piperidine derivative (MF: C16H20N6O.C6H8O7; MW: 504.5; CAS Number: 540737-29-9) [75]. **USRE41783E** (Reissue of US6627754B2) provides pyrrolo[2,3-*d*]pyrimidines as JAK3 inhibitors to treat rheumatoid arthritis, psoriasis, cancer, and leukemia. It claims tofacitinib and its salt [76]. Tofacitinib citrate (Figure 20) is an pyrrolo[2,3-*d*]pyrimidine based piperidine derivative (MF: C16H20N6O·C6H8O7; MW: 504.5; CAS Number: 540737-29-9) [75]. **USRE41783E** (Reissue of US6627754B2) provides pyrrolo[2,3-*d*]pyrimidines as JAK3 inhibitors to treat rheumatoid arthritis, psoriasis, cancer, and leukemia. It claims tofacitinib and its salt [76].

**US6965027B2** claims a crystalline form of tofacitinib mono citrate salt with solid-state properties (solubility, stability, compressibility, etc.), which are acceptable to support tab-

**Figure 20.** Tofacitinib citrate ((3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-*d*]pyrimidin-4-ylamino)-

Cabozantinib S-malate (Figure 21) is a quinolinylphenyl ether derivative (MF: C28H24FN3O5.C4H6O5; MW: 635.6; CAS Number: 1140909-48-3) [78]. **US7579473B2** relates to quinazolines and quinolines as TKIs, and their pharmaceutical compositions to treat psoriasis, multiple sclerosis, and rheumatoid arthritis. It claims cabozantinib and its salts

ß-oxo-1-piperidinepropanenitrile 2-hydroxy-1,2,3-propanetricarboxylate (1:1)).

**US6965027B2** claims a crystalline form of tofacitinib mono citrate salt with solid-state properties (solubility, stability, compressibility, etc.), which are acceptable to support tablet development [77]. **US6965027B2** claims a crystalline form of tofacitinib mono citrate salt with solid-state properties (solubility, stability, compressibility, etc.), which are acceptable to support tablet development [77].

Tofacitinib citrate (Figure 20) is an pyrrolo[2,3-*d*]pyrimidine based piperidine derivative (MF: C16H20N6O.C6H8O7; MW: 504.5; CAS Number: 540737-29-9) [75]. **USRE41783E** (Reissue of US6627754B2) provides pyrrolo[2,3-*d*]pyrimidines as JAK3 inhibitors to treat rheumatoid arthritis, psoriasis, cancer, and leukemia. It claims tofacitinib and its salt [76].

**Figure 19.** Regorafenib monohydrate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-*N*-methylpyridine-2-carboxamide monohydrate).

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 24 of 60

sitions [74].

high stability and good physicochemical features to manufacture pharmaceutical compo-

*4.19. Tofacitinib Citrate* 

**Figure 20.** Tofacitinib citrate ((3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-*d*]pyrimidin-4-ylamino) ß-oxo-1-piperidinepropanenitrile 2-hydroxy-1,2,3-propanetricarboxylate (1:1)). **Figure 20.** Tofacitinib citrate ((3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-*d*]pyrimidin-4-ylamino)-ßoxo-1-piperidinepropanenitrile 2-hydroxy-1,2,3-propanetricarboxylate (1:1)).

#### *4.20. Cabozantinib S-Malate 4.20. Cabozantinib S-Malate*

Cabozantinib S-malate (Figure 21) is a quinolinylphenyl ether derivative (MF: C28H24FN3O5.C4H6O5; MW: 635.6; CAS Number: 1140909-48-3) [78]. **US7579473B2** relates to quinazolines and quinolines as TKIs, and their pharmaceutical compositions to treat psoriasis, multiple sclerosis, and rheumatoid arthritis. It claims cabozantinib and its salts Cabozantinib S-malate (Figure 21) is a quinolinylphenyl ether derivative (MF: C28H24FN<sup>3</sup> O5·C4H6O5; MW: 635.6; CAS Number: 1140909-48-3) [78]. **US7579473B2** relates to quinazolines and quinolines as TKIs, and their pharmaceutical compositions to treat psoriasis, multiple sclerosis, and rheumatoid arthritis. It claims cabozantinib and its salts [79]. **US8877776B2** claims cabozantinib (L)-malate salt having desirable solubility and chemical/physical stability to develop a tablet/capsule dosage forms for intended use [80]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 25 of 60 [79]. **US8877776B2** claims cabozantinib (L)-malate salt having desirable solubility and chemical/physical stability to develop a tablet/capsule dosage forms for intended use [80].

**Figure 21.** Cabozantinib (S)-malate *(N*-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-*N'*-(4-fluorophenyl)cyclopropane-1,1-dicarboxamid (2S)-hydroxybutanedioate). **Figure 21.** Cabozantinib (S)-malate (*N*-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-*N*0 -(4-fluoroph enyl)cyclopropane-1,1-dicarboxamid (2S)-hydroxybutanedioate).

#### *4.21. Ponatinib Hydrochloride 4.21. Ponatinib Hydrochloride*

[83].

Ponatinib hydrochloride (Figure 22) is animidazo[1,2-*b*]pyridazine based piperazine derivative (MF: C29H28ClF3N6O; MW: 569.02; CAS Number: 1114544-31-8) [81]. **US8114874B2** describes imidazo[1,2-*b*]pyridazines as PTKIs and their pharmaceutical compositions to treat cancer and other diseases mediated by PTKs. It claims ponatinib hydrochloride specifically [82]. **US9493470B2** claims stable crystalline form A of ponatinib Ponatinib hydrochloride (Figure 22) is animidazo[1,2-*b*]pyridazine based piperazine derivative (MF: C29H28ClF3N6O; MW: 569.02; CAS Number: 1114544-31-8) [81]. **US8114874B2** describes imidazo[1,2-*b*]pyridazines as PTKIs and their pharmaceutical compositions to treat cancer and other diseases mediated by PTKs. It claims ponatinib hydrochloride specifically [82]. **US9493470B2** claims stable crystalline form A of ponatinib hydrochloride that is

hydrochloride that is advantageous for the commercial preparation of solid dosage forms

**Figure 22.** Ponatinib hydrochloride (3-(imidazo[1,2-*b*]pyridazin-3-ylethynyl)-4-methyl-*N*-{4-[(4-

methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride).

advantageous for the commercial preparation of solid dosage forms because of its physicochemical stability compared to amorphous ponatinib hydrochloride [83]. because of its physicochemical stability compared to amorphous ponatinib hydrochloride [83].

**Figure 21.** Cabozantinib (S)-malate *(N*-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-*N'*-(4-fluoro-

Ponatinib hydrochloride (Figure 22) is animidazo[1,2-*b*]pyridazine based piperazine derivative (MF: C29H28ClF3N6O; MW: 569.02; CAS Number: 1114544-31-8) [81]. **US8114874B2** describes imidazo[1,2-*b*]pyridazines as PTKIs and their pharmaceutical compositions to treat cancer and other diseases mediated by PTKs. It claims ponatinib hydrochloride specifically [82]. **US9493470B2** claims stable crystalline form A of ponatinib hydrochloride that is advantageous for the commercial preparation of solid dosage forms

phenyl)cyclopropane-1,1-dicarboxamid (2S)-hydroxybutanedioate).

*4.21. Ponatinib Hydrochloride* 

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 25 of 60

[79]. **US8877776B2** claims cabozantinib (L)-malate salt having desirable solubility and chemical/physical stability to develop a tablet/capsule dosage forms for intended use [80].

**Figure 22.** Ponatinib hydrochloride (3-(imidazo[1,2-*b*]pyridazin-3-ylethynyl)-4-methyl-*N*-{4-[(4 methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride). **Figure 22.** Ponatinib hydrochloride (3-(imidazo[1,2-*b*]pyridazin-3-ylethynyl)-4-methyl-*N*-{4-[(4 methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 26 of 60

#### *4.22. Trametinib Dimethyl Sulfoxide 4.22. Trametinib Dimethyl Sulfoxide*

Trametinib dimethyl sulfoxide (Figure 23) is a pyridopyrimidine derivative (MF: C26H23FIN5O4.C2H6OS; MW: 693.53; CAS Number: 1187431-43-1) [84]. **US7378423B2** unveils pyrimidine compounds, their salts, synthetic procedures, and compositions to treat ailments caused by unwanted cell proliferation, for example, cancer. It claims trametinib dimethyl sulfoxide specifically [85]. Trametinib dimethyl sulfoxide (Figure 23) is a pyridopyrimidine derivative (MF: C26H23FIN5O4.C2H6OS; MW: 693.53; CAS Number: 1187431-43-1) [84]. **US7378423B2** unveils pyrimidine compounds, their salts, synthetic procedures, and compositions to treat ailments caused by unwanted cell proliferation, for example, cancer. It claims trametinib dimethyl sulfoxide specifically [85].

**Figure 23.** Trametinib dimethyl sulfoxide (*N*-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]- 6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-*d*]pyrimidin-1-yl}phenyl)acetamide dimethyl sulfoxide). **Figure 23.** Trametinib dimethyl sulfoxide (*N*-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]- 6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-*d*]pyrimidin-1-yl}phenyl)acetamide dimethyl sulfoxide).

#### *4.23. Dabrafenib Mesylate 4.23. Dabrafenib Mesylate*

sylate specifically [87].

Dabrafenib mesylate (Figure 24) is a pyrimidine-thiazole based diphenyl sulfonamide derivative (MF: C23H20F3N5O2S2.CH4O3S; MW: 615.68; CAS Number: 1195768-06-9) [86]. **US7994185B2** provides benzene sulfonamide thiazole and oxazole compounds, their pharmaceutical compositions, processes for their preparation, and methods of using these Dabrafenib mesylate (Figure 24) is a pyrimidine-thiazole based diphenyl sulfonamide derivative (MF: C23H20F3N5O2S2.CH4O3S; MW: 615.68; CAS Number: 1195768-06-9) [86]. **US7994185B2** provides benzene sulfonamide thiazole and oxazole compounds, their pharmaceutical compositions, processes for their preparation, and methods of using these

compounds and compositions for treating cancer and melanoma. It claims dabrafenib me-

**Figure 24.** Dabrafenib mesylate (*N*-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-

4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide mesylate).

compounds and compositions for treating cancer and melanoma. It claims dabrafenib mesylate specifically [87]. pharmaceutical compositions, processes for their preparation, and methods of using these compounds and compositions for treating cancer and melanoma. It claims dabrafenib mesylate specifically [87].

**Figure 23.** Trametinib dimethyl sulfoxide (*N*-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]- 6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-*d*]pyrimidin-1-yl}phenyl)acetamide di-

Dabrafenib mesylate (Figure 24) is a pyrimidine-thiazole based diphenyl sulfonamide derivative (MF: C23H20F3N5O2S2.CH4O3S; MW: 615.68; CAS Number: 1195768-06-9) [86]. **US7994185B2** provides benzene sulfonamide thiazole and oxazole compounds, their

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 27 of 60

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 26 of 60

Trametinib dimethyl sulfoxide (Figure 23) is a pyridopyrimidine derivative (MF: C26H23FIN5O4.C2H6OS; MW: 693.53; CAS Number: 1187431-43-1) [84]. **US7378423B2** unveils pyrimidine compounds, their salts, synthetic procedures, and compositions to treat ailments caused by unwanted cell proliferation, for example, cancer. It claims trametinib

*4.22. Trametinib Dimethyl Sulfoxide* 

dimethyl sulfoxide specifically [85].

**Figure 24.** Dabrafenib mesylate (*N*-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide mesylate). **Figure 24.** Dabrafenib mesylate (*N*-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4 yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide mesylate).

#### *4.24. Afatinib Dimaleate 4.24. Afatinib Dimaleate*

methyl sulfoxide).

*4.23. Dabrafenib Mesylate* 

Afatinib dimaleate (Figure 25) is a tetrahydrofuran based quinazolinamine derivative (MF: C32H33ClFN5O11; MW: 718.1; CAS Number: 850140-73-7) [88]. **USRE43431E** (Reissue of US7019012B2) unveils quinazoline derivatives and their physiologically acceptable salts possessing an inhibitory effect on signal transduction mediated by PTKs to treat tumoral diseases, diseases of the lungs, and respiratory tract. It claims afatinib dimaleate precisely [89]. **US8426586B2** claims crystalline afatinib dimaleate, synthesis, and its compositions. The claimed crystalline form is stable and has advantageous properties to develop quality dosage forms [90]. Afatinib dimaleate (Figure 25) is a tetrahydrofuran based quinazolinamine derivative (MF: C32H33ClFN5O11; MW: 718.1; CAS Number: 850140-73-7) [88]. **USRE43431E** (Reissue of US7019012B2) unveils quinazoline derivatives and their physiologically acceptable salts possessing an inhibitory effect on signal transduction mediated by PTKs to treat tumoral diseases, diseases of the lungs, and respiratory tract. It claims afatinib dimaleate precisely [89]. **US8426586B2** claims crystalline afatinib dimaleate, synthesis, and its compositions. The claimed crystalline form is stable and has advantageous properties to develop quality dosage forms [90].

**Figure 25.** Afatinib dimaleate (*N*-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3 furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)but-2-enamide dimaleate). **Figure 25.** Afatinib dimaleate (*N*-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4-(dimethylamino)but-2-enamide dimaleate).

#### *4.25. Ibrutinib 4.25. Ibrutinib*

forms [93].

Ibrutinib (Figure 26) is a piperidine based pyrazolo[3,4-*d*]pyrimidine (MF: C25H24N6O2; MW: 440.50; CAS Number: 936563-96-1) [91]. **US8735403B2** describes pyrazolo[3,4-*d*]pyrimidine based inhibitors of BTK, their synthesis, and compositions to treat diseases, wherein inhibition of BTK delivers therapeutic advantage to the diseased person. It claims ibrutinib specifically [92]. **US9296753B2** claims stable, water-soluble, and non-hygroscopic crystalline ibrutinib that can be used to manufacture quality dosage Ibrutinib (Figure 26) is a piperidine based pyrazolo[3,4-*d*]pyrimidine (MF: C25H24N6O2; MW: 440.50; CAS Number: 936563-96-1) [91]. **US8735403B2** describes pyrazolo[3,4-*d*]pyrimidine based inhibitors of BTK, their synthesis, and compositions to treat diseases, wherein inhibition of BTK delivers therapeutic advantage to the diseased person. It claims ibrutinib specifically [92]. **US9296753B2** claims stable, water-soluble, and non-hygroscopic crystalline ibrutinib that can be used to manufacture quality dosage forms [93].

*4.24. Afatinib Dimaleate* 

velop quality dosage forms [90].

**Figure 26.** Ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-*d*]pyrimidin-1-yl]-1 piperidinyl]-2-propen-1-one). **Figure 26.** Ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-*d*]pyrimidin-1-yl]- 1-piperidinyl]-2-propen-1-one).

Afatinib dimaleate (Figure 25) is a tetrahydrofuran based quinazolinamine derivative (MF: C32H33ClFN5O11; MW: 718.1; CAS Number: 850140-73-7) [88]. **USRE43431E** (Reissue of US7019012B2) unveils quinazoline derivatives and their physiologically acceptable salts possessing an inhibitory effect on signal transduction mediated by PTKs to treat tumoral diseases, diseases of the lungs, and respiratory tract. It claims afatinib dimaleate precisely [89]. **US8426586B2** claims crystalline afatinib dimaleate, synthesis, and its compositions. The claimed crystalline form is stable and has advantageous properties to de-

**Figure 25.** Afatinib dimaleate (*N*-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-

Ibrutinib (Figure 26) is a piperidine based pyrazolo[3,4-*d*]pyrimidine (MF: C25H24N6O2; MW: 440.50; CAS Number: 936563-96-1) [91]. **US8735403B2** describes pyrazolo[3,4-*d*]pyrimidine based inhibitors of BTK, their synthesis, and compositions to treat diseases, wherein inhibition of BTK delivers therapeutic advantage to the diseased person. It claims ibrutinib specifically [92]. **US9296753B2** claims stable, water-soluble, and non-hygroscopic crystalline ibrutinib that can be used to manufacture quality dosage

furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)but-2-enamide dimaleate).

#### *4.26. Ceritinib 4.26. Ceritinib*

*4.25. Ibrutinib* 

forms [93].

Ceritinib (Figure 27) is a pyrimidine based phenylpiperidine derivative (MF: C28H36N<sup>5</sup> O3ClS; MW: 558.14; CAS Number: 1032900-25-6) [94]. **US8039479B2** reveals pyrimidine and pyridine derivatives and their pharmaceutical compositions to treat a condition that responds to inhibition of ALK, FAK, ZAP-70, IGF-1R, or a combination thereof. It claims ceritinib specifically [95]. **US9309229B2** claims a pure and stable crystalline form of ceritinib with desirable physicochemical properties to provide good dosage forms [96]. Ceritinib (Figure 27) is a pyrimidine based phenylpiperidine derivative (MF: C28H36N5O3ClS; MW: 558.14; CAS Number: 1032900-25-6) [94]. **US8039479B2** reveals pyrimidine and pyridine derivatives and their pharmaceutical compositions to treat a condition that responds to inhibition of ALK, FAK, ZAP-70, IGF-1R, or a combination thereof. It claims ceritinib specifically [95]. **US9309229B2** claims a pure and stable crystalline form of ceritinib with desirable physicochemical properties to provide good dosage forms [96].

#### *4.27. Idelalisib 4.27. Idelalisib*

forms [99].

one).

Idelalisib (Figure 28) is a purine based quinazolinone derivative (MF: C22H18FN7O; MW: 415.42; CAS Number: 870281-82-6) [97]. **USRE44638E** (Reissue of US7932260B2) reports substituted quinazolinone compounds as PI3Kδ inhibitors to treat diseases like boneresorption disorders, hematopoietic cancers, lymphomas, multiple myelomas, and leukemia. It claims idelalisib and its salts [98]. **US9469643B2** claims a water-soluble bioavailable Idelalisib (Figure 28) is a purine based quinazolinone derivative (MF: C22H18FN7O; MW: 415.42; CAS Number: 870281-82-6) [97]. **USRE44638E** (Reissue of US7932260B2) reports substituted quinazolinone compounds as PI3K<sup>δ</sup> inhibitors to treat diseases like bone-resorption disorders, hematopoietic cancers, lymphomas, multiple myelomas, and leukemia. It claims idelalisib and its salts [98]. **US9469643B2** claims a water-soluble

and stable polymorph of idelalisib (Form II) that can be used to provide quality dosage

**Figure 28.** Idelalisib (5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-

bioavailable and stable polymorph of idelalisib (Form II) that can be used to provide quality dosage forms [99]. and stable polymorph of idelalisib (Form II) that can be used to provide quality dosage forms [99].

Idelalisib (Figure 28) is a purine based quinazolinone derivative (MF: C22H18FN7O; MW: 415.42; CAS Number: 870281-82-6) [97]. **USRE44638E** (Reissue of US7932260B2) reports substituted quinazolinone compounds as PI3Kδ inhibitors to treat diseases like boneresorption disorders, hematopoietic cancers, lymphomas, multiple myelomas, and leukemia. It claims idelalisib and its salts [98]. **US9469643B2** claims a water-soluble bioavailable

**Figure 27.** Ceritinib (5-Chloro-*N*4-[2-[(1-methylethyl)sulfonyl]phenyl]-*N*2-[5-methyl-2-(1-meth-

ylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine).

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 28 of 60

1-piperidinyl]-2-propen-1-one).

*4.26. Ceritinib* 

*4.27. Idelalisib* 

**Figure 26.** Ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-*d*]pyrimidin-1-yl]-

Ceritinib (Figure 27) is a pyrimidine based phenylpiperidine derivative (MF: C28H36N5O3ClS; MW: 558.14; CAS Number: 1032900-25-6) [94]. **US8039479B2** reveals pyrimidine and pyridine derivatives and their pharmaceutical compositions to treat a condition that responds to inhibition of ALK, FAK, ZAP-70, IGF-1R, or a combination thereof. It claims ceritinib specifically [95]. **US9309229B2** claims a pure and stable crystalline form of ceritinib with desirable physicochemical properties to provide good dosage forms [96].

**Figure 28.** Idelalisib (5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)- **Figure 28.** Idelalisib (5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one).

#### one). *4.28. Nintedanib Esylate 4.28. Nintedanib Esylate*

Nintedanib esylate (Figure 29) is a piperazine based indole carboxylic acid derivative (MF: C31H33N5O4.C2H6O3S; MW: 649.76; CAS Number: 656247-18-6) [100]. **US6762180B1** states indolinone derivatives as PTKIs, synthesis, and compositions to treat proliferative sicknesses. It claims nintedanib and its salts [101]. **US7119093B2** claims a stable nintedanib esylate salt specifically characterized by good crystallinity and low amorphization during grinding and compression. This salt is claimed to have good physicochemical characteristics to support quality dosage forms [102]. Nintedanib esylate (Figure 29) is a piperazine based indole carboxylic acid derivative (MF: C31H33N5O4·C2H6O3S; MW: 649.76; CAS Number: 656247-18-6) [100]. **US6762180B1** states indolinone derivatives as PTKIs, synthesis, and compositions to treat proliferative sicknesses. It claims nintedanib and its salts [101]. **US7119093B2** claims a stable nintedanib esylate salt specifically characterized by good crystallinity and low amorphization during grinding and compression. This salt is claimed to have good physicochemical characteristics to support quality dosage forms [102].

**Figure 29.** Nintedanib esylate (methyl (3Z)-3-[({4-[*N*-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate esylate). **Figure 29.** Nintedanib esylate (methyl (3Z)-3-[({4-[*N*-methyl-2-(4-methylpiperazin-1-yl)acetamido] phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate esylate).

#### *4.29. Palbociclib 4.29. Palbociclib*

Palbociclib (Figure 30) is a pyrido[2,3-*d*]pyrimidine based pyridinylpiperazine derivative (MF: C24H29N7O2; MW: 447.54; CAS: 571190-30-2) [103]. **USRE47739E** (Reissue of US7208489B2) delivers substituted 2-amino pyridines as potent inhibitors of CDK 4, useful for treating inflammation and proliferative cell diseases such as cancer and restenosis. It claims palbociclib and its salts [104]. **US10723730B2** claims a stable crystalline free base of palbociclib with larger primary particle size, reduced specific surface area, lower surface energy measurements, and physicochemical properties to formulate a good dosage form [105]. Palbociclib (Figure 30) is a pyrido[2,3-*d*]pyrimidine based pyridinylpiperazine derivative (MF: C24H29N7O2; MW: 447.54; CAS: 571190-30-2) [103]. **USRE47739E** (Reissue of US7208489B2) delivers substituted 2-amino pyridines as potent inhibitors of CDK 4, useful for treating inflammation and proliferative cell diseases such as cancer and restenosis. It claims palbociclib and its salts [104]. **US10723730B2** claims a stable crystalline free base of palbociclib with larger primary particle size, reduced specific surface area, lower surface energy measurements, and physicochemical properties to formulate a good dosage form [105].

**Figure 30.** Palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-

yl]amino}pyrido[2,3-*d*]pyrimidin-7(8H)-one).

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 30 of 60

**Figure 30.** Palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2 yl]amino}pyrido[2,3-*d*]pyrimidin-7(8H)-one). **Figure 30.** Palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino} pyrido[2,3-*d*]pyrimidin-7(8H)-one).

**Figure 29.** Nintedanib esylate (methyl (3Z)-3-[({4-[*N*-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate esylate).

Palbociclib (Figure 30) is a pyrido[2,3-*d*]pyrimidine based pyridinylpiperazine derivative (MF: C24H29N7O2; MW: 447.54; CAS: 571190-30-2) [103]. **USRE47739E** (Reissue of US7208489B2) delivers substituted 2-amino pyridines as potent inhibitors of CDK 4, useful for treating inflammation and proliferative cell diseases such as cancer and restenosis. It claims palbociclib and its salts [104]. **US10723730B2** claims a stable crystalline free base of palbociclib with larger primary particle size, reduced specific surface area, lower surface energy measurements, and physicochemical properties to formulate a good dosage

Nintedanib esylate (Figure 29) is a piperazine based indole carboxylic acid derivative (MF: C31H33N5O4·C2H6O3S; MW: 649.76; CAS Number: 656247-18-6) [100]. **US6762180B1** states indolinone derivatives as PTKIs, synthesis, and compositions to treat proliferative sicknesses. It claims nintedanib and its salts [101]. **US7119093B2** claims a stable nintedanib esylate salt specifically characterized by good crystallinity and low amorphization during grinding and compression. This salt is claimed to have good physicochemical character-

#### *4.30. Lenvatinib Mesylate 4.30. Lenvatinib Mesylate*

*4.29. Palbociclib* 

form [105].

*4.28. Nintedanib Esylate* 

istics to support quality dosage forms [102].

Lenvatinib mesylate (Figure 31) is a quinoline carboxamide derivative (MF: C21H19Cl N4O4.CH4O3S; MW: 522.96; CAS Number: 857890-39-2) [106]. **US7253286B2** reports nitrogen-containing aromatic derivatives and salts or hydrates thereof to treat various diseases associated with abnormal angiogenesis. It claims lenvatinib and its pharmacologically active salts [107]. **US7612208B2** claims a crystalline form of lenvatinib mesylate with improved features (physical/pharmacokinetics) compared to the free-form [108]. Lenvatinib mesylate (Figure 31) is a quinoline carboxamide derivative (MF: C21H19ClN4O4.CH4O3S; MW: 522.96; CAS Number: 857890-39-2) [106]. **US7253286B2** reports nitrogen-containing aromatic derivatives and salts or hydrates thereof to treat various diseases associated with abnormal angiogenesis. It claims lenvatinib and its pharmacologically active salts [107]. **US7612208B2** claims a crystalline form of lenvatinib mesylate with improved features (physical/pharmacokinetics) compared to the free-form [108].

**Figure 31.** Lenvatinib mesylate (4-[3-chloro-4-(*N'*-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate). **Figure 31.** Lenvatinib mesylate (4-[3-chloro-4-(*N*0 -cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate).

#### *4.31. Cobimetinib Fumarate 4.31. Cobimetinib Fumarate*

*4.32. Osimertinib Mesylate* 

Cobimetinib fumarate (Figure 32) is a piperidine-azetidine based anthranilamide derivative (MF: C46H46F6I2N6O8 (2C21H21F3IN3O2.C4H4O4); MW: 1178.71; CAS Number: 1369665-02-0) [109]. **US7803839B2** provides azetidin-1-yl(2-(2-fluorophenylamino)cyclic)methanone derivatives as inhibitors of MEK that are useful in cancer treatment. It claims cobimetinib and its salts [110]. **US10590102B2** claims a thermodynamically stable and non-hygroscopic crystalline fumarate salt (Form A) of cobimetinib with suitable properties for use in a pharmaceutical composition [111]. Cobimetinib fumarate (Figure 32) is a piperidine-azetidine based anthranilamide derivative (MF: C46H46F6I2N6O<sup>8</sup> (2C21H21F3IN3O2.C4H4O4); MW: 1178.71; CAS Number: 1369665-02-0) [109]. **US7803839B2** provides azetidin-1-yl(2-(2-fluorophenylamino) cyclic)methanone derivatives as inhibitors of MEK that are useful in cancer treatment. It claims cobimetinib and its salts [110]. **US10590102B2** claims a thermodynamically stable and non-hygroscopic crystalline fumarate salt (Form A) of cobimetinib with suitable properties for use in a pharmaceutical composition [111].

**Figure 32.** Cobimetinib fumarate ((S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hy-

Osimertinib mesylate (Figure 33) is a pyrimidine based indole derivative (MF: C28H33N7O2.CH4O3S; MW: 596; CAS Number: 1421373-66-1) [112]. **US8946235B2** states 2- (2,4,5-substituted-anilino)pyrimidines, useful in treating a disease mediated by EGFR, for

droxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemifumarate).

example, cancer. It claims osimertinib mesylate specifically [113].

*4.30. Lenvatinib Mesylate* 

line-6-carboxamide methanesulfonate).

*4.31. Cobimetinib Fumarate* 

**Figure 31.** Lenvatinib mesylate (4-[3-chloro-4-(*N'*-cyclopropylureido)phenoxy]-7-methoxyquino-

Cobimetinib fumarate (Figure 32) is a piperidine-azetidine based anthranilamide derivative (MF: C46H46F6I2N6O8 (2C21H21F3IN3O2.C4H4O4); MW: 1178.71; CAS Number: 1369665-02-0) [109]. **US7803839B2** provides azetidin-1-yl(2-(2-fluorophenylamino)cyclic)methanone derivatives as inhibitors of MEK that are useful in cancer treatment. It

and non-hygroscopic crystalline fumarate salt (Form A) of cobimetinib with suitable prop-

Lenvatinib mesylate (Figure 31) is a quinoline carboxamide derivative (MF: C21H19ClN4O4.CH4O3S; MW: 522.96; CAS Number: 857890-39-2) [106]. **US7253286B2** reports nitrogen-containing aromatic derivatives and salts or hydrates thereof to treat various diseases associated with abnormal angiogenesis. It claims lenvatinib and its pharmacologically active salts [107]. **US7612208B2** claims a crystalline form of lenvatinib mesylate with improved features (physical/pharmacokinetics) compared to the free-form [108].

**Figure 32.** Cobimetinib fumarate ((S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemifumarate). **Figure 32.** Cobimetinib fumarate ((S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2 yl)azetidin-1-yl]methanone hemifumarate).

#### *4.32. Osimertinib Mesylate 4.32. Osimertinib Mesylate*

erties for use in a pharmaceutical composition [111].

Osimertinib mesylate (Figure 33) is a pyrimidine based indole derivative (MF: C28H33N7O2.CH4O3S; MW: 596; CAS Number: 1421373-66-1) [112]. **US8946235B2** states 2- (2,4,5-substituted-anilino)pyrimidines, useful in treating a disease mediated by EGFR, for example, cancer. It claims osimertinib mesylate specifically [113]. Osimertinib mesylate (Figure 33) is a pyrimidine based indole derivative (MF: C28H<sup>33</sup> N7O2.CH4O3S; MW: 596; CAS Number: 1421373-66-1) [112]. **US8946235B2** states 2-(2,4,5 substituted-anilino)pyrimidines, useful in treating a disease mediated by EGFR, for example, cancer. It claims osimertinib mesylate specifically [113]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 31 of 60

**Figure 33.** Osimertinib mesylate (*N*-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1 methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate). **Figure 33.** Osimertinib mesylate (*N*-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1 methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate).

#### *4.33. Alectinib Hydrochloride 4.33. Alectinib Hydrochloride*

Alectinib hydrochloride (Figure 34) is a morpholine-piperidine based carbazole derivatives (MF: C30H34N4O2.HCl; MW: 519.08; CAS Number: 1256589-74-8) [114]. **US9126931B2** relates to tetracyclic compounds as ALK inhibitors for treating a disease accompanied by an abnormality in ALK, for example, cancer, depression, and cognitive function disorder. It claims alectinib and its salts [115]. Alectinib hydrochloride (Figure 34) is a morpholine-piperidine based carbazole derivatives (MF: C30H34N4O2·HCl; MW: 519.08; CAS Number: 1256589-74-8) [114]. **US9126931B2** relates to tetracyclic compounds as ALK inhibitors for treating a disease accompanied by an abnormality in ALK, for example, cancer, depression, and cognitive function disorder. It claims alectinib and its salts [115].

### *4.34. Ribociclib Succinate*

*4.34. Ribociclib Succinate* 

Ribociclib succinate (Figure 35) is a pyridine-piperazine based pyrrolo[2,3-*d*]pyrimidine derivative (MF: C23H30N8O·C4H6O4; MW: 552.64; CAS Number: 1374639-75-4) [116]. **US8415355B2** discloses pyrrolopyrimidine compounds, the process for their preparation, and their pharmaceutical compositions to treat a disease linked with CDK 4 inhibition. It claims ribociclib and its salts [117]. **US9193732B2** claims succinate salt of ribociclib that

**Figure 34.** Alectinib hydrochloride (9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-

Ribociclib succinate (Figure 35) is a pyridine-piperazine based pyrrolo[2,3-*d*]pyrimidine derivative (MF: C23H30N8O.C4H6O4; MW: 552.64; CAS Number: 1374639-75-4) [116]. **US8415355B2** discloses pyrrolopyrimidine compounds, the process for their preparation, and their pharmaceutical compositions to treat a disease linked with CDK 4 inhibition. It claims ribociclib and its salts [117]. **US9193732B2** claims succinate salt of ribociclib that has good stability, non-hygroscopicity, and good solubility. These features make this salt

a suitable salt to develop the desired formulation [118].

oxo-6,11-dihydro-5H-benzo[*b*]carbazole-3-carbonitrile hydrochloride).

has good stability, non-hygroscopicity, and good solubility. These features make this salt a suitable salt to develop the desired formulation [118]. accompanied by an abnormality in ALK, for example, cancer, depression, and cognitive function disorder. It claims alectinib and its salts [115].

Alectinib hydrochloride (Figure 34) is a morpholine-piperidine based carbazole derivatives (MF: C30H34N4O2.HCl; MW: 519.08; CAS Number: 1256589-74-8) [114]. **US9126931B2** relates to tetracyclic compounds as ALK inhibitors for treating a disease

**Figure 33.** Osimertinib mesylate (*N*-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-

methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate).

*4.33. Alectinib Hydrochloride* 

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 31 of 60

**Figure 34.** Alectinib hydrochloride (9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11 oxo-6,11-dihydro-5H-benzo[*b*]carbazole-3-carbonitrile hydrochloride). **Figure 34.** Alectinib hydrochloride (9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11 oxo-6,11-dihydro-5H-benzo[*b*]carbazole-3-carbonitrile hydrochloride). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 32 of 60

**Figure 35.** Ribociclib succinate (7-cyclopentyl-*N,N*-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2 yl]amino}-7H-pyrrolo[2,3-*d*]pyrimidine-6-carboxamide succinate). **Figure 35.** Ribociclib succinate (7-cyclopentyl-*N,N*-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino} -7H-pyrrolo[2,3-*d*]pyrimidine-6-carboxamide succinate).

#### *4.35. Brigatinib 4.35. Brigatinib*

Brigatinib (Figure 36) is a piperazine-piperidine based pyrimidine derivative (MF: C29H39ClN7O2P; MW: 584.10; CAS Number: 1197953-54-0) [119]. **US9012462B2** narrates phosphorous compounds as PTKIs and their use in treating cancers. It claims brigatinib and its salts [120]. **US10385078B2** claims a stable and non-hygroscopic anhydrous crystalline form A of brigatinib suitable for pharmaceutical formulation development [121]. Brigatinib (Figure 36) is a piperazine-piperidine based pyrimidine derivative (MF: C29H39ClN7O2P; MW: 584.10; CAS Number: 1197953-54-0) [119]. **US9012462B2** narrates phosphorous compounds as PTKIs and their use in treating cancers. It claims brigatinib and its salts [120]. **US10385078B2** claims a stable and non-hygroscopic anhydrous crystalline form A of brigatinib suitable for pharmaceutical formulation development [121].

### *4.36. Midostaurin*

Midostaurin (Figure 37) is an indolocarbazole derivative (MF: C35H30N4O4; MW: 570.65; CAS Number: 120685-11-2) [122]. **US5093330A** relates to staurosporine derivatives, their salts, synthesis, and compositions encompassing them to treat cancer and inflammation. It discloses midostaurin [123]. **US7973031B2** claims a method for treating AML using a dosage form (a microemulsion, soft gel, or solid dispersion) of midostaurin, wherein the AML is characterized by deregulated FLT3 receptor tyrosine kinase activity [124].

### *4.37. Neratinib Maleate*

*4.36. Midostaurin* 

[124].

Neratinib maleate (Figure 38) is a pyridine based 4-aminoquinoline derivative (MF: C30H29ClN6O3·C4H4O4; MW: 673.11; CAS Number: 915942-22-2) [125]. **US7399865B2** reports substituted 3-cyanoquinoline compounds and their salts as inhibitors of HER-2 and EGFR to treat cancer. It claims neratinib and its salts [126].

**Figure 36.** Brigatinib (5-chloro-*N*4-[2-(dimethylphosphoryl)phenyl]-*N*2-{2-methoxy-4[4-(4-

Midostaurin (Figure 37) is an indolocarbazole derivative (MF: C35H30N4O4; MW: 570.65; CAS Number: 120685-11-2) [122]. **US5093330A** relates to staurosporine derivatives, their salts, synthesis, and compositions encompassing them to treat cancer and inflammation. It discloses midostaurin [123]. **US7973031B2** claims a method for treating AML using a dosage form (a microemulsion, soft gel, or solid dispersion) of midostaurin, wherein the AML is characterized by deregulated FLT3 receptor tyrosine kinase activity

methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine).

*4.35. Brigatinib* 

*4.36. Midostaurin* 

**Figure 36.** Brigatinib (5-chloro-*N*4-[2-(dimethylphosphoryl)phenyl]-*N*2-{2-methoxy-4[4-(4 methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine). **Figure 36.** Brigatinib (5-chloro-*N*4-[2-(dimethylphosphoryl)phenyl]-*N*2-{2-methoxy-4[4-(4-methy lpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 33 of 60

**Figure 35.** Ribociclib succinate (7-cyclopentyl-*N,N*-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-

Brigatinib (Figure 36) is a piperazine-piperidine based pyrimidine derivative (MF: C29H39ClN7O2P; MW: 584.10; CAS Number: 1197953-54-0) [119]. **US9012462B2** narrates phosphorous compounds as PTKIs and their use in treating cancers. It claims brigatinib and its salts [120]. **US10385078B2** claims a stable and non-hygroscopic anhydrous crystalline form A of brigatinib suitable for pharmaceutical formulation development [121].

yl]amino}-7H-pyrrolo[2,3-*d*]pyrimidine-6-carboxamide succinate).

**Figure 37.** Midostaurin (*N*-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-*N*methylbenzamide). **Figure 37.** Midostaurin (*N*-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo [12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-*N*methylbenzamide). C30H29ClN6O3.C4H4O4; MW: 673.11; CAS Number: 915942-22-2) [125]. **US7399865B2** reports substituted 3-cyanoquinoline compounds and their salts as inhibitors of HER-2 and EGFR to treat cancer. It claims neratinib and its salts [126].

**Figure 38.** Neratinib maleate ((*E*)-*N*-{4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate). **Figure 38.** Neratinib maleate ((*E*)-*N*-{4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-etho xyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate).

Copanlisib dihydrochloride (Figure 39) is a morpholine-pyrimidine based 2,3-dihydroimidazo[1,2-*c*]quinazoline derivative (MF: C23H28N8O4.2HCl; MW: 553.45; CAS Number: 1402152-13-9) [127]. **USRE46856E** (Reissue of US8466283B2) unveils 2,3-dihydroimidazo[1,2-*c*]quinazoline derivatives, pharmaceutical compositions comprising them, and the use of these compounds for treating hyperproliferative and angiogenesis disorders. It claims copanlisib and its salts [128]. **US10383876B2** claims copanlisib dihydrochloride salt that possesses technically advantageous properties (stability, solubility, hygroscopicity,

Copanlisib dihydrochloride (Figure 39) is a morpholine-pyrimidine based 2,3-dihy-

azo[1,2-*c*]quinazoline derivatives, pharmaceutical compositions comprising them, and the use of these compounds for treating hyperproliferative and angiogenesis disorders. It claims copanlisib and its salts [128]. **US10383876B2** claims copanlisib dihydrochloride salt that possesses technically advantageous properties (stability, solubility, hygroscopicity,

etc.) to develop a quality pharmaceutical composition [129].

etc.) to develop a quality pharmaceutical composition [129].

yquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate).

*4.38. Copanlisib Dihydrochloride* 

*4.38. Copanlisib Dihydrochloride* 

### *4.38. Copanlisib Dihydrochloride*

Copanlisib dihydrochloride (Figure 39) is a morpholine-pyrimidine based 2,3-dihydro imidazo[1,2-*c*]quinazoline derivative (MF: C23H28N8O4·2HCl; MW: 553.45; CAS Number: 1402152-13-9) [127]. **USRE46856E** (Reissue of US8466283B2) unveils 2,3-dihydroimidazo [1,2-*c*]quinazoline derivatives, pharmaceutical compositions comprising them, and the use of these compounds for treating hyperproliferative and angiogenesis disorders. It claims copanlisib and its salts [128]. **US10383876B2** claims copanlisib dihydrochloride salt that possesses technically advantageous properties (stability, solubility, hygroscopicity, etc.) to develop a quality pharmaceutical composition [129]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 34 of 60 *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 34 of 60

**Figure 39.** Copanlisib dihydrochloride (2-amino-*N*-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3 dihydroimidazo[1,2-*c*]quinazolin-5-yl}pyrimidine-5-carboxamide dihydrochloride). **Figure 39.** Copanlisib dihydrochloride (2-amino-*N*-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3 dihydroimidazo[1,2-*c*]quinazolin-5-yl}pyrimidine-5-carboxamide dihydrochloride). **Figure 39.** Copanlisib dihydrochloride (2-amino-*N*-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3 dihydroimidazo[1,2-*c*]quinazolin-5-yl}pyrimidine-5-carboxamide dihydrochloride).

#### *4.39. Abemaciclib 4.39. Abemaciclib4.39. Abemaciclib*

Abemaciclib (Figure 40) is a piperazine-pyridine-pyrimidine based benzimidazole derivative (MF: C27H32F2N8; MW: 506.59; CAS Number: 1231929-97-7) [130]. **US7855211B2** reports piperazine-pyridine-pyrimidine based benzimidazole derivatives and salts thereof, a pharmaceutical formulation comprising them to treat cancers selected from the group colorectal cancer, breast cancer, NSCLC, prostate cancer, glioblastoma, MCL, CML, and AML. It claims abemaciclib and its salts [131]. Abemaciclib (Figure 40) is a piperazine-pyridine-pyrimidine based benzimidazole derivative (MF: C27H32F2N8; MW: 506.59; CAS Number: 1231929-97-7) [130]. **US7855211B2** reports piperazine-pyridine-pyrimidine based benzimidazole derivatives and salts thereof, a pharmaceutical formulation comprising them to treat cancers selected from the group colorectal cancer, breast cancer, NSCLC, prostate cancer, glioblastoma, MCL, CML, and AML. It claims abemaciclib and its salts [131]. Abemaciclib (Figure 40) is a piperazine-pyridine-pyrimidine based benzimidazole derivative (MF: C27H32F2N8; MW: 506.59; CAS Number: 1231929-97-7) [130]. **US7855211B2** reports piperazine-pyridine-pyrimidine based benzimidazole derivatives and salts thereof, a pharmaceutical formulation comprising them to treat cancers selected from the group colorectal cancer, breast cancer, NSCLC, prostate cancer, glioblastoma, MCL, CML, and AML. It claims abemaciclib and its salts [131].

**Figure 40.** Abemaciclib (*N*-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2 methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]pyrimidin-2-amine). **Figure 40.** Abemaciclib (*N*-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2 methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]pyrimidin-2-amine). **Figure 40.** Abemaciclib (*N*-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2 methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]pyrimidin-2-amine).

#### *4.40. Acalabrutinib 4.40. Acalabrutinib 4.40. Acalabrutinib*

Acalabrutinib (Figure 41) is a pyrrolidine-pyridine based imidazo[1,5-*a*]pyrazine derivative (MF: C26H23N7O2; MW: 465.51; CAS Number: 1420477-60-6) [132]. **US9290504B2** provides 4-imidazopyridazin-1-yl-benzamides for the treatment of BTK mediated disor-Acalabrutinib (Figure 41) is a pyrrolidine-pyridine based imidazo[1,5-*a*]pyrazine derivative (MF: C26H23N7O2; MW: 465.51; CAS Number: 1420477-60-6) [132]. **US9290504B2** provides 4-imidazopyridazin-1-yl-benzamides for the treatment of BTK mediated disor-Acalabrutinib (Figure 41) is a pyrrolidine-pyridine based imidazo[1,5-*a*]pyrazine derivative (MF: C26H23N7O2; MW: 465.51; CAS Number: 1420477-60-6) [132]. **US9290504B2** provides 4-imidazopyridazin-1-yl-benzamides for the treatment of BTK mediated disorders.

ders. It claims acalabrutinib and its salts [133]. **US9796721B2** claims a stable and non-hy-

ders. It claims acalabrutinib and its salts [133]. **US9796721B2** claims a stable and non-hy-

It claims acalabrutinib and its salts [133]. **US9796721B2** claims a stable and non-hygroscopic anhydrate crystal form of acalabrutinib as having advantageous parameters for making quality pharmaceutical compositions [134]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 35 of 60

**Figure 41.** Acalabrutinib (4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-*a*]pyrazin-1-yl}-*N*-(pyridin-2-yl)benzamide). **Figure 41.** Acalabrutinib (4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-*a*]pyrazin-1 yl}-*N*-(pyridin-2-yl)benzamide).

#### *4.41. Netarsudil Dimesylate 4.41. Netarsudil Dimesylate*

Netarsudil dimesylate (Figure 42) is an isoquinoline based beta-amino acid derivative (MF: C30H35N3O9S2; MW: 645.74; CAS Number: 1422144-42-0) [135]. **US8394826B2** relates to isoquinoline amide and benzamide based compounds as dual inhibitors of Rho kinase and a monoamine transporter (MAT), useful in treating diseases like glaucoma and cancer. It claims netarsudil [136]. **US9415043B2** claims a chemically stable and water-soluble dimesylate salt of netarsudil that can provide a quality ophthalmic solution [137]. Netarsudil dimesylate (Figure 42) is an isoquinoline based beta-amino acid derivative (MF: C30H35N3O9S2; MW: 645.74; CAS Number: 1422144-42-0) [135]. **US8394826B2** relates to isoquinoline amide and benzamide based compounds as dual inhibitors of Rho kinase and a monoamine transporter (MAT), useful in treating diseases like glaucoma and cancer. It claims netarsudil [136]. **US9415043B2** claims a chemically stable and water-soluble dimesylate salt of netarsudil that can provide a quality ophthalmic solution [137]. **Figure 41.** Acalabrutinib (4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-*a*]pyrazin-1-yl}-*N*-(pyridin-2-yl)benzamide). *4.41. Netarsudil Dimesylate* 

#### *4.42. Baricitinib* Netarsudil dimesylate (Figure 42) is an isoquinoline based beta-amino acid deriva-

*4.42. Baricitinib* 

Baricitinib (Figure 43) is a pyrazole-azetidine based pyrrolo[2,3-*d*]pyrimidine derivative (MF: C16H17N7O2S; MW: 371.42; CAS Number: 1187594-09-7) [138]. **US8158616B2** provides azetidine derivatives as JAK inhibitors, synthetic methods, and compositions encompassing them to treat inflammatory and autoimmune disorders, along with cancer. It claims baricitinib and its salts [139]. tive (MF: C30H35N3O9S2; MW: 645.74; CAS Number: 1422144-42-0) [135]. **US8394826B2** relates to isoquinoline amide and benzamide based compounds as dual inhibitors of Rho kinase and a monoamine transporter (MAT), useful in treating diseases like glaucoma and cancer. It claims netarsudil [136]. **US9415043B2** claims a chemically stable and water-soluble dimesylate salt of netarsudil that can provide a quality ophthalmic solution [137].

provides azetidine derivatives as JAK inhibitors, synthetic methods, and compositions encompassing them to treat inflammatory and autoimmune disorders, along with cancer. It claims baricitinib and its salts [139]. **Figure 42.** Netarsudil dimesylate ((S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl-2,4-dimethylbenzoate dimesylate). **Figure 42.** Netarsudil dimesylate ((S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl-2,4-dimethylbenzoate dimesylate).

Baricitinib (Figure 43) is a pyrazole-azetidine based pyrrolo[2,3-*d*]pyrimidine derivative (MF: C16H17N7O2S; MW: 371.42; CAS Number: 1187594-09-7) [138]. **US8158616B2** provides azetidine derivatives as JAK inhibitors, synthetic methods, and compositions

yl]azetidin-3-yl}acetonitrile).

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 36 of 60

**Figure 43.** Baricitinib ({1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[ 2,3-*d*]pyrimidin-4-yl)-1H-pyrazol-1 yl]azetidin-3-yl}acetonitrile). **Figure 43.** Baricitinib ({1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-*d*]pyrimidin-4-yl)-1H-pyrazol-1 yl]azetidin-3-yl}acetonitrile). *4.43. Binimetinib* 

#### *4.43. Binimetinib 4.43. Binimetinib* Binimetinib (Figure 44) is a benzimidazole derivative (MF: C17H15BrF2N4O3; MW:

Binimetinib (Figure 44) is a benzimidazole derivative (MF: C17H15BrF2N4O3; MW: 441.2; CAS Number: 606143-89-9) [140]. **US7777050B2** states alkylated (1H-Benzoimidazol-5-yl)-(4-substituted-phenyl)-amine derivatives, helpful in managing sicknesses like cancer. It claims binimetinib and pharmaceutically acceptable salts thereof [141]. **US9562016B2** claims a crystallized form of binimetinib with better purity and an enhanced physical characteristic, beneficial in pharmaceutical dosage form preparation Binimetinib (Figure 44) is a benzimidazole derivative (MF: C17H15BrF2N4O3; MW: 441.2; CAS Number: 606143-89-9) [140]. **US7777050B2** states alkylated (1H-Benzoimidazol-5-yl)-(4-substituted-phenyl)-amine derivatives, helpful in managing sicknesses like cancer. It claims binimetinib and pharmaceutically acceptable salts thereof [141]. **US9562016B2** claims a crystallized form of binimetinib with better purity and an enhanced physical characteristic, beneficial in pharmaceutical dosage form preparation [142]. 441.2; CAS Number: 606143-89-9) [140]. **US7777050B2** states alkylated (1H-Benzoimidazol-5-yl)-(4-substituted-phenyl)-amine derivatives, helpful in managing sicknesses like cancer. It claims binimetinib and pharmaceutically acceptable salts thereof [141]. **US9562016B2** claims a crystallized form of binimetinib with better purity and an enhanced physical characteristic, beneficial in pharmaceutical dosage form preparation [142].

**Figure 44.** Binimetinib (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-*N*-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide). **Figure 44.** Binimetinib (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-*N*-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide). **Figure 44.** Binimetinib (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-*N*-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide).

#### *4.44. Dacomitinib Monohydrate 4.44. Dacomitinib Monohydrate 4.44. Dacomitinib Monohydrate*

Dacomitinib monohydrate (Figure 45) is a piperidine based quinazolinamine derivatives (MF: C24H25ClFN5O2.H2O; MW: 487.95; CAS Number: 1042385-75-0) [143]. **US7772243B2** unveils 4-anilino-6-substituted alkenoylamino-quinazoline compounds as TKIs to treat proliferative diseases, including cancer and restenosis endometriosis and psoriasis. It claims dacomitinib and its salts [144]. Dacomitinib monohydrate (Figure 45) is a piperidine based quinazolinamine derivatives (MF: C24H25ClFN5O2.H2O; MW: 487.95; CAS Number: 1042385-75-0) [143]. **US7772243B2** unveils 4-anilino-6-substituted alkenoylamino-quinazoline compounds as TKIs to treat proliferative diseases, including cancer and restenosis endometriosis and psoriasis. It claims dacomitinib and its salts [144]. Dacomitinib monohydrate (Figure 45) is a piperidine based quinazolinamine derivatives (MF: C24H25ClFN5O2·H2O; MW: 487.95; CAS Number: 1042385-75-0) [143]. **US7772243B2** unveils 4-anilino-6-substituted alkenoylamino-quinazoline compounds as TKIs to treat proliferative diseases, including cancer and restenosis endometriosis and psoriasis. It claims dacomitinib and its salts [144].

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 37 of 60

**Figure 45.** Dacomitinib monohydrate ((2*E*)-*N*-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate). **Figure 45.** Dacomitinib monohydrate ((2*E*)-*N*-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyqu inazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate). yquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate). *4.45. Encorafenib* 

**Figure 45.** Dacomitinib monohydrate ((2*E*)-*N*-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methox-

#### *4.45. Encorafenib 4.45. Encorafenib* Encorafenib (Figure 46) is a pyrazole based pyrimidine derivative (MF:

Encorafenib (Figure 46) is a pyrazole based pyrimidine derivative (MF: C22H27ClFN7O4S; MW: 540; CAS Number: 1269440-17-6) [145]. **US8501758B2** provides pyrazole based pyrimidine and pharmaceutical compositions comprising them to treat disorders associated with the deregulated activity of B-Raf. It claims encorafenib and its salts Encorafenib (Figure 46) is a pyrazole based pyrimidine derivative (MF: C22H27ClFN7O4S; MW: 540; CAS Number: 1269440-17-6) [145]. **US8501758B2** provides pyrazole based pyrimidine and pharmaceutical compositions comprising them to treat disorders associated with the deregulated activity of B-Raf. It claims encorafenib and its salts [146]. C22H27ClFN7O4S; MW: 540; CAS Number: 1269440-17-6) [145]. **US8501758B2** provides pyrazole based pyrimidine and pharmaceutical compositions comprising them to treat disorders associated with the deregulated activity of B-Raf. It claims encorafenib and its salts [146].

**Figure 46.** Encorafenib (*N*-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(pro-**Figure 46.** Encorafenib (*N*-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate). **Figure 46.** Encorafenib (*N*-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1- (propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate).

#### pan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate). *4.46. Fostamatinib Disodium Hexahydrate 4.46. Fostamatinib Disodium Hexahydrate*

velop the desired dosage form [149].

*4.46. Fostamatinib Disodium Hexahydrate*  Fostamatinib disodium hexahydrate (Figure 47), a phosphate prodrug of tamatinib, is a pyrimidine based pyrido[3,2-*b*][1,4]oxazine derivative (MF: C23H24FN6Na2O9P·6H2O; MW: 732.52; CAS Number: 914295-16-2) [147]. **US7449458B2** reports prodrugs of pharmacologically active 2,4-pyrimidinediamine derivatives, intermediates thereof, the process of manufacturing them, and pharmaceutical compositions comprising them to treat diseases mediated by the activation of PTKs. It claims fostamatinib disodium hexahydrate, which has increased solubility concerning the parent phosphate prodrug [148]. **US8163902B2** claims a thermodynamically stable crystalline form of fostamatinib disodium hexahydrate that is stable over a wide range of relative humidity and requires substantial heating to lose its water molecules. This property makes it a suitable API to de-Fostamatinib disodium hexahydrate (Figure 47), a phosphate prodrug of tamatinib, is a pyrimidine based pyrido[3,2-*b*][1,4]oxazine derivative (MF: C23H24FN6Na2O9P·6H2O; MW: 732.52; CAS Number: 914295-16-2) [147]. **US7449458B2** reports prodrugs of pharmacologically active 2,4-pyrimidinediamine derivatives, intermediates thereof, the process of manufacturing them, and pharmaceutical compositions comprising them to treat diseases mediated by the activation of PTKs. It claims fostamatinib disodium hexahydrate, which has increased solubility concerning the parent phosphate prodrug [148]. **US8163902B2** claims a thermodynamically stable crystalline form of fostamatinib disodium hexahydrate that is stable over a wide range of relative humidity and requires substantial heating to lose its water molecules. This property makes it a suitable API to develop the desired dosage form [149]. Fostamatinib disodium hexahydrate (Figure 47), a phosphate prodrug of tamatinib, is a pyrimidine based pyrido[3,2-*b*][1,4]oxazine derivative (MF: C23H24FN6Na2O9P·6H2O; MW: 732.52; CAS Number: 914295-16-2) [147]. **US7449458B2** reports prodrugs of pharmacologically active 2,4-pyrimidinediamine derivatives, intermediates thereof, the process of manufacturing them, and pharmaceutical compositions comprising them to treat diseases mediated by the activation of PTKs. It claims fostamatinib disodium hexahydrate, which has increased solubility concerning the parent phosphate prodrug [148]. **US8163902B2** claims a thermodynamically stable crystalline form of fostamatinib disodium hexahydrate that is stable over a wide range of relative humidity and requires substantial heating to lose its water molecules. This property makes it a suitable API to develop the desired dosage form [149].

**Figure 47.** Fostamatinib disodium hexahydrate (Disodium (6-[[5-fluoro-2-(3,4,5-trimethoxyanilino) pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-*b*][1,4]oxazin-4-yl)methyl phosphate hexahydrate). **Figure 47.** Fostamatinib disodium hexahydrate (Disodium (6-[[5-fluoro-2-(3,4,5-trimethoxyanilino) pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-*b*][1,4]oxazin-4-yl)methyl phosphate hexahydrate).

#### *4.47. Duvelisib Hydrate 4.47. Duvelisib Hydrate*

Duvelisib hydrate (Figure 48) is a purine based isoquinolone derivative (MF: C22H17ClN6O.H2O; MW: 434.88; CAS Number: 1201438-56-3) [150]. **US8193182B2** provides isoquinolin-1(2H)-one derivatives as modulators of PI3 kinase activity and pharmaceutical compositions comprising them to treat diseases associated with P13 kinase activity. It claims duvelisib and its salts [151]. **USRE46621E** (Reissue of US8809349B2) claims physically and chemically stable polymorphs of duvelisib, salt, solvate, or hydrate that do not readily decompose or change in chemical makeup or physical state for more than 60 months and are suitable to develop the desired dosage forms of the API [152]. Duvelisib hydrate (Figure 48) is a purine based isoquinolone derivative (MF: C22H17Cl N6O·H2O; MW: 434.88; CAS Number: 1201438-56-3) [150]. **US8193182B2** provides isoquinolin-1(2H)-one derivatives as modulators of PI3 kinase activity and pharmaceutical compositions comprising them to treat diseases associated with P13 kinase activity. It claims duvelisib and its salts [151]. **USRE46621E** (Reissue of US8809349B2) claims physically and chemically stable polymorphs of duvelisib, salt, solvate, or hydrate that do not readily decompose or change in chemical makeup or physical state for more than 60 months and are suitable to develop the desired dosage forms of the API [152]. cal compositions comprising them to treat diseases associated with P13 kinase activity. It claims duvelisib and its salts [151]. **USRE46621E** (Reissue of US8809349B2) claims physi-

**Figure 48.** Duvelisib hydrate ((S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one hydrate). 1(2H)-one hydrate). **Figure 48.** Duvelisib hydrate ((S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one hydrate).

#### *4.48. Gilteritinib Fumarate 4.48. Gilteritinib Fumarate*

Gilteritinib fumarate (Figure 49) piperazine-piperidine based pyrazine carboxamide derivative (MF: (C29H44N8O3)2.C4H4O4; MW: 1221.50; CAS Number: 1254053-84-3) [153]. **US8969336B2** states diamino heterocyclic carboxamide derivatives as having outstanding inhibitory activity against EML4-ALK fusion proteins for use in cancer therapy. It claims gilteritinib and its salts [154]. The gilteritinib fumarate salt is stable in heat, humidity, and storage conditions. **US8969336B2** states diamino heterocyclic carboxamide derivatives as having outstanding inhibitory activity against EML4-ALK fusion proteins for use in cancer therapy. It claims Gilteritinib fumarate (Figure 49) piperazine-piperidine based pyrazine carboxamide derivative (MF: (C29H44N8O3)2·C4H4O4; MW: 1221.50; CAS Number: 1254053-84-3) [153]. **US8969336B2** states diamino heterocyclic carboxamide derivatives as having outstanding inhibitory activity against EML4-ALK fusion proteins for use in cancer therapy. It claims gilteritinib and its salts [154]. The gilteritinib fumarate salt is stable in heat, humidity, and storage conditions.

### *4.49. Larotrectinib Sulfate*

Larotrectinib sulfate (Figure 50) is a pyrrolidine based pyrazolo[1,5-*a*]pyrimidine derivative (MF: C21H24F2N6O6S; MW: 526.51; CAS Number: 1223405-08-0) [155]. **US9127013B2** relates to pyrazolo[1,5-*a*] pyrimidine derivatives as TRK family PTKIs that are useful to treat cancer, inflammation, and certain infectious diseases. It claims larotrectinib sulfate

specifically [156]. **US10172861B2** claims crystalline larotrectinib sulfate having stable physicochemical properties, which can be used to develop quality dosage forms [157]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 39 of 60

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 39 of 60

**Figure 50.** Larotrectinib sulfate ((3S)-*N*-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5 *a*]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate). **Figure 50.** Larotrectinib sulfate ((3S)-*N*-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5 *a*]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate).

#### *4.50. Lorlatinib 4.50. Lorlatinib*

oate (2:1)).

**Figure 50.** Larotrectinib sulfate ((3S)-*N*-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5- Lorlatinib (Figure 51) is a pyrazole-pyridine based benzoxadiazacyclotetradecine derivative (MF: C21H19FN6O2; MW: 406.41; CAS Number: 1223403-58-4) [158]. **US8680111B2** discloses macrocyclic compounds as inhibitors of ALK and/or EML4-ALK and their pharmaceutical composition to treat illnesses linked with the deregulation of ALK and EML4- ALK. It claims lorlatinib and its salts [159]. **US10420749B2** claims crystalline polymorphs of lorlatinib having high crystallinity and purity, low hygroscopicity, and favorable dissolution and mechanical properties to develop quality pharmaceutical formulations [160]. Lorlatinib (Figure 51) is a pyrazole-pyridine based benzoxadiazacyclotetradecine derivative (MF: C21H19FN6O2; MW: 406.41; CAS Number: 1223403-58-4) [158]. **US8680111B2** discloses macrocyclic compounds as inhibitors of ALK and/or EML4-ALK and their pharmaceutical composition to treat illnesses linked with the deregulation of ALK and EML4-ALK. It claims lorlatinib and its salts [159]. **US10420749B2** claims crystalline polymorphs of lorlatinib having high crystallinity and purity, low hygroscopicity, and favorable dissolution and mechanical properties to develop quality pharmaceutical formulations [160].

#### *a*]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate). *4.51. Entrectinib*

*4.50. Lorlatinib*  Lorlatinib (Figure 51) is a pyrazole-pyridine based benzoxadiazacyclotetradecine derivative (MF: C21H19FN6O2; MW: 406.41; CAS Number: 1223403-58-4) [158]. **US8680111B2** discloses macrocyclic compounds as inhibitors of ALK and/or EML4-ALK and their pharmaceutical composition to treat illnesses linked with the deregulation of ALK and EML4- Entrectinib (Figure 52) is a tetrahydropyran-piperazine based indazole derivative (MF: C31H34F2N6O2; MW: 560.64; CAS Number: 1108743-60-7) [161]. **US8299057B2** discloses indazole derivatives as potent PKIs that are useful in anticancer therapy. It claims entrectinib and its salts [162]. **US10738037B2** claims a crystalline Form 4 of entrectinib that exhibits greater thermodynamic stability at a temperature of about 40 ◦C than other known polymorphs and offers advantages in preparing dosage forms [163].

ALK. It claims lorlatinib and its salts [159]. **US10420749B2** claims crystalline polymorphs of lorlatinib having high crystallinity and purity, low hygroscopicity, and favorable dis-

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 40 of 60

**Figure 51.** Lorlatinib ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-H][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile). **Figure 51.** Lorlatinib ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-H][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile). entrectinib and its salts [162]. **US10738037B2** claims a crystalline Form 4 of entrectinib that exhibits greater thermodynamic stability at a temperature of about 40oC than other known polymorphs and offers advantages in preparing dosage forms [163].

**Figure 52.** Entrectinib (*N*-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2- (tetrahydro-2H-pyran-4-ylamino)benzamide). **Figure 52.** Entrectinib (*N*-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2- (tetrahydro-2H-pyran-4-ylamino)benzamide).

#### *4.52. Upadacitinib Hemihydrate 4.52. Upadacitinib Hemihydrate*

**Figure 52.** Entrectinib (*N*-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2- (tetrahydro-2H-pyran-4-ylamino)benzamide). *4.52. Upadacitinib Hemihydrate*  Upadacitinib hemihydrate (Figure 53) is an imidazo[1,2-*a*]pyrrolo[2,3-*e*]pyrazine based pyrrolidine derivative (MF: C17H19F3N6O.½H2O; MW: 389.38; CAS Number: 1310726-60-3) [164]. **USRE47221E** (Reissue of US8426411B2) describes tricyclic compounds that inhibit JAK family kinase activity for treating diseases, including rheumatoid arthritis, multiple sclerosis, and psoriasis. It claims upadacitinib [165]. **US9951080B2** claims physicochemically stable crystalline hemihydrate of upadacitinib having solidstate properties to develop quality pharmaceutical dosage forms [166]. Upadacitinib hemihydrate (Figure 53) is an imidazo[1,2-*a*]pyrrolo[2,3-*e*]pyrazine based pyrrolidine derivative (MF: C17H19F3N6O·1/<sup>2</sup> H2O; MW: 389.38; CAS Number: 1310726- 60-3) [164]. **USRE47221E** (Reissue of US8426411B2) describes tricyclic compounds that inhibit JAK family kinase activity for treating diseases, including rheumatoid arthritis, multiple sclerosis, and psoriasis. It claims upadacitinib [165]. **US9951080B2** claims physicochemically stable crystalline hemihydrate of upadacitinib having solid-state properties to develop quality pharmaceutical dosage forms [166].

#### Upadacitinib hemihydrate (Figure 53) is an imidazo[1,2-*a*]pyrrolo[2,3-*e*]pyrazine *4.53. Alpelisib*

based pyrrolidine derivative (MF: C17H19F3N6O.½H2O; MW: 389.38; CAS Number: 1310726-60-3) [164]. **USRE47221E** (Reissue of US8426411B2) describes tricyclic compounds that inhibit JAK family kinase activity for treating diseases, including rheumatoid arthritis, multiple sclerosis, and psoriasis. It claims upadacitinib [165]. **US9951080B2** Alpelisib (Figure 54) is a pyridine-thiazole based pyrrolidine derivative (MF: C19H22F<sup>3</sup> N5O2S; MW: 441.47; CAS Number: 1217486-61-7) [167]. **US8227462B2** unveils pyrrolidine-1,2-dicarboxamide derivatives for the treatment of illnesses ameliorated by inhibition of PI3Ks. It claims alpelisib in a free form and its salts [168].

claims physicochemically stable crystalline hemihydrate of upadacitinib having solid-

#### state properties to develop quality pharmaceutical dosage forms [166]. *4.54. Erdafitinib*

Erdafitinib (Figure 55) is a pyrazole based quinoxaline derivative (MF: C25H30N6O2; MW: 446.56; CAS Number: 1346242-81-6) [169]. **US8895601B2** relates to pyrazole based quinoxaline derivatives and their pharmaceutical compositions to treat diseases like cancer. It claims erdafitinib and its salts [170].

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 41 of 60

**Figure 53.** Upadacitinib hemihydrate ((3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-*a*]pyrrolo[2,3-*e*]pyrazin-8-yl)-*N*-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1)). **Figure 53.** Upadacitinib hemihydrate ((3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-*a*]pyrrolo[2,3-*e*]pyrazin-8 yl)-*N*-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1)). C19H22F3N5O2S; MW: 441.47; CAS Number: 1217486-61-7) [167]. **US8227462B2** unveils pyrrolidine-1,2-dicarboxamide derivatives for the treatment of illnesses ameliorated by inhi-

bition of PI3Ks. It claims alpelisib in a free form and its salts [168].

Alpelisib (Figure 54) is a pyridine-thiazole based pyrrolidine derivative (MF:

*4.53. Alpelisib* 

**Figure 54.** Alpelisib ((2S)-*N*1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidine dicarboxamide). **Figure 54.** Alpelisib ((2S)-*N*1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2 thiazolyl]-1,2-pyrrolidine dicarboxamide). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 42 of 60

**Figure 55.** Erdafitinib (*N*-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-*N*-{2-[(propan-2 yl)amino]ethyl}quinoxalin-6-amine). **Figure 55.** Erdafitinib (*N*-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-*N*-{2-[(propan-2 yl)amino]ethyl}quinoxalin-6-amine).

rivative (MF: C20H15ClF3N5.HCl; MW: 454.28; CAS Number: 1029044-16-3) [171]. **US9169250B2** provides fused azacyclic compounds as dual inhibitors of c-FMS and c-KIT to treat diseases that arise due to deregulation of c-FMS and c-KIT. It claims pexidartinib hydrochloride [172]. **US9802932B2** claims a stable crystalline form of pexidartinib hydrochloride having attributes for developing a quality pharmaceutical composition [173].

**Figure 56.** Pexidartinib hydrochloride (5-[(5-Chloro-1H-pyrrolo[2,3-*b*]pyridin-3-yl)methyl]-*N*-{[6-

mediated by modulation of JAK activity. It claims fedratinib and its salts [175].

Fedratinib dihydrochloride monohydrate (Figure 57) is a pyrrolidine-pyrimidine based benzenesulfonamide derivative (MF: C27H36N6O3S.2HCl.H2O; MW: 615.62; CAS Number: 1374744-69-0) [174]. **US7528143B2** unveils biaryl m-pyrimidine compounds as an inhibitor of the JAK family and their pharmaceutical compositions to treat diseases

(trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine monohydrochloride).

*4.56. Fedratinib Dihydrochloride Monohydrate* 

*4.55. Pexidartinib Hydrochloride* 

#### *4.55. Pexidartinib Hydrochloride 4.55. Pexidartinib Hydrochloride*

yl)amino]ethyl}quinoxalin-6-amine).

Pexidartinib hydrochloride (Figure 56) is a pyrrolo[2,3-*b*]pyridine based pyridine derivative (MF: C20H15ClF3N5·HCl; MW: 454.28; CAS Number: 1029044-16-3) [171]. **US9169250B2** provides fused azacyclic compounds as dual inhibitors of c-FMS and c-KIT to treat diseases that arise due to deregulation of c-FMS and c-KIT. It claims pexidartinib hydrochloride [172]. **US9802932B2** claims a stable crystalline form of pexidartinib hydrochloride having attributes for developing a quality pharmaceutical composition [173]. Pexidartinib hydrochloride (Figure 56) is a pyrrolo[2,3-*b*]pyridine based pyridine derivative (MF: C20H15ClF3N5.HCl; MW: 454.28; CAS Number: 1029044-16-3) [171]. **US9169250B2** provides fused azacyclic compounds as dual inhibitors of c-FMS and c-KIT to treat diseases that arise due to deregulation of c-FMS and c-KIT. It claims pexidartinib hydrochloride [172]. **US9802932B2** claims a stable crystalline form of pexidartinib hydrochloride having attributes for developing a quality pharmaceutical composition [173].

**Figure 55.** Erdafitinib (*N*-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-*N*-{2-[(propan-2-

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 42 of 60

**Figure 56.** Pexidartinib hydrochloride (5-[(5-Chloro-1H-pyrrolo[2,3-*b*]pyridin-3-yl)methyl]-*N*-{[6- (trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine monohydrochloride). **Figure 56.** Pexidartinib hydrochloride (5-[(5-Chloro-1H-pyrrolo[2,3-*b*]pyridin-3-yl)methyl]-*N*-{[6- (trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine monohydrochloride).

#### *4.56. Fedratinib Dihydrochloride Monohydrate 4.56. Fedratinib Dihydrochloride Monohydrate*

Fedratinib dihydrochloride monohydrate (Figure 57) is a pyrrolidine-pyrimidine based benzenesulfonamide derivative (MF: C27H36N6O3S.2HCl.H2O; MW: 615.62; CAS Number: 1374744-69-0) [174]. **US7528143B2** unveils biaryl m-pyrimidine compounds as an inhibitor of the JAK family and their pharmaceutical compositions to treat diseases mediated by modulation of JAK activity. It claims fedratinib and its salts [175]. Fedratinib dihydrochloride monohydrate (Figure 57) is a pyrrolidine-pyrimidine based benzenesulfonamide derivative (MF: C27H36N6O3S·2HCl·H2O; MW: 615.62; CAS Number: 1374744-69-0) [174]. **US7528143B2** unveils biaryl m-pyrimidine compounds as an inhibitor of the JAK family and their pharmaceutical compositions to treat diseases mediated by modulation of JAK activity. It claims fedratinib and its salts [175].

### *4.57. Zanubrutinib*

*4.57. Zanubrutinib* 

Zanubrutinib (Figure 58) is a piperidine based pyrazolo[1,5-*a*]pyrimidine derivative (MF: C27H29N5O3; MW: 471.56; CAS Number: 1691249-45-2) [176]. **US9447106B2** states substituted pyrazolo[1,5-*a*]pyrimidines as BTK modulators and used these compounds to treat diseases intervened by BTK. It claims zanubrutinibas and its salts [177]. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 43 of 60

**Figure 57.** Fedratinib dihydrochloride monohydrate (*N*-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzene-1-sulfonamide dihydrochloride monohydrate). **Figure 57.** Fedratinib dihydrochloride monohydrate (*N*-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1 yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzene-1-sulfonamide dihydrochloride monohydrate).

**Figure 58.** Zanubrutinib ((S)-7-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro-

Avapritinib (Figure 59) is a pyrazole-piperazine-pyrimidine based pyrrolo[2,1 *f*][1,2,4]triazine derivative (MF: C26H27FN10; MW: 498.57; CAS Number: 1703793-34-3) [178]. **US9944651B2** refers to piperazine-based pyrrolo[2,1-*f*][1,2,4]triazine derivatives for treating conditions like mastocytosis and mast cell diseases by modifying the activity of

Zanubrutinib (Figure 58) is a piperidine based pyrazolo[1,5-*a*]pyrimidine derivative (MF: C27H29N5O3; MW: 471.56; CAS Number: 1691249-45-2) [176]. **US9447106B2** states substituted pyrazolo[1,5-*a*]pyrimidines as BTK modulators and used these compounds to

pyrazolo[1,5-*a*]pyrimidine-3-carboxamide).

KIT. It claims avapritinib and its salts [179].

*4.58. Avapritinib* 

**Figure 58.** Zanubrutinib ((S)-7-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-*a*]pyrimidine-3-carboxamide). **Figure 58.** Zanubrutinib ((S)-7-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7 tetrahydropyrazolo[1,5-*a*]pyrimidine-3-carboxamide).

**Figure 57.** Fedratinib dihydrochloride monohydrate (*N*-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzene-1-sulfonamide dihydrochloride

treat diseases intervened by BTK. It claims zanubrutinibas and its salts [177].

Zanubrutinib (Figure 58) is a piperidine based pyrazolo[1,5-*a*]pyrimidine derivative (MF: C27H29N5O3; MW: 471.56; CAS Number: 1691249-45-2) [176]. **US9447106B2** states substituted pyrazolo[1,5-*a*]pyrimidines as BTK modulators and used these compounds to

#### *4.58. Avapritinib 4.58. Avapritinib*

monohydrate).

*4.57. Zanubrutinib* 

Avapritinib (Figure 59) is a pyrazole-piperazine-pyrimidine based pyrrolo[2,1 *f*][1,2,4]triazine derivative (MF: C26H27FN10; MW: 498.57; CAS Number: 1703793-34-3) [178]. **US9944651B2** refers to piperazine-based pyrrolo[2,1-*f*][1,2,4]triazine derivatives for treating conditions like mastocytosis and mast cell diseases by modifying the activity of KIT. It claims avapritinib and its salts [179]. Avapritinib (Figure 59) is a pyrazole-piperazine-pyrimidine based pyrrolo[2,1-*f*][1,2,4] triazine derivative (MF: C26H27FN10; MW: 498.57; CAS Number: 1703793-34-3) [178]. **US9944651B2** refers to piperazine-based pyrrolo[2,1-*f*][1,2,4]triazine derivatives for treating conditions like mastocytosis and mast cell diseases by modifying the activity of KIT. It claims avapritinib and its salts [179].

### *4.59. Selumetinib Sulfate*

Selumetinib sulfate (Figure 60) is a benzimidazole derivative (MF: C17H17BrClFN4O7S; MW: 555.76; CAS Number: 943332-08-9) [180]. **US7425637B2** reports *N*3-alkylated benzimidazole compounds that inhibit MEK and are helpful to treat cancer and inflammation. It claims selumetinib and its salts [181]. **US9156795B2** claims a stable crystalline hydrogen sulfate salt of selumetinib with enhanced solubility and bioavailability, making it a suitable API to develop desired pharmaceutical dosage forms [182].

### *4.60. Pemigatinib*

Pemigatinib (Figure 61) is a morpholine based pyrrolo[30 ,20 :5,6]pyrido[4,3-*d*]pyrimidine derivative (MF: C24H27F2N5O4; MW: 487.5; CAS Number: 1513857-77-6) [183]. **US9611267B2** relates to tricyclic compounds as inhibitors of FGFR, useful in ailments facilitated by FGFR malfunctioning like cancer. It claims pemigatinib and its salts [184].

### *4.61. Tucatinib*

Tucatinib (Figure 62) is a quinazoline-oxazoline based triazolo[1,5-*a*]pyridine derivative (MF: C26H24N8O2; MW: 480.52; CAS Number: 937263-43-9) [185]. **US8648087B2** discloses *N*4-phenyl-quinazoline-4-amine derivatives as TKIs to treat cancer and inflammation. It claims tucatinib [186].

### *4.62. Capmatinib Dihydrochloride Monohydrate*

Capmatinib dihydrochloride monohydrate (Figure 63) is an imidazo[1,2-*b*][1,2,4]triazine based quinoline derivative (MF: C23H21Cl2FN6O2; MW: 503.36; CAS Number: 1865733-40- 9) [187]. **US7767675B2** reveals imidazotriazines and imidazopyrimidines as MET inhibitors and their pharmaceutical compositions useful in cancer treatment. It claims capmatinib and its salts [188]. **US8420645B2** claims a stable capmatinib dihydrochloride monohydrate with pharmaceutical attributes to manufacture quality pharmaceutical formulations [189].

*4.59. Selumetinib Sulfate* 

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 44 of 60

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 44 of 60

**Figure 60.** Selumetinib sulfate (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-hydroxyethoxy)carbamoyl]-1-methyl-1H-benzimidazol-3-ium hydrogen sulfate). **Figure 60.** Selumetinib sulfate (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-hydroxyethoxy) carbamoyl]-1-methyl-1H-benzimidazol-3-ium hydrogen sulfate). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 45 of 60

*4.61. Tucatinib* 

tion. It claims tucatinib [186].

cilitated by FGFR malfunctioning like cancer. It claims pemigatinib and its salts [184]. **Figure 61.** Pemigatinib (3-(2,6-difluoro-3,5-dimethoxyphenyl)1-ethyl-8-(morpholin-4-ylmethyl)- 1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-*d*]pyrimidin-2-one). **Figure 61.** Pemigatinib (3-(2,6-difluoro-3,5-dimethoxyphenyl)1-ethyl-8-(morpholin-4-ylmethyl)- 1,3,4,7-tetrahydro-2H-pyrrolo[30 ,20 :5,6]pyrido[4,3-*d*]pyrimidin-2-one).

closes *N*4-phenyl-quinazoline-4-amine derivatives as TKIs to treat cancer and inflamma-

**Figure 62.** Tucatinib (*N*6-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-*N*4-(3-methyl-4-{[1,2,4]tria-

Capmatinib dihydrochloride monohydrate (Figure 63) is an imidazo[1,2-*b*][1,2,4]triazine based quinoline derivative (MF: C23H21Cl2FN6O2; MW: 503.36; CAS Number: 1865733-40-9) [187]. **US7767675B2** reveals imidazotriazines and imidazopyrimidines as MET inhibitors and their pharmaceutical compositions useful in cancer treatment. It claims capmatinib and its salts [188]. **US8420645B2** claims a stable capmatinib dihydrochloride monohydrate with pharmaceutical attributes to manufacture quality pharmaceu-

zolo[1,5-*a*]pyridin-7-yloxy}phenyl)quinazoline-4,6-diamine).

*4.62. Capmatinib Dihydrochloride Monohydrate* 

tical formulations [189].

1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-*d*]pyrimidin-2-one).

**Figure 62.** Tucatinib (*N*6-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-*N*4-(3-methyl-4-{[1,2,4]triazolo[1,5-*a*]pyridin-7-yloxy}phenyl)quinazoline-4,6-diamine). **Figure 62.** Tucatinib (*N*6-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-*N*4-(3-methyl-4-{[1,2,4]triazolo [1,5-*a*]pyridin-7-yloxy}phenyl)quinazoline-4,6-diamine). *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 46 of 60

**Figure 61.** Pemigatinib (3-(2,6-difluoro-3,5-dimethoxyphenyl)1-ethyl-8-(morpholin-4-ylmethyl)-

Tucatinib (Figure 62) is a quinazoline-oxazoline based triazolo[1,5-*a*]pyridine derivative (MF: C26H24N8O2; MW: 480.52; CAS Number: 937263-43-9) [185]. **US8648087B2** discloses *N*4-phenyl-quinazoline-4-amine derivatives as TKIs to treat cancer and inflamma-

*4.62. Capmatinib Dihydrochloride Monohydrate* 

**Figure 63.** Capmatinib dihydrochloride monohydrate (2-fluoro-*N*-methyl-4-{7-[(quinolin-6-yl)methyl]imidazo[1,2-*b*][1,2,4]triazin-2-yl}benzamide dihydrochloride monohydrate). **Figure 63.** Capmatinib dihydrochloride monohydrate (2-fluoro-*N*-methyl-4-{7-[(quinolin-6-yl)methyl] imidazo[1,2-*b*][1,2,4]triazin-2-yl}benzamide dihydrochloride monohydrate).

#### *4.63. Selpercatinib 4.63. Selpercatinib*

*4.61. Tucatinib* 

tion. It claims tucatinib [186].

Selpercatinib (Figure 64) is a pyridine-diazabicycloheptane based pyrazolo[1,5-*a*]pyridine derivative (MF: C29H31N7O3; MW: 525.61; CAS Number: 2152628-33-4) [190]. **US10112942B2** uncovers pyrazolo[1,5-*a*]pyridines as RET inhibitors, useful to treat RETassociated diseases. It claims selpercatinib and its salts [191]. **US10584124B2** claims a stable crystalline polymorph of selpercatinib that is useful for developing pharmaceutical Selpercatinib (Figure 64) is a pyridine-diazabicycloheptane based pyrazolo[1,5-*a*]pyridine derivative (MF: C29H31N7O3; MW: 525.61; CAS Number: 2152628-33-4) [190]. **US10112942B2** uncovers pyrazolo[1,5-*a*]pyridines as RET inhibitors, useful to treat RET-associated diseases. It claims selpercatinib and its salts [191]. **US10584124B2** claims a stable crystalline polymorph of selpercatinib that is useful for developing pharmaceutical formulations [192].

### formulations [192]. *4.64. Ripretinib*

Ripretinib (Figure 65) is a naphthyridine based phenylurea derivative (MF: C24H21BrF N5O2; MW: 510.36; CAS Number: 1442472-39-0) [193]. **US8461179B1** uncovers dihydronaphthyridine derivatives that inhibit c-KIT and that have utility to treat GIST, mast cell leukemia, or mastocytosis. It claims ripretinib and its salts [194].

### *4.65. Pralsetinib*

*4.64. Ripretinib* 

Pralsetinib (Figure 66) is a pyridine-pyrimidine based pyrazole derivative (MF: C27H<sup>32</sup> FN9O2; MW: 533.61; CAS Number: 2097132-94-8) [195]. **US10030005B2** discloses pyrazole based RET inhibitors and their pharmaceutical compositions to treat a condition mediated by aberrant RET activity, e.g., cancer. It claims pralsetinib [196].

### *4.66. Trilaciclib Dihydrochloride*

Trilaciclib dihydrochloride (Figure 67) is a piperazine-pyridine based pyrazino[10 ,20 :1,5] pyrrole derivative (MF: C24H30N8O·2HCl; MW: 519.48; CAS Number: 1977495-97-8) [197]. **US8598186B2** reveals tricyclic compounds as CDK inhibitors, which have utility in the

Ripretinib (Figure 65) is a naphthyridine based phenylurea derivative (MF: C24H21BrFN5O2; MW: 510.36; CAS Number: 1442472-39-0) [193]. **US8461179B1** uncovers dihydronaphthyridine derivatives that inhibit c-KIT and that have utility to treat GIST,

3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-*a*]pyridine-3-carbonitrile).

mast cell leukemia, or mastocytosis. It claims ripretinib and its salts [194].

treatment of disorders intervened by CDK malfunction like cancer. It claims trilaciclib and its salts [198]. associated diseases. It claims selpercatinib and its salts [191]. **US10584124B2** claims a stable crystalline polymorph of selpercatinib that is useful for developing pharmaceutical formulations [192].

Selpercatinib (Figure 64) is a pyridine-diazabicycloheptane based pyrazolo[1,5-*a*]pyridine derivative (MF: C29H31N7O3; MW: 525.61; CAS Number: 2152628-33-4) [190]. **US10112942B2** uncovers pyrazolo[1,5-*a*]pyridines as RET inhibitors, useful to treat RET-

**Figure 63.** Capmatinib dihydrochloride monohydrate (2-fluoro-*N*-methyl-4-{7-[(quinolin-6-yl)me-

thyl]imidazo[1,2-*b*][1,2,4]triazin-2-yl}benzamide dihydrochloride monohydrate).

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 46 of 60

*4.63. Selpercatinib* 

**Figure 65.** Ripretinib (1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl)-3-phenylurea). **Figure 65.** Ripretinib (1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3 yl]-2-fluorophenyl)-3-phenylurea).

#### *4.65. Pralsetinib 4.67. Tepotinib Hydrochloride Monohydrate*

Pralsetinib (Figure 66) is a pyridine-pyrimidine based pyrazole derivative (MF: C27H32FN9O2; MW: 533.61; CAS Number: 2097132-94-8) [195]. **US10030005B2** discloses pyrazole based RET inhibitors and their pharmaceutical compositions to treat a condition mediated by aberrant RET activity, e.g., cancer. It claims pralsetinib [196]. Tepotinib hydrochloride monohydrate (Figure 68) is a piperidine-pyrimidine based dihydropyridazine derivative (MF: C29H28N6O2·HCl·H2O; MW: 547.05; CAS Number: 1946826-82-9) [199]. **US8580781B2** reveals certain pyridazinones as MET inhibitors to treat tumors. It claims tepotinibor and its salts [200]. Tepotinib hydrochloride hydrate is claimed explicitly in **US8329692B2** [201].

#### O *4.68. Umbralisib Tosylate*

*4.64. Ripretinib* 

N N O NH N N F Umbralisibtosylate (Figure 69) is a chromen-4-one based pyrazolo[3,4-*d*]pyrimidine derivative (MF: C38H32F3N5O6S; 743.75; 1532533-72-4) [202]. **US10570142B2** provides pyrazolo[3,4-*d*]pyrimidines as inhibitors of PI3K<sup>δ</sup> and their pharmaceutical compositions to treat PI3K<sup>δ</sup> mediated disorders. It claims umbralisib tosylate having at least 95% enantiomeric excess [203]. **US10414773B2** unveils a stable crystalline form of umbralisib tosylate possessing specified particle sizes with enhanced solubility and improved pharmacokinetics. This property makes it suitable to prepare a quality oral dosage form [204].

#### NH *4.69. Tivozanib Hydrochloride Monohydrate*

*4.66. Trilaciclib Dihydrochloride* 

claims trilaciclib and its salts [198].

NH N Tivozanib hydrochloride monohydrate (Figure 70) is an isoxazole base quinoline derivative (MF: C22H19ClN4O5·HCl·H2O; MW: 509.34; CAS Number: 682745-41-1) [205]. **US6821987B2** and **US7211587B2** unveil quinoline derivatives having azolyl group, useful

Trilaciclib dihydrochloride (Figure 67) is a piperazine-pyridine based pyrazino[1′,2′:1,5]pyrrole derivative (MF: C24H30N8O.2HCl; MW: 519.48; CAS Number: 1977495-97-8) [197]. **US8598186B2** reveals tricyclic compounds as CDK inhibitors, which have utility in the treatment of disorders intervened by CDK malfunction like cancer. It

**Figure 67.** Trilaciclib dihydrochloride (2′-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-7′,8′ dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-*d*]pyrimidin]-6′-one).

N

for treating tumors, chronic rheumatism, psoriasis, and Kaposi's sarcoma. These patents claim tivozanib and its salts [206,207]. **US7166722B2** claims a physically stable crystalline form of tivozanib hydrochloride monohydrate stable under high temperature and humidity. This form is suitable for developing quality dosage forms [208]. Pralsetinib (Figure 66) is a pyridine-pyrimidine based pyrazole derivative (MF: C27H32FN9O2; MW: 533.61; CAS Number: 2097132-94-8) [195]. **US10030005B2** discloses pyrazole based RET inhibitors and their pharmaceutical compositions to treat a condition mediated by aberrant RET activity, e.g., cancer. It claims pralsetinib [196]. O NH O N N F

**Figure 65.** Ripretinib (1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-

mediated by aberrant RET activity, e.g., cancer. It claims pralsetinib [196].

N

Pralsetinib (Figure 66) is a pyridine-pyrimidine based pyrazole derivative (MF: C27H32FN9O2; MW: 533.61; CAS Number: 2097132-94-8) [195]. **US10030005B2** discloses pyrazole based RET inhibitors and their pharmaceutical compositions to treat a condition

**Figure 65.** Ripretinib (1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 47 of 60

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 47 of 60

3-yl]-2-fluorophenyl)-3-phenylurea).

3-yl]-2-fluorophenyl)-3-phenylurea).

*4.65. Pralsetinib* 

*4.65. Pralsetinib* 

**Figure 68.** Tepotinib hydrochloride monohydrate (3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile hydrochloride monohydrate). zolo[3,4-*d*]pyrimidin-1-yl)-ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one tosylate)). **Figure 68.** Tepotinib hydrochloride monohydrate (3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy] pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile hydrochloride monohydrate).

treat PI3Kδ mediated disorders. It claims umbralisib tosylate having at least 95% enantiomeric excess [203]. **US10414773B2** unveils a stable crystalline form of umbralisib tosylate possessing specified particle sizes with enhanced solubility and improved pharmacokinetics. This property makes it suitable to prepare a quality oral dosage form [204].

**Figure 69.** Umbralisib tosylate ((S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyra-

Umbralisibtosylate (Figure 69) is a chromen-4-one based pyrazolo[3,4-*d*]pyrimidine

*4.68. Umbralisib Tosylate* 

*4.67. Tepotinib Hydrochloride Monohydrate* 

claimed explicitly in **US8329692B2** [201].

monohydrate).

*4.68. Umbralisib Tosylate* 

Tepotinib hydrochloride monohydrate (Figure 68) is a piperidine-pyrimidine based dihydropyridazine derivative (MF: C29H28N6O2.HCl.H2O; MW: 547.05; CAS Number: 1946826-82-9) [199]. **US8580781B2** reveals certain pyridazinones as MET inhibitors to treat tumors. It claims tepotinibor and its salts [200]. Tepotinib hydrochloride hydrate is

**Figure 68.** Tepotinib hydrochloride monohydrate (3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile hydrochloride

Umbralisibtosylate (Figure 69) is a chromen-4-one based pyrazolo[3,4-*d*]pyrimidine derivative (MF: C38H32F3N5O6S; 743.75; 1532533-72-4) [202]. **US10570142B2** provides pyrazolo[3,4-*d*]pyrimidines as inhibitors of PI3Kδ and their pharmaceutical compositions to treat PI3Kδ mediated disorders. It claims umbralisib tosylate having at least 95% enantiomeric excess [203]. **US10414773B2** unveils a stable crystalline form of umbralisib tosylate possessing specified particle sizes with enhanced solubility and improved pharmacokinetics. This property makes it suitable to prepare a quality oral dosage form [204].

**Figure 69.** Umbralisib tosylate ((S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-*d*]pyrimidin-1-yl)-ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one tosylate)). **Figure 69.** Umbralisib tosylate ((S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4 *d*]pyrimidin-1-yl)-ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one tosylate)). form of tivozanib hydrochloride monohydrate stable under high temperature and humidity. This form is suitable for developing quality dosage forms [208]. form of tivozanib hydrochloride monohydrate stable under high temperature and humidity. This form is suitable for developing quality dosage forms [208].

**Figure 70.** Tivozanib hydrochloride monohydrate (1-{2-chloro-4-[(6,7-dimethoxyquinolin-4 yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea hydrochloride monohydrate). **Figure 70.** Tivozanib hydrochloride monohydrate (1-{2-chloro-4-[(6,7-dimethoxyquinolin-4 yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea hydrochloride monohydrate). **Figure 70.** Tivozanib hydrochloride monohydrate (1-{2-chloro-4-[(6,7-dimethoxyquinolin-4 yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea hydrochloride monohydrate).

#### *4.70. Infigratinib Phosphate 4.70. Infigratinib Phosphate 4.70. Infigratinib Phosphate*

**5. Expert Opinion** 

**5. Expert Opinion** 

Infigratinib (Figure 71) is a piperazine based pyrimidine derivative (MF: C26H31Cl2N7O3. H3PO4; MW: 658.47; CAS Number: 1310746-10-1) [209]. **US8552002B2** claims infigratinib and its salts [210]. **US9067896B2** claims a monophosphoric acid salt of infigratinib as well as its anhydrous crystalline polymorph (Form A) and amorphous polymorph. The stability and physicochemical parameters of the crystalline Form A were better than other disclosed polymorphs [211]. Infigratinib (Figure 71) is a piperazine based pyrimidine derivative (MF: C26H31Cl2N7O3. H3PO4; MW: 658.47; CAS Number: 1310746-10-1) [209]. **US8552002B2** claims infigratinib and its salts [210]. **US9067896B2** claims a monophosphoric acid salt of infigratinib as well as its anhydrous crystalline polymorph (Form A) and amorphous polymorph. The stability and physicochemical parameters of the crystalline Form A were better than other disclosed polymorphs [211]. Infigratinib (Figure 71) is a piperazine based pyrimidine derivative (MF: C26H31Cl2N7O3. H3PO4; MW: 658.47; CAS Number: 1310746-10-1) [209]. **US8552002B2** claims infigratinib and its salts [210]. **US9067896B2** claims a monophosphoric acid salt of infigratinib as well as its anhydrous crystalline polymorph (Form A) and amorphous polymorph. The stability and physicochemical parameters of the crystalline Form A were better than other disclosed polymorphs [211].

**Figure 71.** Infigratinib phosphate (3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)phenylamino]pyrimidin-4-yl}-1-methylurea phosphate). **Figure 71.** Infigratinib phosphate (3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)phenylamino]pyrimidin-4-yl}-1-methylurea phosphate). **Figure 71.** Infigratinib phosphate (3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1 yl)phenylamino]pyrimidin-4-yl}-1-methylurea phosphate).

has also approved antibodies as PKIs such as trastuzumab and bevacizumab. A few antibodies are also in the clinical trial (amivantamab and patritumab). This review is limited to small molecules as PKIs. Accordingly, USFDA approved antibodies such as PKIs have not been discussed here. The physicochemical properties of about 55 USFDA approved

has also approved antibodies as PKIs such as trastuzumab and bevacizumab. A few antibodies are also in the clinical trial (amivantamab and patritumab). This review is limited to small molecules as PKIs. Accordingly, USFDA approved antibodies such as PKIs have not been discussed here. The physicochemical properties of about 55 USFDA approved

### **5. Expert Opinion**

In 2001, USFDA approved the marketing of the first clinical PKI, imatinib. From 2001 to 31 May 2021, about 70 PKIs have been approved by the USFDA (Table 2). The USFDA has also approved antibodies as PKIs such as trastuzumab and bevacizumab. A few antibodies are also in the clinical trial (amivantamab and patritumab). This review is limited to small molecules as PKIs. Accordingly, USFDA approved antibodies such as PKIs have not been discussed here. The physicochemical properties of about 55 USFDA approved PKIs from 2001 to 2020 have been described in the literature [22,23]. However, these reports are silent about the patent data of the PKIs reported therein.

According to the patent literature, and the data presented in Tables 2 and 3, the major players that developed the marketed PKIs include Novartis (imatinib, lapatinib, everolimus, nilotinib, pazopanib, trametinib, dabrafenib, ceritinib, ribociclib, midostaurin, alpelisib, capmatinib, and infigratinib), Pfizer (tofacitinib, palbociclib, dacomitinib, and lorlatinib), Astrazeneca (gefitinib, osimertinib, acalabrutinib, and selumetinib), Bayers (sorafenib, regorafenib, copanlisib, and larotrectinib), and PF Prism (temsirolimus, crizotinib, axitinib, and bosutinib). Nearly 535 PKs have been reported [6]. However, the major primary target of the approved PKIs includes ALK, BCR-Abel, B-RAF, BTK, CDK, EGFR, JAK, MEK, PDGFR, PI3K, RET, and VEGFR (Table 2). Accordingly, there remains a large number of unexplored PKs. Some KIs have specificity for multiple kinases and are called multikinase inhibitors (MKIs), such as sunitinib, regorafenib, imatinib, sorafenib, axitinib, lenvatinib, cabozantinib, vandetanib, and pazopanib. The MKIs are supposed to reduce the chances of developing resistance. However, they are also linked to causing adverse effects in patients, for example, hypertension, gastric upset, and dermatological reactions [212]. The development of the covalent PKIs (ibrutinib, dacomitinib, osimertinib, afatinib, and neratinib) had been an unwilling strategy because they can bind to certain proteins and cause toxicity. Furthermore, the allosteric PKIs (trametinib, ascinimib, and selumetinib) are considered better than covalent inhibitors as they are not supposed to bind with other proteins. However, many new kinases have been identified possessing cysteine residues at their active sites. Therefore, the design of potent and selective covalent inhibitors may be useful against such kinases [213,214]. The pharmaceutical industries are trying to develop more potent and safer PKIs that can be used to treat many more PKs associated disorders with fewer adverse events [23]. Some example of PKIs, which are under development and/or waiting for the USFDA approval, include abrocitinib, belumosudil, dovitinib, sitravatinib, abivertinib, enzastaurin, rivoceranib (apatinib), asciminib, ensartinib, mobocertinib, momelotinib, pacritinib, quizartinib, vorolanib, GLPG3970, CA-4948, BAY1834845, BAY1830839, and PF-06650833 [213,214].

The PKIs contain one or more heterocyclic moieties in their structure that can explain the difference in their binding to the target and thus the spectrum of activity. The primary heterocyclic moieties include quinazoline, quinoline, isoquinoline, pyridine, pyrimidine, pyrazole, benzimidazole, indazole, imidazole, indole, carbazole, or their fused structures. This observation suggests that many clinical PKIs have been developed by the chemical modification of a formerly approved drug, and PKs are promiscuous targets. Further, most of the PKIs are marketed as acid-addition salts (hydrochloride, mesylate, tosylate, phosphate, malate, citrate, esylate, fumarate, succinate, and sulfate). This observation indicates the basic nature of the chemical nucleus of the PKIs.

The majority of the PKIs are approved to treat cancer and inflammatory disorders. Some of the PKIs have shown efficacy towards autoimmune diseases, Alzheimer's disease (neflamapimod, tideglusib, and saracitinib), and Parkinson's disease (DNL201). It is also expected that PKIs of PKC/WNK that control the activity of ion transporters may be developed to treat hypertension [214].

The malignant cells have genomic instability, which may cause the development of resistance to PKIs. This phenomenon is the reason for developing 2nd, 3rd, and later generations of PKIs targeting the equivalent PKs and their related disorders [212]. To combat resistance development, scientists are exploring different chemical templates and pharmacophores to develop novel PKIs [22]. Besides, inflammatory conditions do not exhibit genomic instability. Therefore, the PKIs, which are approved to treat inflammatory disorders, seldom demonstrate the development of resistance [22,23].

The main marketed dosage form of about 66 USFDA approved PKIs is either a tablet or capsule (Table 2). These are solid dosage forms. The quality of the formulation of a solid dosage form depends upon the solid-state properties (stability, solubility, compressibility, etc.) of the drug [215]. Therefore, many patents related to salts and polymorphs (mostly crystalline forms) of the USFDA approved PKIs have been obtained by the innovator companies. The innovator companies have done this to capture the market for a longer time.

The development of the PKIs is considered a medical breakthrough. However, the prices of these therapeutics cause financial toxicity. The financial burden can make the patients non-compliant with the treatment instructions as they may take lower doses than the prescribed doses. This causes failure of the treatment [216,217]. One way to avoid financial toxicity is to develop the generic version of a drug [218]. Currently, seven PKIs have been genericized (imatinib, erlotinib, sorafenib, dasatinib, lapatinib, temsirolimus, and everolimus) (Table 3). These generic versions must have lower prices than the innovator products. The data given in Table 3 also suggest that twelve more PKIs (gefitinib, sunitinib, pazopanib, vandetanib, axitinib, bosutinib, tofacitinib, idelalisib, nintedanib, lenvatinib, midostaurin, and neratinib) may be genericized by 2025 due to basic/compound/governing patent expiry or expiry of the drug exclusivity. It means by the end of 2025, 19 PKIs will have their generic version in the USA market. Besides, it is also expected that the generic version of about 48 PKIs will be available in the USA market by the end of 2030. Thus, it is hoped that the generic availability of these PKIs will reduce the financial toxicity on a patient.

Although great strides have been made in developing small molecule such as PKIs during the past 20 years, this field is still in its infancy. PKs are ubiquitous, and hence specificity has always been an issue regarding the design of new therapies targeting them. The major disadvantage of the existing PKIs is that they target a minor portion of the kinome, with countless clinically significant kinases missing validated inhibitors [22,23]. There are essential kinases without any inhibitors, and this is a critical area for further research. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed. Other innovative strategies are also expected soon. A summary of the PKIs is provided in Figure 72.

In conclusion, there is a huge scope for discovering PKIs, and it will dominate other cancer discovery strategies for decades. The rate of discovery of better and selective PKIs having less propensity for resistance development will be faster than the last two decades because of the better understanding of the molecular and structural aspects of the human kinases. The development of PKIs to treat hypertension, Alzheimer's disease, and Parkinson's disease are foreseeable.

In conclusion, there is a huge scope for discovering PKIs, and it will dominate other cancer discovery strategies for decades. The rate of discovery of better and selective PKIs having less propensity for resistance development will be faster than the last two decades because of the better understanding of the molecular and structural aspects of the human kinases. The development of PKIs to treat hypertension, Alzheimer's disease, and Parkinson's disease are foreseeable. **Author Contributions:** Conceptualization, M.I. and S.A.K.; methodology, S.M.B.A. and M.A. (Majid Alhomrani); validation, D.U.M. and E.H.A.; formal analysis, A.S.A. (Abdulhakeem S. Alamri), M.T., A., S.I.A., M.A.B. and A.K.A.; resources, W.F.A. and O.A.; data curation, M.A. (Mohammed AlMotairi)and A.S.A. (Ahmed Subeh Alshrari); writing—original draft preparation, M.I.; writing—review and editing, S.A.K., D.U.M., M.T., A.; visualization, S.I.A. and M.A.B.; supervision, M.I. and S.A.K.; project administration, Y.M.; funding acquisition, A.A. All authors have read and agreed to the published version of the manuscript.

**Author Contributions:** Conceptualization, M.I., and S.A.K.; methodology, S.M.B.A. and M.A. **Funding:** This research received no external funding.

(Majid Alhomrani); validation, D.U.M. and E.H.A.; formal analysis, A.S.A. (Abdulhakeem S. Alamri), M.T., Abida, S.I.A., M.A.B. and A.K.A.; resources, W.F.A. and O.A.; data curation, M.A. **Institutional Review Board Statement:** Not applicable.

(Mohammed AlMotairi) and A.S.A. (Ahmed Subeh Alshrari); writing—original draft preparation, **Informed Consent Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

M.I.; writing—review and editing, S.A.K., D.U.M., M.T., A.; visualization, S.I.A. and M.A.B.; supervision, M.I. and S.A.K.; project administration, Y.M.; funding acquisition, A.A. All authors have **Data Availability Statement:** Data sharing not applicable.

read and agreed to the published version of the manuscript. **Funding:** This research received no external funding. **Acknowledgments:** The authors are thankful to AlMaarefa University, Riyadh for providing support to write this review article.

**Institutional Review Board Statement:** Not applicable. **Conflicts of Interest:** The authors declare no conflict of interest.

**Data Availability Statement:** Data sharing not applicable.

### **Abbreviations**

ALK: Anaplastic lymphoma kinase; ALL: Acute lymphoblastic leukemia; AML: Acute myelogenous leukemia; API: Active pharmaceutical ingredient; ARCC: Advanced renal cell carcinoma; ATC: Anaplastic thyroid cancer; ATP: Adenosine triphosphate; BCR-Abl: Breakpoint cluster region/ abl oncogene; BRAF/B-raf: Murine sarcoma viral oncogene homolog; BTK: Bruton's tyrosine kinase; CDK: Cyclin-dependent protein kinase; CLL: Chronic lymphocytic leukemia; CML: Chronic myelonoid leukemia; CSF1R: Colony stimulating factor 1 receptor; DTC: Differentiated thyroid cancer; EGFR: Epidermal growth factor receptor; FKBP12/mTOR: FK Binding Protein-12/mammalian target of rapamycin; FL: Follicular lymphoma; Flt3: fms-like tyrosine kinase 3; GISTs: Gastrointestinal stromal tumors; GTP: Guanosine triphosphate; HCC: Hepatocellular carcinoma; HER-1/HER-2: Human epidermal growth factor receptor 1/2; HGFR: Hepatocyte growth factor receptor; ILDs: Interstitial lung disease; IPF: Idiopathic pulmonary fibrosis; ITP: Immune thrombocytopenic purpura; JAK: Janus kinase; MAPK/MEK1/2: Mitogen-activated protein kinase kinase; MAT: Monoamine transporter; MCL: Mantle cell lymphoma; MTC: Medullary thyroid cancer; mUC: Metastatic urothelial carcinoma); MZL: Marginal zone lymphoma; NF1: Neurofibromatosis type 1; NSCLC: Non-small cell lung cancer; PDGFR: Platelet-derived growth factor receptor; Ph<sup>+</sup> -ALL: Philadelphia chromosome-Positive Acute lymphoblastic leukemia; Ph<sup>+</sup> -CML: Philadelphia chromosome-positive chronic myeloid leukemia; PI3K: Phosphatidylinositol 3-kinase; PKIs: Protein kinase inhibitors; PKs: Protein kinases; pNET: Primitive neuroectodermal tumor; RCC: Renal cell carcinoma; SLL: Small lymphocytic lymphoma; SSc: Systemic sclerosis; STS: Soft-tissue sarcomas; TKI: Tyrosine Kinase inhibitors; Tyk2: Tyrosine kinase; USFDA: United States Food and Drug Administration; VEGFR: Vascular endothelial growth factor receptor.

### **References**

